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A
                TexT book
                    of
               Immunology
                edITed by
          ArkAbrATA bAnerjee
  b.sc bIoTech(h) from The unIversITy of
                 burdwAn
                    &
 TrAIned In mAgenTA pIgmenT producTIon
from fungus In lAb. condITIon ,shrm bIoTech
                 kolkATA
                    &
           mbA from wbuT,AIcTe
  ……………………1 sT edITIon 2011……………………




         IMMUNO BIOLOGY
An immune system is a system of biological structures and processes within an organism that protects
against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents,
from viruses to parasitic worms, and needs to distinguish them from the organism's own
healthy cells and tissues in order to function properly. Detection is complicated as pathogens
can evolve rapidly, producing adaptations that avoid the immune system and allow the pathogens to
successfully infect their hosts.

Immunity is a biological term that describes a state of having sufficient biological defenses to
avoid infection, disease, or other unwanted biological invasion. Immunity involves both specific and non-
specific components. The non-specific components act either as barriers or as eliminators of wide range
of pathogens irrespective of antigenic specificity. Other components of the immune system adapt
themselves to each new disease encountered and are able to generate pathogen-specific immunity.
Adaptive immunity is often sub-divided into two major types depending on how the immunity was
introduced. Naturally acquired immunity occurs through contact with a disease causing agent, when the
contact was not deliberate, whereas artificially acquired immunity develops only through deliberate
actions such as vaccination. Both naturally and artificially acquired immunity can be further subdivided
depending on whether immunity is induced in the host or passively transferred from a immune
host. Passive immunity is acquired through transfer of antibodies or activated T-cells from an immune
host, and is short lived -- usually lasting only a few months -- whereas active immunity is induced in the
host itself by antigen, and lasts much longer, sometimes life-long. The diagram below summarizes these
divisions of immunity.




A further subdivision of adaptive immunity is characterized by the cells involved; humoral immunity is the
aspect of immunity that is mediated by secreted antibodies, whereas the protection provided by cell
mediated immunity involves T-lymphocytes alone. Humoral immunity is active when the organism
generates its own antibodies, and passive when antibodies are transferred between individuals. Similarly,
cell mediated immunity is active when the organisms’ own T-cells are stimulated and passive when T
cells come from another organism.




Passive immunity
Passive immunity is the transfer of active immunity, in the form of readymade antibodies, from one
individual to another. Passive immunity can occur naturally, when maternal antibodies are transferred to
the fetus through the placenta, and can also be induced artificially, when high levels
of human (or horse) antibodies specific for a pathogen or toxin are transferred to non-immune individuals.
Passive immunization is used when there is a high risk of infection and insufficient time for the body to
develop    its   own     immune     response,       or   to    reduce     the   symptoms     of   ongoing
or immunosuppressive diseases. Passive immunity provides immediate protection, but the body does not
develop memory, therefore the patient is at risk of being infected by the same pathogen later.

Naturally acquired passive immunity
Maternal passive immunity is a type of naturally acquired passive immunity, and refers to antibody-
mediated immunity conveyed to a fetus by its mother during pregnancy. Maternal antibodies (MatAb) are
passed through the placenta to the fetus by an FcRn receptor on placental cells. This occurs around the
third month of gestation. IgG is the only antibodyisotype that can pass through the placenta. Passive
immunity is also provided through the transfer of IgA antibodies found in breast milk that are transferred to
the gut of the infant, protecting against bacterial infections, until the newborn can synthesize its own
antibodies.

Artificially acquired passive immunity
Artificially acquired passive immunity is a short-term immunization induced by the transfer of antibodies,
which can be administered in several forms; as human or animal blood plasma, as pooled human
immunoglobulin for intravenous (IVIG) or intramuscular (IG) use, and in the form of monoclonal
antibodies (MAb). Passive transfer is used prophylactically in the case of immunodeficiency diseases,
such as hypogammaglobulinemia. It is also used in the treatment of several types of acute infection, and
to treat poisoning.Immunity derived from passive immunization lasts for only a short period of time, and
there is also a potential risk for hypersensitivity reactions, and serum sickness, especially from gamma
globulin of non-human origin.
The artificial induction of passive immunity has been used for over a century to treat infectious disease,
and prior to the advent of antibiotics, was often the only specific treatment for certain infections.
Immunoglobulin therapy continued to be a first line therapy in the treatment of severe respiratory
diseases until the 1930’s, even after sulfonamide antibiotics were introduced.

Passive transfer of cell-mediated immunity
Passive or "adoptive transfer" of cell-mediated immunity, is conferred by the transfer of "sensitized" or
activated T-cells from one individual into another. It is rarely used in humans because it
requires histocompatible (matched) donors, which are often difficult to find. In unmatched donors this type
of transfer carries severe risks of graft versus host disease. It has, however, been used to treat certain
diseases including some types of cancer and immunodeficiency. This type of transfer differs from a bone
marrow transplant, in which (undifferentiated) hematopoietic stem cells are transferred.




Active immunity
The time course of an immune response. Due to the
 formation of immunological memory, reinfection at later time points leads to a rapid increase in antibody production and
                     effector T cell activity. These later infections can be mild or even inapparent.

When B cells and T cells are activated by a pathogen, memory B-cells and T- cells develop. Throughout
the lifetime of an animal these memory cells will “remember” each specific pathogen encountered, and
are able to mount a strong response if the pathogen is detected again. This type of immunity is
both active and adaptive because the body's immune system prepares itself for future challenges. Active
immunity often involves both the cell-mediated and humoral aspects of immunity as well as input from
the innate immune system. The innate system is present from birth and protects an individual from
pathogens regardless of experiences, whereas adaptive immunity arises only after an infection or
immunization and hence is "acquired" during life.


Naturally acquired active immunity
Naturally acquired active immunity occurs when a person is exposed to a live pathogen, and develops a
primary immune response, which leads to immunological memory.This type of immunity is “natural”
because it is not induced by deliberate exposure. Many disorders of immune system function can affect
the formation of active immunity such asimmunodeficiency (both acquired and congenital forms)
and immunosuppression.


Artificially acquired active immunity
Artificially acquired active immunity can be induced by a vaccine, a substance that contains antigen. A
vaccine stimulates a primary response against the antigen without causing symptoms of the disease. The
term vaccination was coined by Edward Jenner and adapted by Louis Pasteur for his pioneering work in
vaccination. The method Pasteur used entailed treating the infectious agents for those diseases so they
lost the ability to cause serious disease. Pasteur adopted the name vaccine as a generic term in honor of
Jenner's discovery, which Pasteur's work built upon.

Layered defense
The immune system protects organisms from infection with layered defenses of increasing specificity. In
simple terms, physical barriers prevent pathogens such as bacteria and virusesfrom entering the
organism. If a pathogen breaches these barriers, the innate immune system provides an immediate, but
non-specific response. Innate immune systems are found in all plants and animals. If pathogens
successfully evade the innate response, vertebrates possess a third layer of protection, the adaptive
immune system, which is activated by the innate response. Here, the immune system adapts its response
during an infection to improve its recognition of the pathogen. This improved response is then retained
after the pathogen has been eliminated, in the form of an immunological memory, and allows the adaptive
immune system to mount faster and stronger attacks each time this pathogen is encountered.
Components of the immune system



               Innate immune system                               Adaptive immune system



  Response is non-specific                          Pathogen and antigen specific response



  Exposure leads to immediate maximal response Lag time between exposure and maximal response



  Cell-mediated and humoral components              Cell-mediated and humoral components



  No immunological memory                           Exposure leads to immunological memory



  Found in nearly all forms of life                 Found only in jawed vertebrates


Both innate and adaptive immunity depend on the ability of the immune system to distinguish between
self and non-self molecules. In immunology, self molecules are those components of an organism's body
that can be distinguished from foreign substances by the immune system. Conversely, non-self molecules
are those recognized as foreign molecules. One class of non-self molecules are called antigens (short
for antibody generators) and are defined as substances that bind to specific immune receptors and elicit
an immune respons.

Surface barriers
Several barriers protect organisms from infection, including mechanical, chemical, and biological barriers.
The waxy cuticle of many leaves, the exoskeleton of insects, the shells and membranes of externally
deposited eggs, and skin are examples of the mechanical barriers that are the first line of defense against
infection. However, as organisms cannot be completely sealed against their environments, other systems
act to protect body openings such as the lungs, intestines, and the genitourinary tract. In the
lungs, coughing and sneezingmechanically eject pathogens and other irritants from the respiratory tract.
The flushing action of tears and urine also mechanically expels pathogens, while mucus secreted by the
respiratory and gastrointestinal tract serves to trap and entangle microorganisms.
Chemical barriers also protect against infection. The skin and respiratory tract secrete antimicrobial
peptides such as the β-defensins. Enzymes such as lysozyme and phospholipase A2 in saliva, tears,
and breast milk are also antibacterials. Vaginal secretions serve as a chemical barrier
following menarche, when they become slightly acidic, while semencontains defensins and zinc to kill
pathogens. In the stomach, gastric acid and proteases serve as powerful chemical defenses against
ingested pathogens.
Within the genitourinary and gastrointestinal tracts, commensal flora serve as biological barriers by
competing with pathogenic bacteria for food and space and, in some cases, by changing the conditions in
their environment, such as pH or available iron. This reduces the probability that pathogens will be able to
reach sufficient numbers to cause illness. However, since most antibiotics non-specifically target bacteria
and do not affect fungi, oral antibiotics can lead to an “overgrowth” of fungi and cause conditions such as
a vaginalcandidiasis (a yeast infection). There is good evidence that re-introduction of probiotic flora, such
as pure cultures of the lactobacilli normally found in unpasteurized yoghurt, helps restore a healthy
balance of microbial populations in intestinal infections in children and encouraging preliminary data in
studies on bacterial gastroenteritis, inflammatory bowel diseases,urinary tract infection and post-surgical
infections.

Innate immune system
 The innate immune system comprises the cells and mechanisms that defend the host from infection by
other organisms, in a non-specific manner. This means that the cells of the innate system recognize and
respond to pathogens in a generic way, but unlike the adaptive immune system, it does not confer long-
lasting or protective immunity to the host. Innate immune systems provide immediate defense against
infection, and are found in all classes of plant and animal life.
The innate system is thought to constitute an evolutionarily older defense strategy, and is the dominant
immune system found in plants, fungi, insects, and in primitive multicellular organisms.
The major functions of the vertebrate innate immune system include:

   Recruiting immune cells to sites of infection, through the production of chemical factors, including
    specialized chemical mediators, called cytokines.
   Activation of the complement cascade to identify bacteria, activate cells and to promote clearance of
    dead cells or antibody complexes.
   The identification and removal of foreign substances present in organs, tissues, the blood and lymph,
    by specialized white blood cells.
   Activation of the adaptive immune system through a process known as antigen presentation


Cells of the innate immune response

(a) Leukocytes
White blood cells (WBCs), or leukocytes (also spelled "leucocytes"), are cells of the immune
system involved in defending the body against both infectious disease and foreign materials.
Five different and diverse types of leukocytes exist, but they are all produced and derived from
a multipotent cell in the bone marrow known as a hematopoietic stem cell. Leukocytes are found
throughout the body, including the blood andlymphatic system.
The number of WBCs in the blood is often an indicator of disease. There are normally between 4×109 and
1.1×1010 white blood cells in a litreof blood, making up approximately 1% of blood in a healthy adult. An
increase in the number of leukocytes over the upper limits is calledleukocytosis, and a decrease below
the lower limit is called leukopenia. The physical properties of leukocytes, such as volume, conductivity,
and granularity, may change due to activation, the presence of immature cells, or the presence
of malignant leukocytes in leukemia.
scanning electron microscope image of normal circulating
human blood. In addition to the irregularly shaped leukocytes, both red blood cells and many small disc-
shapedplatelets are visible.

Types
There are several different types of white blood cells. They all have many things in common, but are all
distinct in form and function. A major distinguishing feature of some leukocytes is the presence
of granules; white blood cells are often characterized as granulocytes or agranulocytes:

   Granulocytes (polymorphonuclear leukocytes): leukocytes characterised by the presence of
    differently staining granules in their cytoplasm when viewed under light microscopy. These granules
    are membrane-bound enzymes which primarily act in the digestion of endocytosed particles. There
    are three types of granulocytes: neutrophils, basophils, and eosinophils, which are named according
    to their staining properties.
   Agranulocytes (mononuclear leucocytes): leukocytes characterized by the apparent absence
    of granules in their cytoplasm. Although the name implies a lack of granules these cells do contain
    non-specific azurophilic granules, which are lysosomes. The cells include lymphocytes, monocytes,
    and macrophages.


1.Neutrophil
Neutrophil granulocytes are generally referred to as either neutrophils or polymorphonuclear
neutrophils (or PMNs), and are subdivided into segmented neutrophils (or segs) and banded
neutrophils (or bands). Neutrophils are the most abundant type of white blood cells in mammals and
form an essential part of the innate immune system. They form part of the polymorphonuclear cell family
(PMNs) together withbasophils and eosinophils.

Neutrophils are normally found in the blood stream. However, during the beginning (acute) phase
of inflammation, particularly as a result ofbacterial infection and some cancers, neutrophils are one of the
first-responders of inflammatory cells to migrate toward the site of inflammation, firstly through the blood
vessels, then through interstitial tissue, following chemical signals (such as Interleukin-8 (IL-8) and C5a)
in a process called chemotaxis. They are the predominant cells in pus, accounting for its whitish/yellowish
appearance.
Neutrophils are recruited to the site of injury within minutes following trauma and are the hallmark of acute
inflammation.
A neutrophil, stained with Wright's stain. This cell is approximately 12 µm in
diameter

With the eosinophil and the basophil, they form the class of polymorphonuclear cells, named for
the nucleus's characteristic multilobulated shape (as compared to lymphocytes and monocytes, the other
types of white cells). Neutrophils are the most abundant white blood cells in humans (approximately
10^11 are produced daily) ; they account for approximately 70% of all white blood cells (leukocytes).
A minor difference is found between the neutrophils from a male subject and a female subject. The cell
nucleus of a neutrophil from a female subject shows a small additional X chromosome structure, known
as a "neutrophil drumstick".
The average half-life of non-activated neutrophils in the circulation is about 12 hours. Upon activation,
they marginate (position themselves adjacent to the blood vessel endothelium), and undergo selectin-
dependent capture followed by integrin-dependent adhesion in most cases, after which they migrate into
tissues, where they survive for 1–2 days.
Neutrophils are much more numerous than the longer-lived monocyte/macrophage phagocytes.
A pathogen (disease-causing microorganism or virus) is likely to first encounter a neutrophil. Some
experts hypothesize that the short lifetime of neutrophils is an evolutionary adaptation. The short lifetime
of neutrophils minimizes propagation of those pathogens that parasitize phagocytes because the more
time such parasites spend outside a host cell, the more likely they will be destroyed by some component
of the body's defenses. Also, because neutrophil antimicrobial products can also damage host tissues,
their short life limits damage to the host during inflammation.
Neutrophils will often be phagocytosed themselves by macrophages after digestion                           of
pathogens. PECAM-1 and phosphatidylserine on the cell surface are involved in this process.




                                 Neutrophil granulocyte migrates from the blood vessel to the matrix, sensing
proteolytic enzymes, in order to determine intercellular connections (to the improvement of its mobility) and
envelop bacteria through phagocytosis
Neutrophils undergo a process called chemotaxis, which allows them to migrate toward sites of infection
or inflammation. Cell surface receptors allow neutrophils to detect chemical gradients of molecules such
as interleukin-8 (IL-8), interferon gamma (IFN-gamma), and C5a, which these cells use to direct the path
of their migration.

Anti-microbial function
Being highly motile, neutrophils quickly congregate at a focus of infection, attracted
by cytokines expressed by activated endothelium, mast cells, andmacrophages. Neutrophils express and
release cytokines, which in turn amplify inflammatory reactions by several other cell types.
In addition to recruiting and activating other cells of the immune system, neutrophils play a key role in the
front-line defence against invading pathogens. Neutrophils have three strategies for directly attacking
micro-organisms: phagocytosis (ingestion), release of soluble anti-microbials (including granule proteins)
and generation of neutrophil extracellular traps (NETs).

Phagocytosis
Neutrophils are phagocytes, capable of ingesting microorganisms or particles. They can internalize and
kill many microbes, each phagocytic event resulting in the formation of a phagosome into which reactive
oxygen species and hydrolytic enzymes are secreted. The consumption of oxygen during the generation
of reactive oxygen species has been termed the "respiratory burst", although unrelated to respiration or
energy production.The respiratory burst involves the activation of the enzyme NADPH oxidase, which
produces large quantities of superoxide, a reactive oxygen species. Superoxide dismutates,
spontaneously or through catalysis via enzymes known as superoxide dismutases (Cu/ZnSOD and
MnSOD), to hydrogen peroxide, which is then converted to hypochlorous acid HClO, by the green heme
enzyme myeloperoxidase. It is thought that the bactericidal properties of HClO are enough to kill bacteria
phagocytosed by the neutrophil, but this may instead be step necessary for the activation of proteases.

Role in disease
Low neutrophil counts are termed neutropenia. This can be congenital (genetic disorder) or it can develop
later, as in the case of aplastic anemia or some kinds of leukemia. It can also be a side-
effect of medication, most prominently chemotherapy. Neutropenia makes an individual highly susceptible
to infections. Neutropenia can be the result of colonization by intracellular neutrophilic parasites.
Functional disorders of neutrophils are often hereditary. They are disorders of phagocytosis or
deficiencies in the respiratory burst (as in chronic granulomatous disease, a rare immune deficiency,
and myeloperoxidase deficiency).
In alpha 1-antitrypsin deficiency, the important neutrophil enzyme elastase is not adequately inhibited
by alpha 1-antitrypsin, leading to excessive tissue damage in the presence of inflammation - most
prominently pulmonary emphysema.
In Familial Mediterranean fever (FMF), a mutation in the pyrin (or marenostrin) gene, which is expressed
mainly in neutrophil granulocytes, leads to a constitutively active acute phase response and causes
attacks of fever, arthralgia, peritonitis, and - eventually - amyloidosis

Neutrophil Extracellular Traps(NETs)
Zychlinsky and colleagues recently described a new striking observation that activation of neutrophils
causes the release of web-like structures of DNA; this represents a third mechanism for killing
bacteria. These neutrophil extracellular traps (NETs) comprise a web of fibers composed
of chromatin and serine proteases that trap and kill microbes extracellularly. It is suggested that NETs
provide a high local concentration of antimicrobial components and bind, disarm, and kill microbes
independent of phagocytic uptake. In addition to their possible antimicrobial properties, NETs may serve
as a physical barrier that prevents further spread of pathogens. Trapping of bacteria may be a particularly
important role for NETs in sepsis, where NET are formed within blood vessels. Recently, NETs have been
shown to play a role in inflammatory diseases, as NETs could be detected in preeclampsia, a pregnancy
related inflammatory disorder in which neutrophils are known to be activated.


2.Eosinophil




Eosinophil granulocytes, usually called eosinophils or eosinophiles (or, less commonly, acidophils),
are white blood cells that are one of the immune system components responsible for combating
multicellular parasites and certain infections in vertebrates. Along withmast cells, they also control
mechanisms        associated     with allergy and asthma.      They     are granulocytes that develop
during haematopoiesisin the bone marrow before migrating into blood.
These cells are eosinophilic or 'acid-loving' as shown by their affinity to coal and tar dyes:
Normally transparent, it is this affinity that causes them to appear brick-red after staining with eosin, a
red dye, using the Romanowsky method. The staining is concentrated in small granules within the
cellular cytoplasm, which contain many chemical mediators, such as histamine and proteins such
as eosinophil peroxidase, ribonuclease (RNase), deoxyribonucleases, lipase, plasminogen, and major
basic protein. These mediators are released by a process called degranulation following activation of the
eosinophil, and are toxic to both parasite and host tissues.
In normal individuals, eosinophils make up about 1-6% of white blood cells, and are about
12-17 micrometers in size. They are found in the medulla and the junction between the cortex and
medulla of the thymus, and, in the lower gastrointestinal tract, ovary, uterus, spleen, and lymph nodes,
but not in the lung, skin, esophagus, or some other internal organs[vague] under normal conditions. The
presence of eosinophils in these latter organs is associated with disease. Eosinophils persist in the
circulation for 8–12 hours, and can survive in tissue for an additional 8–12 days in the absence of
stimulation. Pioneering work in the 1980s elucidated that eosinophils were unique granulocytes, having
the capacity to survive for extended periods of time after their maturation as demonstrated by ex-vivo
culture experiments.
Eosinophil under the microscope (40x) from a peripheral blood
smear. Red blood cells surround the eosinophil, two platelets at the top left corner.

An increase in eosinophils, i.e., the presence of more than 500 eosinophils/microlitre of blood is called
an eosinophilia, and is typically seen in people with a parasitic infestation of theintestines,
a collagen vascular disease (such as rheumatoid arthritis), malignant diseases such as Hodgkin's
disease, extensive skin diseases (such as exfoliative dermatitis), Addison's disease, in the squamous
epithelium of the esophagus in the case of reflux esophagitis, eosinophilic esophagitis, and with the use
of certain drugs such as penicillin. In 1989, contaminated L-tryptophan supplements caused a deadly
form of eosinophilia known as eosinophilia-myalgia syndrome, which was reminiscent of the Toxic Oil
Syndrome in Spain in 1981.

Eosinophil development, migration and activation
Eosinophils develop and mature in bone marrow. They differentiate from myeloid precursor cells in
response to the cytokines interleukin 3 (IL-3), interleukin 5 (IL-5), and granulocyte macrophage colony-
stimulating factor (GM-CSF). Eosinophils produce and store many secondary granule proteins prior to
their exit from the bone marrow. After maturation, eosinophils circulate in blood and migrate to
inflammatory      sites   in     tissues,    or     to    sites     of helminth infection in    response
to chemokines like CCL11 (eotaxin-1), CCL24 (eotaxin-2), CCL5 (RANTES), and certain leukotrienes like
leukotriene B4 (LTB4) and MCP1/4. At these infectious sites, eosinophils are activated by Type 2
cytokines released from a specific subset ofhelper T cells (Th2); IL-5, GM-CSF, and IL-3 are important for
eosinophil activation as well as maturation. There is evidence to suggest that eosinophil granule protein
expression is regulated by the non-coding RNA EGOT (gene).

Eosinophil granule proteins
Following activation by an immune stimulus, eosinophils degranulate to release an array of cytotoxic
granule cationic proteins that are capable of inducing tissue damage and dysfunction. These include:

   major basic protein (MBP)
   eosinophil cationic protein (ECP)
   eosinophil peroxidase (EPO)
   eosinophil-derived neurotoxin (EDN)

Major basic protein, eosinophil peroxidase, and eosinophil cationic protein are toxic to many
tissues. Eosinophil       cationic          protein         and       eosinophil-derived        neurotoxin
are ribonucleaseswith antiviral activity. Major basic protein induces mast cell and basophil degranulation,
and is implicated in peripheral nerve remodelling. Eosinophil cationic protein creates toxic pores in the
membranes of target cells allowing potential entry of other cytotoxic molecules to the cell, can
inhibit proliferation of T cells, suppress antibody production by B cells, induce degranulation by mast cells,
and stimulate fibroblast cells to secrete mucus and glycosaminoglycan. Eosinophil peroxidase
forms reactive oxygen species and reactive nitrogen intermediates that promote oxidative stress in the
target, causing cell death by apoptosis and necrosis.

Functions of eosinophils
Following activation, eosinophils effector functions include production of:

   cationic granule proteins and their release by degranulation. reactive oxygen species such
    as superoxide, peroxide, and hypobromite (hypobromous acid, which is preferentially produced
    by eosinophil peroxidase).
   lipid mediators like the eicosanoids from the leukotriene (e.g., LTC4, LTD4, LTE4)
    and prostaglandin (e.g., PGE2) families. enzymes, such as elastase.
   growth factors such as TGF beta, VEGF, and PDGF.
   cytokines such as IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-13, and TNF alpha.

In addition, eosinophils play a role in fighting viral infections, which is evident from the abundance
of RNAses they contain within their granules, and in fibrin removal during inflammation.
Eosinophils along with basophils and mast cells, are important mediators of allergic
responses and asthma pathogenesis and are associated with disease severity. They also
fighthelminth (worm) colonization and may be slightly elevated in the presence of certain parasites.
Eosinophils are also involved in many other biological processes, including postpubertalmammary
gland development, oestrus cycling, allograft rejection and neoplasia. They have also recently been
implicated in antigen presentation to T cells.




Treatment
Treatments used to combat autoimmune diseases and conditions caused by eosinophils include:

   corticosteroids- promote apoptosis. Numbers of eosinophils in blood are rapidly reduced
   monoclonal antibody therapy- e.g., mepoluzimab or reslizumab against IL-5, prevents
    eosinophilopoiesis
   antagonists of leukotriene synthesis or receptors
   Gleevec (STI571)- inhibits PDGF-BB in hypereosinophilic leukemia


3.Basophil
Basophil granulocytes, sometimes referred to as basophils, are the least common of the granulocytes,
representing about 0.01% to 0.3% of circulatingwhite blood cells.
The name comes from the fact that these leukocytes are basophilic, i.e., they are susceptible
to staining by basic dyes, as shown in the picture.
Basophils contain large cytoplasmic granules which obscure the cell nucleus under the microscope.
However, when unstained, the nucleus is visible and it usually has 2 lobes. The mast cell,
a cell in tissues, has many similar characteristics. For example, both cell types store histamine, a
chemical that is secreted by the cells when stimulated in certain ways (histamine causes some of the
symptoms of an allergic reaction). Like all circulating granulocytes, basophils can be recruited out of
the blood into a tissue when needed.




               Basophil                                        Basophil granulocyte

Basophils of mouse and human have consistent immunophenotypes as follows: FcεRI+,
CD123, CD49b(DX-5)+, CD69+, Thy-1.2+,                                2B4+, CD11bdull, CD117(c-
    –      –      –      –     –      –       –       –       –      –
kit) , CD24 , CD19 , CD80 ,CD14 , CD23 , Ly49c , CD122 , CD11c , Gr-1 ,  NK1.1–, B220–, CD3–,
γδTCR–, αβTCR–, α4 and β4-integrin negative.


Secretions
When                                   activated,                                  basophils degranulate to
release histamine, proteoglycans (e.g. heparin and chondroitin),                             and proteolytic
enzymes (e.g. elastase and lysophospholipase). They also secrete lipid mediators like leukotrienes, and
several cytokines. Histamine and proteoglycans are pre-stored in the cell's granules while the other
secreted substances are newly generated. Each of these substances contributes to inflammation. Recent
evidence suggests that basophils are an important source of the cytokine, interleukin-4, perhaps more
important than T cells. Interleukin-4 is considered one of the critical cytokines in the development of
allergies and the production of IgE antibody by the immune system. There are other substances that can
activate basophils to secrete which suggests that these cells have other roles in inflammation.
Basopenia (a low basophil count) is difficult to demonstrate as the normal basophil count is so low; it has
been reported in association with autoimmune urticaria (a chronic itching condition). Basophilia is also
uncommon but may be seen in some forms of leukaemia or lymphoma.

Function
Basophils appear in many specific kinds of inflammatory reactions, particularly those that cause allergic
symptoms. Basophils contain anticoagulant heparin, which prevents blood from clotting too quickly. They
also contain the vasodilator histamine, which promotes blood flow to tissues. They can be found in
unusually high numbers at sites of ectoparasite infection, e.g.,ticks. Like eosinophils, basophils play a role
in both parasitic infections and allergies. They are found in tissues where allergic reactions are occurring
and probably contribute to the severity of these reactions. Basophils have protein receptors on their cell
surface that bindIgE, an immunoglobulin involved in macroparasite defense and allergy. It is the bound
IgE antibody that confers a selective response of these cells to environmental substances, for
example, pollen proteins or helminth antigens. Recent studies in mice suggest that basophils may also
regulate the behavior of T cells and mediate the magnitude of the secondary immune response.
4.Lymphocyt
This is under the adaptive immune system.




                                   A stained lymphocyte surrounded byred blood cells viewed using a light
microscope.




                                   A scanning electron microscope(SEM) image of a single human lymphocyte.

A particular class of leukocytes known as lymphocyte mostly carry out the specific acquired immune
response.Lymphocytes are much more common in the lymphatic system. Lymphocytes are distinguished
by having a deeply staining nucleus which may be eccentric in location, and a relatively small amount of
cytoplasm.Lymphocytes provide both the specificity and memory which are characteristic of the adaptive
immune response.

Development
Mammalian stem cells differentiate into several kinds of blood cell within the bone marrow. This process
is calledhaematopoiesis. All lymphocytes originate, during this process, from a common lymphoid
progenitor before differentiating into their distinct lymphocyte types. The differentiation of lymphocytes
follows various pathways in a hierarchical fashion as well as in a more plastic fashion. The formation of
lymphocytes is known as lymphopoiesis. B cells mature into B lymphocytes in the bone marrow, while T
cells migrate to and mature in a distinct organ, called the thymus. Following maturation, the lymphocytes
enter the circulation and peripheral lymphoid organs (e.g. the spleen and lymph nodes) where they
survey for invading pathogensand/or tumor cells.
The lymphocytes involved in adaptive immunity (i.e. B and T cells) differentiate further after exposure to
an antigen; they form effector and memory lymphocytes. Effector lymphocytes function to eliminate the
antigen, either by releasing antibodies (in the case of B cells), cytotoxic granules (cytotoxic T cells) or by
signaling to other cells of the immune system (helper T cells).Memory cells remain in the peripheral
tissues and circulation for an extended time ready to respond to the same antigen upon future exposure.

Characteristics
Microscopically, in a Wright's stained peripheral blood smear, a normal lymphocyte has a large, dark-
staining nucleus with little to no eosinophiliccytoplasm. In normal situations, the coarse, dense nucleus of
a lymphocyte is approximately the size of a red blood cell (about 7 micrometres in diameter). Some
lymphocytes show a clear perinuclear zone (or halo) around the nucleus or could exhibit a small clear
zone to one side of the nucleus. Polyribosomes are a prominent feature in the lymphocytes and can be
viewed with an electron microscope. The ribosomes are involved in protein synthesis allowing the
generation of large quantities of cytokines and immunoglobulins by these cells.
It is impossible to distinguish between T cells and B cells in a peripheral blood smear. Normally, flow
cytometry testing is used for specific lymphocyte population counts. This can be used to specifically
determine the percentage of lymphocytes that contain a particular combination of specific cell surface
proteins, such as immunoglobulins or cluster of differentiation (CD) markers or that produce particular
proteins (for example,cytokines using intracellular cytokine staining (ICCS)). In order to study the function
of a lymphocyte by virtue of the proteins it generates, other scientific techniques like
the ELISPOT or secretion assay techniques can be used.

Lymphocytes and disease
A lymphocyte count is usually part of a peripheral complete blood cell count and is expressed as
percentage of lymphocytes to total white blood cells counted.
A general increase in the number of lymphocytes is known as lymphocytosis whereas a decrease
is lymphocytopenia.

High
An increase in lymphocyte concentration is usually a sign of a viral infection (in some rare
case, leukemias are found through an abnormally raised lymphocyte count in an otherwise normal
person).

Low
A low normal to low absolute lymphocyte concentration is associated with increased rates of infection
after surgery or trauma.
One basis for low T cell lymphocytes occurs when the human immunodeficiency virus (HIV) infects and
destroys T cells (specifically, the CD4+ subgroup of T lymphocytes). Without the key defense that these T
cells provide, the body becomes susceptible to opportunistic infections that otherwise would not affect
healthy people. The extent of HIV progression is typically determined by measuring the percentage of
CD4+ T cells in the patient's blood. The effects of other viruses or lymphocyte disorders can also often be
estimated by counting the numbers of lymphocytes present in the blood.

Types
The blood has three types of lymphocytes:

   B cells: B cells make antibodies that bind to pathogens to enable their destruction. (B cells not only
    make antibodies that bind to pathogens, but after an attack, some B cells will retain the ability to
    produce an antibody to serve as a 'memory' system.)
   T cells:
     CD4+ (helper) T cells co-ordinate the immune response and are important in the defense against
        intracellular bacteria. In acute HIV infection, these T cells are the main index to identify the
individual's immune system activity. Research has shown that CD8+ cells are also another index
          to identify human's immune activity.
     CD8+ cytotoxic T cells are able to kill virus-infected and tumor cells.
     γδ T cells possess an alternative T cell receptor as opposed to CD4+ and CD8+ αβ T cells and
          share characteristics of helper T cells, cytotoxic T cells and natural killer cells.
   Natural killer cells: Natural killer cells are able to kill cells of the body which are displaying a signal to
    kill them, as they have been infected by a virus or have become cancerous.


T cell




                                       Scanning electron micrograph of T lymphocyte (right), a platelet (center)
and ared blood cell (left)

T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a
central role in cell-mediated immunity. They can be distinguished from other lymphocyte types, such as B
cells and natural killer cells (NK cells) by the presence of a special receptor on their cell surface called T
cell receptors (TCR). The abbreviation T, in T cell, stands for thymus, since this is the principal organ
responsible for the T cell's maturation. Several different subsets of T cells have been discovered, each
with a distinct function.




Types
Helper
T helper cell (TH cells) assist other white blood cells in immunologic processes, including maturation of B
cells into plasma cells and activation of cytotoxic T cells and macrophages, among other functions. These
cells are also known as CD4+ T cells because they express the CD4 protein on their surface. Helper T
cells become activated when they are presented with peptide antigens by MHC class II molecules that are
expressed on the surface of Antigen Presenting Cells (APCs). Once activated, they divide rapidly and
secrete small proteins called cytokines that regulate or assist in the active immune response. These cells
can differentiate into one of several subtypes, including TH1, TH2, TH3, TH17, or TFH, which secrete
different cytokines to facilitate a different type of immune response. The mechanism by which T cells are
directed into a particular subtype is poorly understood, though signalling patterns from the APC are
thought to play an important role.

Cytotoxic
Cytotoxic T cells (TC cells, or CTLs) destroy virally infected cells and tumor cells, and are also implicated
in transplant rejection. These cells are also known as CD8+ T cells since they express
the CD8 glycoprotein at their surface. These cells recognize their targets by binding to antigen associated
with MHC class I, which is present on the surface of nearly every cell of the body. Through IL-10,
adenosine and other molecules secreted by regulatory T cells, the CD8+ cells can be inactivated to an
anergic state, which prevent autoimmune diseases such as experimental autoimmune encephalomyelitis.

Memory
Memory T cells are a subset of antigen-specific T cells that persist long-term after an infection has
resolved. They quickly expand to large numbers of effector T cells upon re-exposure to their cognate
antigen, thus providing the immune system with "memory" against past infections. Memory T cells
comprise two subtypes: central memory T cells (TCM cells) and effector memory T cells (TEM cells).
Memory cells may be either CD4+ or CD8+. Memory T cells typically express the cell surface protein
CD45RO.

Regulatory
Regulatory T cells (Treg cells), formerly known as suppressor T cells, are crucial for the maintenance
of immunological tolerance. Their major role is to shut down T cell-mediated immunity toward the end of
an immune reaction and to suppress auto-reactive T cells that escaped the process of negative selection
in the thymus. Two major classes of CD4+ regulatory T cells have been described, including the naturally
occurring Treg cells and the adaptive Treg cells. Naturally occurring Treg cells (also known as
CD4+CD25+FoxP3+ Treg cells) arise in the thymus, whereas the adaptive Treg cells (also known as Tr1 cells
or Th3 cells) may originate during a normal immune response. Naturally occurring Treg cells can be
distinguished from other T cells by the presence of an intracellular molecule called FoxP3. Mutations of
the FOXP3 gene can prevent regulatory T cell development, causing the fatal autoimmune disease IPEX.

Natural killer
Natural killer T cells (NKT cells) are a special kind of lymphocyte that bridges the adaptive immune
system with the innate immune system. Unlike conventional T cells that recognize peptide antigen
presented by major histocompatibility complex (MHC) molecules, NKT cells recognize glycolipid antigen
presented by a molecule called CD1d. Once activated, these cells can perform functions ascribed to both
Th and Tc cells (i.e., cytokine production and release of cytolytic/cell killing molecules). They are also able
to recognize and eliminate some tumor cells and cells infected with herpes viruses.

γδ
γδ T cells (gamma delta T cells) represent a small subset of T cells that possess a distinct T cell
receptor (TCR) on their surface. A majority of T cells have a TCR composed of twoglycoprotein chains
called α- and β- TCR chains. However, in γδ T cells, the TCR is made up of one γ-chain and one δ-chain.
This group of T cells is much less common (2% of total T cells) than the αβ T cells, but are found at their
highest abundance in the gut mucosa, within a population of lymphocytes known as intraepithelial
lymphocytes (IELs). The antigenic molecules that activate γδ T cells are still widely unknown. However,
γδ T cells are not MHC restricted and seem to be able to recognize whole proteins rather than requiring
peptides to be presented by MHC molecules on antigen presenting cells. Some murine γδ T cells
recognize MHC class IB molecules though. Human Vγ9/Vδ2 T cells, which constitute the major γδ T cell
population in peripheral blood, are unique in that they specifically and rapidly respond to a set of non-
peptidic phosphorylated metabolites precursors of cholesterol, collectively named phosphoantigens.
Phosphoantigens are produced by virtually all living cells. The most common phosphoantigens from
animal and human cells (including cancer cells) are isopentenyl pyrophosphate (IPP) and its isomer
dimethylallyl pyrophosphate (DMAPP), while in microbes the most common phosphoantigens are
precursors of eubacterial dimethylallyl pyrophosphate (Hydroxy-DMAPP, also known as HMBPP)and
corresponding mononucleotide conjugates. Plant cells produce both types of phosphoantigens. Drugs
activating human Vγ9/Vδ2 T cells comprise synthetic phosphoantigens and aminobisphosphonates,
which respectively mimick natural phosphoantigens and by up-regulating endogenous IPP/DMAPP.
Typical recognition markers for lymphocytes[

CLASS         FUNCTION                                  PROPORTION PHENOTYPIC MARKER(S)

              Lysis of virally infected cells and tumour
NK cells                                                 7% (2-13%)     CD16 CD56 but not CD3
              cells

Helper T      Release cytokines and growth factors
                                                        46% (28-59%) TCRαβ, CD3 and CD4
cells         that regulate other immune cells

Cytotoxic T Lysis of virally infected cells, tumour
                                                        19% (13-32%) TCRαβ, CD3 and CD8
cells       cells and allografts

γδ T cells    Immunoregulation and cytotoxicity                         TCRγδ and CD3

B cells       Secretion of antibodies                   23% (18-47%) MHC class II, CD19 and CD21


Development in the thymus
All T cells originate from haematopoietic stem cells in the bone marrow. Haematopoietic progenitors
derived from haematopoietic stem cells populate the thymus and expand by cell division to generate a
large population of immature thymocytes. The earliest thymocytes express neither CD4 nor CD8, and are
therefore classed as double-negative (CD4-CD8-) cells. As they progress through their development they
become double-positive thymocytes (CD4+CD8+), and finally mature to single-positive (CD4+CD8- or CD4-
CD8+) thymocytes that are then released from the thymus to peripheral tissues.
About 98% of thymocytes die during the development processes in the thymus by failing either positive
selection or negative selection, whereas the other 2% survive and leave the thymus to become mature
immunocompetent T cells.
The thymus contributes more naive T cells at younger ages. As the thymus shrinks by about 3% a year
throughout middle age, there is a corresponding fall in the thymic production of naive T cells, leaving
peripheral T cell expansion to play a greater role in protecting older subjects.

Positive selection
Positive selection "selects for" T-cells capable of interacting with MHC. Double-
positive thymocytes (CD4+/CD8+) move deep into the thymic cortex where they are presented with self-
antigens (i.e., antigens that are derived from molecules belonging to the host of the T cell) complexed
with MHC molecules on the surface of cortical epithelial cells. Only those thymocytes that bind the
MHC/antigen complex with adequate affinity will receive a vital "survival signal." The implication of this
binding is that all T cells must be able to recognize self antigens to a certain degree. Developing
thymocytes that do not have adequate affinity cannot serve useful functions in the body (i.e. the cells
must be able to interact with MHC and peptide complexes in order to effect immune responses). Also, the
thymocyte must be able to recognize antigens that are self from non-self.). Because of this,
the thymocytes with no affinity for self antigens die by apoptosis and are engulfed by macrophages.
A thymocyte's fate is also determined during positive selection. Double-positive cells (CD4 +/CD8+) that are
positively selected on MHC class II molecules will eventually become CD4+cells, while cells positively
selected on MHC class I molecules mature into CD8+ cells. A T cell becomes a CD4+ cell by
downregulating expression of its CD8 cell surface receptors. If the cell does not lose its signal through the
ITAM pathway, it will continue downregulating CD8 and become a CD4 +, single positive cell. But if there is
signal drop, the cell stops downregulating CD8 and switches over to downregulating CD4 molecules
instead, eventually becoming a CD8+, single positive cell.
This process does not remove thymocytes that may cause autoimmunity. The potentially autoimmune
cells are removed by the process of negative selection (discussed below).

Negative selection
Negative selection removes thymocytes that are capable of strongly binding with "self" peptides
presented by MHC. Thymocytes that survive positive selection migrate towards the boundary of the
thymic cortex and thymic medulla. While in the medulla, they are again presented with self-antigen in
complex with MHC molecules on antigen-presenting cells (APCs) such as dendritic
cells and macrophages. Thymocytes that interact too strongly with the antigen receive an apoptotic signal
that leads to cell death. The vast majority of all thymocytes end up dying during this process. The
remaining cells exit the thymus as mature naive T cells. This process is an important component
of immunological tolerance and serves to prevent the formation of self-reactive T cells that are capable of
inducing autoimmune diseases in the host.
In summary, positive selection selects for T cells that are capable of recognizing self antigens through
MHC. Negative selection selects for T cells that bind too strongly to self antigens. These two selection
processes allow for Tolerance of self by the immune system. They do not necessarily occur in a
chronological order and can occur simultaneously in the thymus.

Maturation paradox
Positive and negative selection should theoretically kill all developing T cells. The first stage of selection
kills all T cells that do not interact with self-MHC, while the second stage selection kills all cells that do.
This poses the question: How do we have immunity at all? Currently, two models attempt to explain this:


    1.   Differential Avidity Hypothesis - the strength of the signal dictates the
         fate of the T cell.

The differential avidity hypothesis (or simply avidity hypothesis) is one of two models that attempt to
explain how humans have immunity despite such aggressive selection (positive and negative) to kill
developing T cells during their maturation process. The other model is the Differential Signaling
Hypothesis.

The Avidity hypothesis states that the affinity of the T-cell receptor for the MHC:peptide complex along
with the density of the complex provide different signal strength upon binding which in terms dictate the
outcome:


    1. strong signal leads to negative selection and thus apoptosis.
    2. weak signal leads to positive selection and thus rescued from apoptosis.

    2.   Differential Signaling Hypothesis - the signals that are transduced
         differ at each stage.
The differential avidity hypothesis (or simply avidity hypothesis) is one of two models that attempt to
explain how humans have immunity despite such aggressive selection (positive and negative) to kill
developing T cells during their maturation process. The other model is the Differential Signaling
Hypothesis.

The Avidity hypothesis states that the affinity of the T-cell receptor for the MHC:peptide complex along
with the density of the complex provide different signal strength upon binding which in terms dictate the
outcome:


    1. strong signal leads to negative selection and thus apoptosis.
    2. weak signal leads to positive selection and thus rescued from apoptosis.




Activation
Although the specific mechanisms of activation vary slightly between different types of T cells, the "two-
signal model" in CD4+ T cells holds true for most. Activation of CD4+ T cells occurs through the
engagement of both the T cell receptor and CD28 on the T cell by the Major histocompatibility
complex peptide and B7 family members on the APC, respectively. Both are required for production of an
effective immune response; in the absence of CD28 co-stimulation, T-cell receptor signalling alone results
in anergy. The signalling pathways downstream from both CD28 and the T cell receptor involve many
proteins.
The first signal is provided by binding of the T cell receptor to a short peptide presented by the major
histocompatibility complex (MHC) on another cell. This ensures that only a T cell with a TCR specific to
that peptide is activated. The partner cell is usually a professional antigen presenting cell (APC), usually
a dendritic cell in the case of naïve responses, although B cells and macrophages can be important
APCs. The peptides presented to CD8+ T cells by MHC class I molecules are 8-9 amino acids in length;
the peptides presented to CD4+ cells by MHCclass II molecules are longer, as the ends of the binding
cleft of the MHC class II molecule are open.
The second signal comes from co-stimulation, in which surface receptors on the APC are induced by a
relatively small number of stimuli, usually products of pathogens, but sometimes breakdown products of
cells, such as necrotic-bodies or heat-shock proteins. The only co-stimulatory receptor expressed
constitutively by naïve T cells is CD28, so co-stimulation for these cells comes from
the CD80 and CD86proteins, which together constitute the B7 protein, (B7.1 and B7.2 respectively) on
the APC. Other receptors are expressed upon activation of the T cell, such as OX40 and ICOS, but these
largely depend upon CD28 for their expression. The second signal licenses the T cell to respond to an
antigen. Without it, the T cell becomes anergic, and it becomes more difficult for it to activate in future.
This mechanism prevents inappropriate responses to self, as self-peptides will not usually be presented
with suitable co-stimulation.
The T cell receptor exists as a complex of several proteins. The actual T cell receptor is composed of two
separate peptide chains, which are produced from the independent T cell receptor alpha and beta (TCRα
and TCRβ) genes. The other proteins in the complex are the CD3proteins: CD3εγ and CD3εδ
heterodimers and, most important, a CD3ζ homodimer, which has a total of six ITAM motifs. The ITAM
motifs on the CD3ζ can be phosphorylated by Lck and in turn recruit ZAP-70. Lck and/or ZAP-70 can also
phosphorylate the tyrosines on many other molecules, not least CD28, , LAT and SLP-76, which allows
the aggregation of signalling complexes around these proteins.
Phosphorylated LAT recruits SLP-76 to the membrane, where it can then bring in PLCγ, VAV1, Itk and
potentially PI3K. Both PLCγ and PI3K act on PI(4,5)P2 on the inner leaflet of the membrane to create the
active      intermediaries     diacylglycerol     (DAG),     inositol-1,4,5-trisphosphate    (IP3),     and
phosphatidlyinositol-3,4,5-trisphosphate (PIP3). DAG binds and activates some PKCs, most important, in
T cells PKCθ, a process important for activating the transcription factors NF-κB and AP-1. IP3 is released
from the membrane by PLCγ and diffuses rapidly to activate receptors on the ER, which induce the
release of calcium. The released calcium then activates calcineurin, and calcineurin activates NFAT,
which then translocates to the nucleus. NFAT is a transcription factor, which activates the transcription of
a pleiotropic set of genes, most notable, IL-2, a cytokine
that       promotes       long       term        proliferation     of       activated       T       cells.




T cell activation

B cell
B cells are lymphocytes that play a large role in the humoral immune response (as opposed to the cell-
mediated immune response, which is governed by T cells). The principal functions of B cells are to
make antibodies against antigens, perform the role of antigen-presenting cells(APCs) and eventually
develop into memory B cells after activation by antigen interaction. B cells are an essential component of
the adaptive immune system.
The abbreviation "B", in B cell, comes from the bursa of Fabricius in birds, where they mature. In
mammals, immature B cells are formed in thebone marrow, which is used as a backronym for the cells'
name.




The cells of the immune system that make antibodies to invading pathogens like viruses. They form memory cells
that remember the same pathogen for faster antibody production in future infections.

B cells exist as clones. All B cells derive from a particular cell, and thus, the antibodies their differentiated
progenies (see below) produce can recognize and/or bind the same components (epitope) of a given
antigen. Such clonality has important consequences, as immunogenic memory relies on it. The great
diversity in immune response comes about because there are up to 109 clones with specificities for
recognizing different antigens. A single B cell or a clone of cells with shared specificity upon encountering
its specific antigen divides to produce many B cells. Most of such B cells differentiate into plasma cells
that secrete antibodies into blood that bind the same epitope that elicited proliferation in the first place. A
small minority survives as memory cells that can recognize only the same epitope. However, with each
cycle, the number of surviving memory cells increases. The increase is accompanied by affinity
maturation which induces the survival of B cells that bind to the particular antigen with high affinity. This
subsequent amplification with improved specificity of immune response is known as secondary immune
response. B cells that encounter antigen for the first time are known as naive B cells.

Development of B cells
Immature B cells are produced in the bone marrow of most mammals. Rabbits are an exception; their B
cells develop in the appendix-sacculus rotundus. After reaching the IgM+ immature stage in the bone
marrow, these immature B cells migrate to the spleen, where they are called transitional B cells, and
some of these cells differentiate into mature B lymphocytes.
B cell development occurs through several stages, each stage representing a change in the genome
content at the antibody loci. An antibody is composed of two identical light (L) and two identical heavy (H)
chains, and the genes specifying them are found in the 'V' (Variable) region and the 'C' (Constant) region.
In the heavy-chain 'V' region there are three segments; V, D and J, which recombine randomly, in a
process called VDJ recombination, to produce a unique variable domain in the immunoglobulin of each
individual B cell. Similar rearrangements occur for light-chain 'V' region except there are only two
segments involved; V and J. The list below describes the process of immunoglobulin formation at the
different stages of B cell development.
When the B cell fails in any step of the maturation process, it will die by a mechanism called apoptosis,
here called clonal deletion. B cells are continuously produced in the bone marrow. When B cell receptors
on the surface of the cell matches the detected antigens present in the body, the B cell proliferates and
secretes a free form of those receptors (antibodies) with identical binding sites as the ones on the original
cell surface. After activation, the cell proliferates and B memory cells would form to recognise the same
antigen. This information would then be used as a part of the adaptive immune system for a more efficient
and more powerful immune response for future encounters with that antigen.
B cell membrane receptors evolve and change throughout the B cell life span. TACI, BCMA and BAFF-
R are present on both immature B cells and mature B cells. All of these 3 receptors may be inhibited
by Belimumab. CD20 is expressed on all stages of B cell development except the first and last; it is
present from pre-pre B cells through memory cells, but not on either pro-B cells or plasma cells.

Immune Tolerance
Like its fellow lymphocyte, the T cell, immature B cells are tested for auto-reactivity by the immune system
before leaving the bone marrow. In the bone marrow (the central lymphoid organ), central tolerance is
produced. The immature B cells whose B cell Receptors (BCRs) bind too strongly to self antigens will not
be allowed to mature. If B cells are found to be highly reactive to self, three mechanisms can occur.

   Clonal deletion: the removal, usually by apoptosis, of B cells of a particular self antigen specificity.
   Receptor editing: the BCRs of self reactive B cells are given an opportunity to rearrange their
    conformation. This process occurs via the continued expression of the Recombination activating
    gene (RAG). Through the help of RAG, receptor editing involves light chain gene rearrangement of
    the B cell receptor. If receptor editing fails to produce a BCR that is less autoreactive, apoptosis will
    occur. Note that defects in the RAG-1 and RAG-2 genes are implicated in Severe Combined
    Immunodeficiency (SCID). The inability to recombine and generate new receptors lead to failure of
    maturity for both B cells and T cells.

   Anergy: B cells enter a state of permanent unresponsiveness when they bind with weakly cross-
    linking self antigens that are small and soluble.


Functions
The human body makes millions of different types of B cells each day that circulate in
the blood and lymphatic system performing the role of immune surveillance. They do not
produceantibodies until they become fully activated. Each B cell has a unique receptor protein (referred to
as the B cell receptor (BCR)) on its surface that will bind to one particular antigen. The BCR is a
membrane-bound immunoglobulin, and it is this molecule that allows the distinction of B cells from other
types of lymphocyte, as well as being the main protein involved in B cell activation. Once a B cell
encounters its cognate antigen and receives an additional signal from a T helper cell, it can further
differentiate into one of the two types of B cells listed below (plasma B cells and memory B cells). The B
cell may either become one of these cell types directly or it may undergo an intermediate differentiation
step, the germinal centerreaction, where the B cell will hypermutate the variable region of
its immunoglobulin gene ("somatic hypermutation") and possibly undergo class switching.

B cell types
 .    Plasma B cells (also known as plasma cells) are large B cells that have been exposed to antigen
and produce and secrete large amounts ofantibodies, which assist in the destruction of microbes by
binding to them and making them easier targets for phagocytes and activation of thecomplement system.
They are sometimes referred to as antibody factories. An electron micrograph of these cells reveals large
amounts of rough endoplasmic reticulum, responsible for synthesizing the antibody, in the
cell's cytoplasm. These are short lived cells and undergo apoptosis when the inciting agent that induced
immune response is eliminated. This occurs because of cessation of continuous exposure to
various colony stimulating factors required for survival.

   Memory B cells are formed from activated B cells that are specific to the antigen encountered during
    the primary immune response. These cells are able to live for a long time, and can respond quickly
    following a second exposure to the same antigen.

   B-1 cells express IgM in greater quantities than IgG and their receptors show polyspecificity,
    meaning that they have low affinities for many different antigens, but have a preference for other
    immunoglobulins, self antigens and common bacterial polysaccharides. B-1 cells are present in low
    numbers in the lymph nodes and spleen and are instead found predominantly in the peritoneal and
    pleural cavities.

   B-2 cells are the conventional B cells.


Marginal-zone B cells

Marginal zone B cells are noncirculating mature B cells that segregate anatomically into the marginal
zone (MZ) of the spleen. This region contains multiple subtypes ofmacrophages, dendritic cells, and the
MZ B cells; it is not fully formed until 2 to 3 weeks after birth in rodents and 1 to 2 years in humans. The
MZ B cells within this region typically express high levels of sIgM, CD21, CD1, CD9 with low to negligible
levels of sIgD, CD23, CD5, and CD11b that help to distinguish them phenotypically from FO B cells and
B1 B cells.
Similar to B1 B cells, MZ B cells can be rapidly recruited into the early adaptive immune responses in a T
cell independent manner. The MZ B cells are especially well positioned as a first line of defense against
systemic blood-borne antigens that enter the circulation and become trapped in the spleen. MZ B cells
also display a lower activation threshold than their FO B cell counterparts with heightened propensity for
PC differentiation that contributes further to the accelerated primary antibody response
Follicular B Cells
Follicular B cells (FO B cells) are a type of B cell that reside in primary and secondary lymphoid follicles
(containing germinal centers) of secondary and tertiary lymphoid organs, including spleen and lymph
nodes.
The mature B cells from the spleen can be divided into two main populations: the FO B cells, which
constitute the majority, and the marginal zone B-cells, lining outside the marginal sinus and border the red
pulp. FO B cells express high levels of IgM, IgD, and CD23; lower C21; and no CD1 or CD5, readily
distinguishing this compartment from B1 B cells andmarginal zone B-cells . FO B cells organize into the
primary follicles of B cell zones focused around follicular dendritic cells in the white pulp of the spleen and
the cortical areas of peripheral lymph nodes. Multiphoton-based live imaging of lymph nodes indicate
continuous movement of FO B cells within these follicular areas at velocites of ~6 µm per min. Recent
studies indicate movement along the processes of FDC as a guidance system for mature resting B cells
in peripheral lymph nodes. Unlike their MZ counterpart, FO B cells freely recirculate, comprising >95% of
the B cells in peripheral lymph nodes.
The BCR repertoire of the follicular B cell compartment also appears under positive selection pressures
during final maturation in the spleen. However, diversity is substantially broader than B1 B and MZ B cell
compartments. More importantly, FO B cells require CD40-CD40L dependent T cell help to promote
effective primary immune responses and antibody isotype switch and to establish high-affinity B cell
memory.
Recognition of antigen by B cells
A critical difference between B cells and T cells is how each lymphocyte recognizes its antigen. B cells
recognize their cognate antigen in its native form. They recognize free (soluble) antigen in the blood or
lymph using their BCR or membrane bound-immunoglobulin. In contrast, T cells recognize their cognate
antigen in a processed form, as a peptide fragment presented by anantigen presenting
cell's MHC molecule to the T cell receptor.

Activation of B cells
B cell recognition of antigen is not the only element necessary for B cell activation (a combination of
clonal proliferation and terminal differentiation into plasma cells). B cells that have not been exposed to
antigen, also known as naïve B cells, can be activated in a T cell-dependent or -independent manner.
B cell activation

T cell-dependent activation
Once a pathogen is ingested by an antigen-presenting cell such as a macrophage or dendritic cell, the
pathogen's proteins are then digested to peptides and attached to a class II MHC protein. This complex is
then moved to the outside of the cell membrane. The macrophage is now activated to deliver multiple
signals to a specific T cell that recognizes the peptide presented. The T cell is then stimulated to produce
autocrines (Refer to Autocrine signalling), resulting in the proliferation and differentiation to effector and
memory T cells. Helper T cells (i.e. CD4+ T cells) then activate specific B cells through a phenomenon
known as an Immunological synapse. Activated B cells subsequently produce antibodies which assist in
inhibiting pathogens until phagocytes (i.e. macrophages, neutrophils) or the complement system for
example clears the host of the pathogen(s).
Most antigens are T-dependent, meaning T cell help is required for maximal antibody production. With a
T-dependent antigen, the first signal comes from antigen cross linking the B cell receptor (BCR) and the
second signal comes from co-stimulation provided by a T cell. T dependent antigens contain proteins that
are presented on B cell Class II MHC to a special subtype of T cell called a Th2 cell. When a B cell
processes and presents the same antigen to the primed Th cell, the T cell secretes cytokines that activate
the B cell. These cytokines trigger B cell proliferation and differentiation into plasma cells. Isotype
switching to IgG, IgA, and IgE and memory cell generation occur in response to T-dependent antigens.
This isotype switching is known as Class Switch Recombination (CSR). Once this switch has occurred,
that particular B cell will usually no longer make the earlier isotypes, IgM or IgD.




T cell-dependent B cell activation, showing a TH2-cell (left), B cell (right), and several interaction molecules




T cell-independent activation
Many antigens are T cell-independent in that they can deliver both of the signals to the B
cell. Mice without a thymus (nude orathymic mice that do not produce any T cells) can respond to T
independent antigens. Many bacteria have repeating carbohydrate epitopes that stimulate B cells, by
cross-linking the IgM antigen receptors in the B cell, responding with IgM synthesis in the absence of T
cell help. There are two types of T cell independent activation; Type 1 T cell-independent(polyclonal)
activation, and type 2 T cell-independent activation (in which macrophages present several of the same
antigen in a way that causes cross-linking of antibodies on the surface of B cells).

The ancestral roots of B cells
In    an     October        2006     issue    of Nature     Immunology,     certain    B      cells    of
basal vertebrates (like fish and amphibians) were shown to be capable of phagocytosis, a function usually
associated with cells of the innate immune system. The authors postulate that these phagocytic B cells
represent the ancestral history shared between macrophages and lymphocytes. B cells may have
evolved from macrophage-like cells during the formation of the adaptive immune system.
B cells in humans (and other vertebrates) are nevertheless able to endocytose antibody-fixed pathogens,
and it is through this route that MHC Class II presentation by B cells is possible, allowing Th2 help and
stimulation of B cell proliferation. This is purely for the benefit of MHC Class II presentation, not as a
significant method of reducing the pathogen load.

B cell-related pathology
Aberrant antibody production by B cells is implicated in many autoimmune diseases, such as rheumatoid
arthritis and systemic lupus erythematosus.

5.Monocyte
Monocyte is a type of white blood cell, part of the human body's immune system. Monocytes have
several roles in the immune system and this includes: (1) replenish resident macrophages and dendritic
cells under normal states, and (2) in response to inflammationsignals, monocytes can move quickly
(approx. 8-12 hours) to sites of infection in the tissues and divide/differentiate into macrophages and
dendritic cells to elicit an immune response. Half of them are stored in the spleen. Monocytes are usually
identified in stained smears by their large bilobate nucleus.

Monocytes can be used to generate dendritic cells in vitro by adding cytokines like Granulocyte Monocyte
Colony Stimulating Factor (GMCSF) and IL-4.




Monocyte


Physiology
Monocytes are produced by the bone marrow from haematopoietic stem cell precursors
called monoblasts. Monocytes circulate in the bloodstream for about one to three days and then typically
move into tissues throughout the body. They constitute between three to eight percent of
the leukocytes in the blood. Half of them are stored as a reserve in the spleen in clusters in the red
pulp's Cords of Billroth. In the tissues monocytes mature into different types of macrophages at different
anatomical locations.
Monocytes which migrate from the bloodstream to other tissues will then differentiate into tissue
resident macrophages or dendritic cells. Macrophages are responsible for protecting tissues from foreign
substances but are also suspected to be the predominant cells involved in triggering atherosclerosis.
They are cells that possess a large smooth nucleus, a large area of cytoplasm and many
internal vesicles for processing foreign material.
Monocytes and their macrophage and dendritic cell progeny serve three main functions in the immune
system. These are phagocytosis, antigen presentation and cytokine production.Phagocytosis is the
process of uptake of microbes and particles followed by digestion and destruction of this material.
Monocytes can         perform   phagocytosis    using   intermediary  (opsonising)   proteins     such
as antibodies or complement that coat the pathogen, as well as by binding to the microbe directly via
pattern-recognition receptors that recognize pathogens. Monocytes are also capable of killing infected
host cells via antibody, termed antibody-mediated cellular cytotoxicity. Vacuolization may be present in a
cell that has recently phagocytized foreign matter.
Microbial fragments that remain after such digestion can serve as antigen. The fragments can be
incorporated into MHC molecules and then traffic to the cell surface of monocytes (and macrophages and
dendritic cells). This process is called antigen presentation and it leads to activation of T lymphocytes,
which then mount a specific immune response against the antigen.
Other microbial products can directly activate monocytes and this leads to production of pro-inflammatory
and with some delay of anti-inflammatory cytokines. Typical cytokines produced by monocytes are
TNF tumor necrosis factor, IL-1 interleukin-1and IL-12 interleukin-12.

Monocyte subpopulations
There are at least three types of monocytes in human blood :
a) the classical monocyte is characterized by high level expression of the CD14 cell surface receptor
(CD14++ CD16- monocyte)
b) the non-classical monocyte shows low level expression of CD14 and with additional co-expression of
the CD16 receptor (CD14+CD16++ monocyte).
c) the intermediate monocyte with high level expression of CD14 and low level expression of CD16
(CD14++CD16+ monocytes).
There appears to be a developmental relationship in that the classical monocytes develop into the
intermediate monocytes to then become the non-classical monocytes CD14+CD16+ monocytes. Hence
the non-classical monocytes may represent a more mature version. After stimulation with microbial
products the CD14+CD16++ monocytes produce high amounts of pro-inflammatory cytokines like tumor
necrosis factor and interleukin-12.

Diagnostic use
A monocyte count is part of a complete blood count and is expressed either as a ratio of monocytes to the
total number of white blood cells counted, or by absolute numbers. Both may be useful in determining or
refuting a possible diagnosis.

Monocytosis
Monocytosis is the state of excess monocytes in the peripheral blood. It may be indicative of various
disease states. Examples of processes that can increase a monocyte count include:

   chronic inflammation
   stress response
   hyperadrenocorticism
   immune-mediated disease
   infectious mononucleosis
   pyogranulomatous disease
   necrosis
   red cell regeneration
   Viral Fever
   sarcoidosis
A high count of CD14+CD16+ monocytes is found in severe infection (sepsis) and a very low count of
these cells is found after therapy with immuno-suppressive glucocorticoids

Monocytopenia
Monocytopenia is a form of leukopenia associated with a deficiency of monocytes.



(b) Mast cell
A mast cell (or mastocyte) is a resident cell of several types of tissues and contains many granules rich
in histamine andheparin. Although best known for their role in allergy and anaphylaxis, mast cells play an
important protective role as well, being intimately involved in wound healing and defense
against pathogens.




Mast cells


Localization
Mast cells are found in connective tissues throughout the body,close to blood vessels and particularly
areas of the respiratory ,urogenital and gastrointestinal tracks.It has large characteristic electron-dense
granules in their cytoplasm,which are very important for their function.the origin of mast cell is uncertain
but they probably also originate in the bone marrow.

Classification
Two types of mast cells are recognized, those from connective tissue and a distinct set of mucosal mast
cells. The activities of the latter are dependent on T-cells.
Mast cells are present in most tissues characteristically surrounding blood vessels and nerves, and are
especially prominent near the boundaries between the outside world and the internal milieu, such as
the skin, mucosa of the lungs and digestive tract, as well as in the mouth, conjunctiva, and nose.

Physiology
Mast cells play a key role in the inflammatory process. When activated, a mast cell rapidly releases its
characteristic granules and various hormonal mediators into the interstitium. Mast cells can be stimulated
to degranulate by direct injury (e.g. physical or chemical [such as opioids, alcohols, and certain antibiotics
such as polymyxins]), cross-linking of Immunoglobulin E (IgE) receptors, or by activated complement
proteins.
Mast cells express a high-affinity receptor (FcεRI) for the Fc region of IgE, the least-abundant member of
the antibodies. This receptor is of such high affinity that binding of IgE molecules is essentially
irreversible. As a result, mast cells are coated with IgE. IgE is produced by Plasma cells (the antibody-
producing cells of the immune system). IgE molecules, like all antibodies, are specific to one
particular antigen.




                              The role of mast cells in the development of allergy.

In allergic reactions, mast cells remain inactive until an allergen binds to IgE already in association with
the cell (see above). Other membrane activation events can either prime mast cells for subsequent
degranulation or can act in synergy with FceRI signal transduction. Allergens are
generally proteins or polysaccharides. The allergen binds to the antigen-binding sites, which are situated
on the variable regions of the IgE molecules bound to the mast cell surface. It appears that binding of two
or more IgE molecules (cross-linking) is required to activate the mast cell. The clustering of the
intracellular domains of the cell-bound Fc receptors, which are associated with the cross-linked IgE
molecules, causes a complex sequence of reactions inside the mast cell that lead to its activation.
Although this reaction is most well understood in terms of allergy, it appears to have evolved as a defense
system against intestinal worm infestations (tapeworms, etc.).


The molecules thus released into the extracellular environment include:



    preformed mediators (from the granules):
      serine proteases, such as tryptase
      histamine (2-5 pg/cell)
      serotonin
      proteoglycans, mainly heparin (active as anticoagulant)
    newly formed lipid mediators (eicosanoids):
      prostaglandin D2
      leukotriene C4
      platelet-activating factor
    cytokines
      Eosinophil chemotactic factor

Histamine dilates post capillary venules, activates the endothelium, and increases blood vessel
permeability. This leads to local edema(swelling), warmth, redness, and the attraction of other
inflammatory cells to the site of release. It also irritates nerve endings (leading to itchingor pain).
Cutaneous signs of histamine release are the "flare and wheal"-reaction. The bump and redness
immediately following a mosquito bite are a good example of this reaction, which occurs seconds after
challenge of the mast cell by an allergen.




                                                           Structure of histamine

The other physiologic activities of mast cells are much less well-understood. Several lines of evidence
suggest that mast cells may have a fairly fundamental role in innate immunity – they are capable of
elaborating a vast array of important cytokines and other inflammatory mediators such as TNFa, they
express multiple "pattern recognition receptors" thought to be involved in recognizing broad classes of
pathogens, and mice without mast cells seem to be much more susceptible to a variety of infections.[citation
needed]


Mast cell granules carry a variety of bioactive chemicals. These granules have been found to be
transferred to adjacent cells of the immune system andneurons via transgranulation via their pseudopodia

Role in disease
Allergic disease
Many forms of cutaneous and mucosal allergy are mediated for a large part by mast cells; they play a
central role in asthma, eczema, itch (from various causes) and allergic rhinitis andallergic
conjunctivitis. Antihistamine drugs act by blocking the action of histamine on nerve
endings. Cromoglicate-based drugs (sodium cromoglicate, nedocromil) block a calcium channel essential
for mast cell degranulation, stabilizing the cell and preventing release of histamine and related
mediators. Leukotriene antagonists (such as montelukast andzafirlukast) block the action of leukotriene
mediators, and are being used increasingly in allergic diseases.

Anaphylaxis
In anaphylaxis (a severe systemic reaction to allergens, such as nuts, bee stings or drugs), body-wide
degranulation of mast cells leads to vasodilation and, if severe, symptoms of life-threatening shock.[citation
needed]



Autoimmunity
Mast cells are implicated in the pathology associated with the autoimmune disorders rheumatoid
arthritis, bullous pemphigoid, and multiple sclerosis. They have been shown to be involved in the
recruitment of inflammatory cells to the joints (e.g. rheumatoid arthritis) and skin (e.g. bullous pemphigoid)
and this activity is dependent on antibodies and complement components.

Mast cell disorders
Mastocytosis is a rare condition featuring proliferation of mast cells. It exists in
a cutaneous and systemic form, with the former being limited to the skin and the latter involving multiple
organs. Mast cell tumors are often seen in dogs and cats.

(c)Phagocyte
Phagocytes are the white blood cells that protect the body by ingesting (phagocytosing) harmful foreign
particles, bacteria, and dead or dyingcells. Their name comes from the Greek phagein, "to eat" or
"devour", and "-cyte", the suffix in biology denoting "cell", from the Greek kutos, "hollow vessel". They are
essential for fighting infections and for subsequent immunity. Phagocytes are important throughout the
animal kingdom and are highly developed within vertebrates. One litre of human blood contains about six
billion phagocytes. Phagocytes were first discovered in 1882 by Ilya Ilyich Mechnikov while he was
studying starfish larvae. Mechnikov was awarded the 1908 Nobel Prize in Physiology or Medicine for his
discovery. Phagocytes occur in many species; some amoebae behave like macrophage phagocytes,
which suggests that phagocytes appeared early in the evolution of life.
Phagocytes of humans and other animals are called "professional" or "non-professional" depending on
how effective they are atphagocytosis. The professional phagocytes include cells
called neutrophils, monocytes, macrophages, dendritic cells, and mast cells.The main difference between
professional and non-professional phagocytes is that the professional phagocytes have molecules
calledreceptors on their surfaces that can detect harmful objects, such as bacteria, that are not normally
found in the body. Phagocytes are crucial in fighting infections, as well as in maintaining healthy tissues
by removing dead and dying cells that have reached the end of their lifespan.
During an infection, chemical signals attract phagocytes to places where the pathogen has invaded the
body. These chemicals may come from bacteria or from other phagocytes already present. The
phagocytes move by a method called chemotaxis. When phagocytes come into contact with bacteria, the
receptors on the phagocyte's surface will bind to them. This binding will lead to the engulfing of the
bacteria by the phagocyte. Some phagocytes kill the ingested pathogen with oxidants and nitric
oxide. After phagocytosis, macrophages and dendritic cells can also participate in antigen presentation, a
process in which a phagocyte moves parts of the ingested material back to its surface. This material is
then displayed to other cells of the immune system. Some phagocytes then travel to the body's lymph
nodes and display the material to white blood cells called lymphocytes. This process is important in
building immunity. However, many pathogens have evolved methods to evade attacks by phagocytes.




Methods of killing
The killing of microbes is a critical function of phagocytes that is either performed within the phagocyte
(intracellular killing) or outside of the phagocyte (extracellular killing).




Simplified diagram of the phagocytosis and destruction of a bacterial cell

Oxygen-dependent intracellular
When a phagocyte ingests bacteria (or any material), its oxygen consumption increases. The increase in
oxygen consumption, called arespiratory burst, produces reactive oxygen-containing molecules that are
anti-microbial. The oxygen compounds are toxic to both the invader and the cell itself, so they are kept in
compartments inside the cell. This method of killing invading microbes by using the reactive oxygen-
containing molecules is referred to as oxygen-dependent intracellular killing, of which there are two types.
The first type is the oxygen-dependent production of a superoxide, which is an oxygen-rich bacteria-killing
substance. The superoxide is converted to hydrogen peroxide and singlet oxygen by an enzyme
called superoxide dismutase. Superoxides also react with the hydrogen peroxide to produce hydroxyl
radicals which assist in killing the invading microbe.
The second type involves the use of the enzyme myeloperoxidase from neutrophil granules. When
granules fuse with a phagosome, myeloperoxidase is released into the phagolysosome, and this enzyme
uses hydrogen peroxide and chlorine to create hypochlorite, a substance used in domestic bleach.
Hypochlorite is extremely toxic to bacteria.Myeloperoxidase contains a heme pigment, which accounts for
the green color of secretions rich in neutrophils, such as pus and infected sputum.
Oxygen-independent intracellular
Phagocytes can also kill microbes by oxygen-independent methods, but these are not as effective as the
oxygen-dependent ones. There are four main types. The first uses electrically charged proteins which
damage the bacterium's membrane. The second type uses lysozymes; these enzymes break down the
bacterial cell wall. The third type uses lactoferrins, which are present in neutrophil granules and remove
essential iron from bacteria. The fourth type uses proteases and hydrolytic enzymes; these enzymes are
used to digest the proteins of destroyed bacteria.

Extracellular
Interferon-gamma—which was once called macrophage activating factor—stimulates macrophages to
produce nitric oxide. The source of interferon-gamma can be CD4+ T cells, CD8+ T cells, natural killer
cells, B cells, natural killer T cells, monocytes, macrophages, or dendritic cells. Nitric oxide is then
released from the macrophage and, because of its toxicity, kills microbes near the macrophage. Activated
macrophages produce and secrete tumor necrosis factor. This cytokine—a class of signaling molecule—
kills cancer cells and cells infected by viruses, and helps to activate the other cells of the immune system.
In some diseases, e.g., the rare chronic granulomatous disease, the efficiency of phagocytes is impaired,
and recurrent bacterial infections are a problem. In this disease there is an abnormality affecting different
elements of oxygen-dependent killing. Other rare congenital abnormalities, such as Chediak-Higashi
syndrome, are also associated with defective killing of ingested microbes.

Role in apoptosis
Apoptosis (pronounced /ˌæpəˈtoʊsɪs/ or /ˌæpəpˈtoʊsɪs/) is the process of programmed cell death (PCD)
that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes
(morphology) and death. These changes include blebbing, loss of cell membrane asymmetry and
attachment, cell shrinkage, nuclear fragmentation, chromatin condensation,
and chromosomal DNA fragmentation. (See also Apoptosis DNA fragmentation.) Apoptosis differs
from necrosis, in which the cellular debris can damage the organism.
In an animal, cells are constantly dying. A balance between cell division and cell death keeps the number
of cells relatively constant in adults. There are two different ways a cell can die: by necrosis or by
apoptosis. In contrast to necrosis, which often results from disease or trauma, apoptosis—or programmed
cell death—is a normal healthy function of cells. The body has to rid itself of millions of dead or dying cells
every day, and phagocytes play a crucial role in this process.
Dying cells that undergo the final stages of apoptosis display molecules, such as phosphatidylserine, on
their cell surface to attract phagocytes. Phosphatidylserine is normally found on the cytosolic surface of
the plasma membrane, but is redistributed during apoptosis to the extracellular surface by a hypothetical
protein known as scramblase. These molecules mark the cell for phagocytosis by cells that possess the
appropriate receptors, such as macrophages. The removal of dying cells by phagocytes occurs in an
orderly manner without eliciting an inflammatory response and is an important function of phagocytes.
Apoptosis—phagocytes clear fragments of dead cells from the
body.


Interactions with other cells
Phagocytes are usually not bound to any particular organ but move through the body interacting with the
other phagocytic and non-phagocytic cells of the immune system. They can communicate with other cells
by producing chemicals called cytokines, which recruit other phagocytes to the site of infections or
stimulate dormant lymphocytes. Phagocytes form part of the innate immune system which animals,
including humans, are born with. Innate immunity is very effective but non-specific in that it does not
discriminate between different sorts of invaders. On the other hand, the adaptive immune system of jawed
vertebrates—the basis of acquired immunity—is highly specialized and can protect against almost any
type of invader. The adaptive immune system is dependent on lymphocytes, which are not phagocytes
but produce protective proteins called antibodies which tag invaders for destruction and
prevent viruses from infecting cells. Phagocytes, in particular dendritic cells and macrophages, stimulate
lymphocytes to produce antibodies by an important process called antigen presentation.

What is opsonization?
This is the process of making a microbes easier to phagocytose.Opsonization is a process in
which pathogens are coated with a substance called an opsonin, marking the pathogen out for destruction
by the immune system. Once a pathogen has been opsonized, it is killed via one of two mechanisms. The
pathogen may be ingested and killed by an immune cell, or killed directly withoutingestion.
The process of killing and ingesting a pathogen is called phagocytosis. Cells called phagocytes ingest the
pathogens and then kill them by exposing them to toxic chemicals. The chemicals are stored in small
membrane-bound parcels within the phagocytes, and these parcels are triggered to open when a
phagocyte ingests a pathogen.

Opsonization also leads to pathogen death in a second mechanism called antibody-dependent cellular
cytotoxicity, in which immune cells directly kill pathogens without ingesting them. In this
process, antibodiesact as opsonins, and then trigger immune cells called granulocytes. These cells then
release toxic chemicals into the environment around the pathogens to kill them. In addition to killing
pathogens, this process also causes tissue damage via inflammation.

There are several different substances which may act as opsonins; all of these are proteins which are
active in the immune system. Two antibody types called IgG and IgA are both opsonins. IgG is active in
blood and tissues, and IgA is active in mucosal surfaces such as the airways, urogenital system, and gut.
Several proteins which act in the complement system are also opsonins. The complement system is a
cascade of reactions between a number of different proteins. The end result of the cascade
is opsonization of pathogens, as well as direct pathogen killing via the formation of a protein complex
which punctures holes in bacterial cell walls.

Phagocytosis
Phagocytosis (from Greek phago, meaning eating, cyte, meaning vessel, and osis meaning process) is
the cellular process of engulfing solid particles by the cell membrane to form an
internal phagosome by phagocytes and protists. Phagocytosis is a specific form ofendocytosis involving
the vesicular internalization of solid particles, such as bacteria, and is, therefore, distinct from other forms
of endocytosis such as the vesicular internalization of various liquids. Phagocytosis is involved in the
acquisition of nutrients for some cells, and, in the immune system, it is a major mechanism used to
remove pathogens and cell debris. Bacteria, dead tissue cells, and small mineral particles are all
examples of objects that may be phagocytosed.
The process is homologous to eating only at the level of single-celled organisms; in multicellular animals,
the process has been adapted to eliminate debris and pathogens, as opposed to taking in fuel for cellular
processes, except in the case of the Trichoplax.
Phagocytosis in three
steps:
1. Unbound phagocyte surface receptors do not trigger phagocytosis.
2. Binding of receptors causes them to cluster.
3. Phagocytosis is triggered and the particle is taken up by the phagocyte.


In immune system
Phagocytosis in mammalian immune cells is activated by attachment to Pathogen-associated molecular
patterns (PAMPS), which leads toNF-κB activation. Opsonins such as C3b and antibodies can act as
attachment sites and aid phagocytosis of pathogens.
Engulfment of material is facilitated by the actin-myosin contractile system. The phagosome of ingested
material is then fused with the lysosome, leading to degradation.
Degradation can be oxygen-dependent or oxygen-independent.

   Oxygen-dependent degradation depends on NADPH and the production of reactive oxygen
    species. Hydrogen peroxide andmyeloperoxidase activate a halogenating system, which leads to the
    destruction of bacteria.
   Oxygen-independent degradation depends on the release of granules, containing proteolytic
    enzymes such as defensins, lysozyme, and cationic proteins. Other antimicrobial peptides are
    present in these granules, including lactoferrin, which sequesters iron to provide unfavourable growth
    conditions for bacteria.

It is possible for cells other than dedicated phagocytes (such as dendritic cells) to engage in
phagocytosis.

In apoptosis
Following apoptosis, the dying cells need to be taken up into the surrounding tissues by macrophages in
a process called Efferocytosis. One of the features of an apoptotic cell is the presentation of a variety of
intracellular molecules on the cell surface, such as Calreticulin, Phosphatidylserine (From the inner layer
of the plasma membrane), Annexin A1, and oxidisedLDL. These molecules are recognised by receptors
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A Text Book of Immunology

  • 1. A TexT book of Immunology edITed by ArkAbrATA bAnerjee b.sc bIoTech(h) from The unIversITy of burdwAn & TrAIned In mAgenTA pIgmenT producTIon from fungus In lAb. condITIon ,shrm bIoTech kolkATA & mbA from wbuT,AIcTe ……………………1 sT edITIon 2011…………………… IMMUNO BIOLOGY
  • 2. An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own healthy cells and tissues in order to function properly. Detection is complicated as pathogens can evolve rapidly, producing adaptations that avoid the immune system and allow the pathogens to successfully infect their hosts. Immunity is a biological term that describes a state of having sufficient biological defenses to avoid infection, disease, or other unwanted biological invasion. Immunity involves both specific and non- specific components. The non-specific components act either as barriers or as eliminators of wide range of pathogens irrespective of antigenic specificity. Other components of the immune system adapt themselves to each new disease encountered and are able to generate pathogen-specific immunity. Adaptive immunity is often sub-divided into two major types depending on how the immunity was introduced. Naturally acquired immunity occurs through contact with a disease causing agent, when the contact was not deliberate, whereas artificially acquired immunity develops only through deliberate actions such as vaccination. Both naturally and artificially acquired immunity can be further subdivided depending on whether immunity is induced in the host or passively transferred from a immune host. Passive immunity is acquired through transfer of antibodies or activated T-cells from an immune host, and is short lived -- usually lasting only a few months -- whereas active immunity is induced in the host itself by antigen, and lasts much longer, sometimes life-long. The diagram below summarizes these divisions of immunity. A further subdivision of adaptive immunity is characterized by the cells involved; humoral immunity is the aspect of immunity that is mediated by secreted antibodies, whereas the protection provided by cell mediated immunity involves T-lymphocytes alone. Humoral immunity is active when the organism generates its own antibodies, and passive when antibodies are transferred between individuals. Similarly, cell mediated immunity is active when the organisms’ own T-cells are stimulated and passive when T cells come from another organism. Passive immunity Passive immunity is the transfer of active immunity, in the form of readymade antibodies, from one individual to another. Passive immunity can occur naturally, when maternal antibodies are transferred to
  • 3. the fetus through the placenta, and can also be induced artificially, when high levels of human (or horse) antibodies specific for a pathogen or toxin are transferred to non-immune individuals. Passive immunization is used when there is a high risk of infection and insufficient time for the body to develop its own immune response, or to reduce the symptoms of ongoing or immunosuppressive diseases. Passive immunity provides immediate protection, but the body does not develop memory, therefore the patient is at risk of being infected by the same pathogen later. Naturally acquired passive immunity Maternal passive immunity is a type of naturally acquired passive immunity, and refers to antibody- mediated immunity conveyed to a fetus by its mother during pregnancy. Maternal antibodies (MatAb) are passed through the placenta to the fetus by an FcRn receptor on placental cells. This occurs around the third month of gestation. IgG is the only antibodyisotype that can pass through the placenta. Passive immunity is also provided through the transfer of IgA antibodies found in breast milk that are transferred to the gut of the infant, protecting against bacterial infections, until the newborn can synthesize its own antibodies. Artificially acquired passive immunity Artificially acquired passive immunity is a short-term immunization induced by the transfer of antibodies, which can be administered in several forms; as human or animal blood plasma, as pooled human immunoglobulin for intravenous (IVIG) or intramuscular (IG) use, and in the form of monoclonal antibodies (MAb). Passive transfer is used prophylactically in the case of immunodeficiency diseases, such as hypogammaglobulinemia. It is also used in the treatment of several types of acute infection, and to treat poisoning.Immunity derived from passive immunization lasts for only a short period of time, and there is also a potential risk for hypersensitivity reactions, and serum sickness, especially from gamma globulin of non-human origin. The artificial induction of passive immunity has been used for over a century to treat infectious disease, and prior to the advent of antibiotics, was often the only specific treatment for certain infections. Immunoglobulin therapy continued to be a first line therapy in the treatment of severe respiratory diseases until the 1930’s, even after sulfonamide antibiotics were introduced. Passive transfer of cell-mediated immunity Passive or "adoptive transfer" of cell-mediated immunity, is conferred by the transfer of "sensitized" or activated T-cells from one individual into another. It is rarely used in humans because it requires histocompatible (matched) donors, which are often difficult to find. In unmatched donors this type of transfer carries severe risks of graft versus host disease. It has, however, been used to treat certain diseases including some types of cancer and immunodeficiency. This type of transfer differs from a bone marrow transplant, in which (undifferentiated) hematopoietic stem cells are transferred. Active immunity
  • 4. The time course of an immune response. Due to the formation of immunological memory, reinfection at later time points leads to a rapid increase in antibody production and effector T cell activity. These later infections can be mild or even inapparent. When B cells and T cells are activated by a pathogen, memory B-cells and T- cells develop. Throughout the lifetime of an animal these memory cells will “remember” each specific pathogen encountered, and are able to mount a strong response if the pathogen is detected again. This type of immunity is both active and adaptive because the body's immune system prepares itself for future challenges. Active immunity often involves both the cell-mediated and humoral aspects of immunity as well as input from the innate immune system. The innate system is present from birth and protects an individual from pathogens regardless of experiences, whereas adaptive immunity arises only after an infection or immunization and hence is "acquired" during life. Naturally acquired active immunity Naturally acquired active immunity occurs when a person is exposed to a live pathogen, and develops a primary immune response, which leads to immunological memory.This type of immunity is “natural” because it is not induced by deliberate exposure. Many disorders of immune system function can affect the formation of active immunity such asimmunodeficiency (both acquired and congenital forms) and immunosuppression. Artificially acquired active immunity Artificially acquired active immunity can be induced by a vaccine, a substance that contains antigen. A vaccine stimulates a primary response against the antigen without causing symptoms of the disease. The term vaccination was coined by Edward Jenner and adapted by Louis Pasteur for his pioneering work in vaccination. The method Pasteur used entailed treating the infectious agents for those diseases so they lost the ability to cause serious disease. Pasteur adopted the name vaccine as a generic term in honor of Jenner's discovery, which Pasteur's work built upon. Layered defense The immune system protects organisms from infection with layered defenses of increasing specificity. In simple terms, physical barriers prevent pathogens such as bacteria and virusesfrom entering the organism. If a pathogen breaches these barriers, the innate immune system provides an immediate, but non-specific response. Innate immune systems are found in all plants and animals. If pathogens successfully evade the innate response, vertebrates possess a third layer of protection, the adaptive immune system, which is activated by the innate response. Here, the immune system adapts its response during an infection to improve its recognition of the pathogen. This improved response is then retained after the pathogen has been eliminated, in the form of an immunological memory, and allows the adaptive immune system to mount faster and stronger attacks each time this pathogen is encountered.
  • 5. Components of the immune system Innate immune system Adaptive immune system Response is non-specific Pathogen and antigen specific response Exposure leads to immediate maximal response Lag time between exposure and maximal response Cell-mediated and humoral components Cell-mediated and humoral components No immunological memory Exposure leads to immunological memory Found in nearly all forms of life Found only in jawed vertebrates Both innate and adaptive immunity depend on the ability of the immune system to distinguish between self and non-self molecules. In immunology, self molecules are those components of an organism's body that can be distinguished from foreign substances by the immune system. Conversely, non-self molecules are those recognized as foreign molecules. One class of non-self molecules are called antigens (short for antibody generators) and are defined as substances that bind to specific immune receptors and elicit an immune respons. Surface barriers Several barriers protect organisms from infection, including mechanical, chemical, and biological barriers. The waxy cuticle of many leaves, the exoskeleton of insects, the shells and membranes of externally deposited eggs, and skin are examples of the mechanical barriers that are the first line of defense against infection. However, as organisms cannot be completely sealed against their environments, other systems act to protect body openings such as the lungs, intestines, and the genitourinary tract. In the lungs, coughing and sneezingmechanically eject pathogens and other irritants from the respiratory tract. The flushing action of tears and urine also mechanically expels pathogens, while mucus secreted by the respiratory and gastrointestinal tract serves to trap and entangle microorganisms. Chemical barriers also protect against infection. The skin and respiratory tract secrete antimicrobial peptides such as the β-defensins. Enzymes such as lysozyme and phospholipase A2 in saliva, tears, and breast milk are also antibacterials. Vaginal secretions serve as a chemical barrier following menarche, when they become slightly acidic, while semencontains defensins and zinc to kill pathogens. In the stomach, gastric acid and proteases serve as powerful chemical defenses against ingested pathogens. Within the genitourinary and gastrointestinal tracts, commensal flora serve as biological barriers by competing with pathogenic bacteria for food and space and, in some cases, by changing the conditions in their environment, such as pH or available iron. This reduces the probability that pathogens will be able to reach sufficient numbers to cause illness. However, since most antibiotics non-specifically target bacteria
  • 6. and do not affect fungi, oral antibiotics can lead to an “overgrowth” of fungi and cause conditions such as a vaginalcandidiasis (a yeast infection). There is good evidence that re-introduction of probiotic flora, such as pure cultures of the lactobacilli normally found in unpasteurized yoghurt, helps restore a healthy balance of microbial populations in intestinal infections in children and encouraging preliminary data in studies on bacterial gastroenteritis, inflammatory bowel diseases,urinary tract infection and post-surgical infections. Innate immune system The innate immune system comprises the cells and mechanisms that defend the host from infection by other organisms, in a non-specific manner. This means that the cells of the innate system recognize and respond to pathogens in a generic way, but unlike the adaptive immune system, it does not confer long- lasting or protective immunity to the host. Innate immune systems provide immediate defense against infection, and are found in all classes of plant and animal life. The innate system is thought to constitute an evolutionarily older defense strategy, and is the dominant immune system found in plants, fungi, insects, and in primitive multicellular organisms. The major functions of the vertebrate innate immune system include:  Recruiting immune cells to sites of infection, through the production of chemical factors, including specialized chemical mediators, called cytokines.  Activation of the complement cascade to identify bacteria, activate cells and to promote clearance of dead cells or antibody complexes.  The identification and removal of foreign substances present in organs, tissues, the blood and lymph, by specialized white blood cells.  Activation of the adaptive immune system through a process known as antigen presentation Cells of the innate immune response (a) Leukocytes White blood cells (WBCs), or leukocytes (also spelled "leucocytes"), are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a hematopoietic stem cell. Leukocytes are found throughout the body, including the blood andlymphatic system. The number of WBCs in the blood is often an indicator of disease. There are normally between 4×109 and 1.1×1010 white blood cells in a litreof blood, making up approximately 1% of blood in a healthy adult. An increase in the number of leukocytes over the upper limits is calledleukocytosis, and a decrease below the lower limit is called leukopenia. The physical properties of leukocytes, such as volume, conductivity, and granularity, may change due to activation, the presence of immature cells, or the presence of malignant leukocytes in leukemia.
  • 7. scanning electron microscope image of normal circulating human blood. In addition to the irregularly shaped leukocytes, both red blood cells and many small disc- shapedplatelets are visible. Types There are several different types of white blood cells. They all have many things in common, but are all distinct in form and function. A major distinguishing feature of some leukocytes is the presence of granules; white blood cells are often characterized as granulocytes or agranulocytes:  Granulocytes (polymorphonuclear leukocytes): leukocytes characterised by the presence of differently staining granules in their cytoplasm when viewed under light microscopy. These granules are membrane-bound enzymes which primarily act in the digestion of endocytosed particles. There are three types of granulocytes: neutrophils, basophils, and eosinophils, which are named according to their staining properties.  Agranulocytes (mononuclear leucocytes): leukocytes characterized by the apparent absence of granules in their cytoplasm. Although the name implies a lack of granules these cells do contain non-specific azurophilic granules, which are lysosomes. The cells include lymphocytes, monocytes, and macrophages. 1.Neutrophil Neutrophil granulocytes are generally referred to as either neutrophils or polymorphonuclear neutrophils (or PMNs), and are subdivided into segmented neutrophils (or segs) and banded neutrophils (or bands). Neutrophils are the most abundant type of white blood cells in mammals and form an essential part of the innate immune system. They form part of the polymorphonuclear cell family (PMNs) together withbasophils and eosinophils. Neutrophils are normally found in the blood stream. However, during the beginning (acute) phase of inflammation, particularly as a result ofbacterial infection and some cancers, neutrophils are one of the first-responders of inflammatory cells to migrate toward the site of inflammation, firstly through the blood vessels, then through interstitial tissue, following chemical signals (such as Interleukin-8 (IL-8) and C5a) in a process called chemotaxis. They are the predominant cells in pus, accounting for its whitish/yellowish appearance. Neutrophils are recruited to the site of injury within minutes following trauma and are the hallmark of acute inflammation.
  • 8. A neutrophil, stained with Wright's stain. This cell is approximately 12 µm in diameter With the eosinophil and the basophil, they form the class of polymorphonuclear cells, named for the nucleus's characteristic multilobulated shape (as compared to lymphocytes and monocytes, the other types of white cells). Neutrophils are the most abundant white blood cells in humans (approximately 10^11 are produced daily) ; they account for approximately 70% of all white blood cells (leukocytes). A minor difference is found between the neutrophils from a male subject and a female subject. The cell nucleus of a neutrophil from a female subject shows a small additional X chromosome structure, known as a "neutrophil drumstick". The average half-life of non-activated neutrophils in the circulation is about 12 hours. Upon activation, they marginate (position themselves adjacent to the blood vessel endothelium), and undergo selectin- dependent capture followed by integrin-dependent adhesion in most cases, after which they migrate into tissues, where they survive for 1–2 days. Neutrophils are much more numerous than the longer-lived monocyte/macrophage phagocytes. A pathogen (disease-causing microorganism or virus) is likely to first encounter a neutrophil. Some experts hypothesize that the short lifetime of neutrophils is an evolutionary adaptation. The short lifetime of neutrophils minimizes propagation of those pathogens that parasitize phagocytes because the more time such parasites spend outside a host cell, the more likely they will be destroyed by some component of the body's defenses. Also, because neutrophil antimicrobial products can also damage host tissues, their short life limits damage to the host during inflammation. Neutrophils will often be phagocytosed themselves by macrophages after digestion of pathogens. PECAM-1 and phosphatidylserine on the cell surface are involved in this process. Neutrophil granulocyte migrates from the blood vessel to the matrix, sensing proteolytic enzymes, in order to determine intercellular connections (to the improvement of its mobility) and envelop bacteria through phagocytosis
  • 9. Neutrophils undergo a process called chemotaxis, which allows them to migrate toward sites of infection or inflammation. Cell surface receptors allow neutrophils to detect chemical gradients of molecules such as interleukin-8 (IL-8), interferon gamma (IFN-gamma), and C5a, which these cells use to direct the path of their migration. Anti-microbial function Being highly motile, neutrophils quickly congregate at a focus of infection, attracted by cytokines expressed by activated endothelium, mast cells, andmacrophages. Neutrophils express and release cytokines, which in turn amplify inflammatory reactions by several other cell types. In addition to recruiting and activating other cells of the immune system, neutrophils play a key role in the front-line defence against invading pathogens. Neutrophils have three strategies for directly attacking micro-organisms: phagocytosis (ingestion), release of soluble anti-microbials (including granule proteins) and generation of neutrophil extracellular traps (NETs). Phagocytosis Neutrophils are phagocytes, capable of ingesting microorganisms or particles. They can internalize and kill many microbes, each phagocytic event resulting in the formation of a phagosome into which reactive oxygen species and hydrolytic enzymes are secreted. The consumption of oxygen during the generation of reactive oxygen species has been termed the "respiratory burst", although unrelated to respiration or energy production.The respiratory burst involves the activation of the enzyme NADPH oxidase, which produces large quantities of superoxide, a reactive oxygen species. Superoxide dismutates, spontaneously or through catalysis via enzymes known as superoxide dismutases (Cu/ZnSOD and MnSOD), to hydrogen peroxide, which is then converted to hypochlorous acid HClO, by the green heme enzyme myeloperoxidase. It is thought that the bactericidal properties of HClO are enough to kill bacteria phagocytosed by the neutrophil, but this may instead be step necessary for the activation of proteases. Role in disease Low neutrophil counts are termed neutropenia. This can be congenital (genetic disorder) or it can develop later, as in the case of aplastic anemia or some kinds of leukemia. It can also be a side- effect of medication, most prominently chemotherapy. Neutropenia makes an individual highly susceptible to infections. Neutropenia can be the result of colonization by intracellular neutrophilic parasites. Functional disorders of neutrophils are often hereditary. They are disorders of phagocytosis or deficiencies in the respiratory burst (as in chronic granulomatous disease, a rare immune deficiency, and myeloperoxidase deficiency). In alpha 1-antitrypsin deficiency, the important neutrophil enzyme elastase is not adequately inhibited by alpha 1-antitrypsin, leading to excessive tissue damage in the presence of inflammation - most prominently pulmonary emphysema. In Familial Mediterranean fever (FMF), a mutation in the pyrin (or marenostrin) gene, which is expressed mainly in neutrophil granulocytes, leads to a constitutively active acute phase response and causes attacks of fever, arthralgia, peritonitis, and - eventually - amyloidosis Neutrophil Extracellular Traps(NETs) Zychlinsky and colleagues recently described a new striking observation that activation of neutrophils causes the release of web-like structures of DNA; this represents a third mechanism for killing bacteria. These neutrophil extracellular traps (NETs) comprise a web of fibers composed of chromatin and serine proteases that trap and kill microbes extracellularly. It is suggested that NETs
  • 10. provide a high local concentration of antimicrobial components and bind, disarm, and kill microbes independent of phagocytic uptake. In addition to their possible antimicrobial properties, NETs may serve as a physical barrier that prevents further spread of pathogens. Trapping of bacteria may be a particularly important role for NETs in sepsis, where NET are formed within blood vessels. Recently, NETs have been shown to play a role in inflammatory diseases, as NETs could be detected in preeclampsia, a pregnancy related inflammatory disorder in which neutrophils are known to be activated. 2.Eosinophil Eosinophil granulocytes, usually called eosinophils or eosinophiles (or, less commonly, acidophils), are white blood cells that are one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along withmast cells, they also control mechanisms associated with allergy and asthma. They are granulocytes that develop during haematopoiesisin the bone marrow before migrating into blood. These cells are eosinophilic or 'acid-loving' as shown by their affinity to coal and tar dyes: Normally transparent, it is this affinity that causes them to appear brick-red after staining with eosin, a red dye, using the Romanowsky method. The staining is concentrated in small granules within the cellular cytoplasm, which contain many chemical mediators, such as histamine and proteins such as eosinophil peroxidase, ribonuclease (RNase), deoxyribonucleases, lipase, plasminogen, and major basic protein. These mediators are released by a process called degranulation following activation of the eosinophil, and are toxic to both parasite and host tissues. In normal individuals, eosinophils make up about 1-6% of white blood cells, and are about 12-17 micrometers in size. They are found in the medulla and the junction between the cortex and medulla of the thymus, and, in the lower gastrointestinal tract, ovary, uterus, spleen, and lymph nodes, but not in the lung, skin, esophagus, or some other internal organs[vague] under normal conditions. The presence of eosinophils in these latter organs is associated with disease. Eosinophils persist in the circulation for 8–12 hours, and can survive in tissue for an additional 8–12 days in the absence of stimulation. Pioneering work in the 1980s elucidated that eosinophils were unique granulocytes, having the capacity to survive for extended periods of time after their maturation as demonstrated by ex-vivo culture experiments.
  • 11. Eosinophil under the microscope (40x) from a peripheral blood smear. Red blood cells surround the eosinophil, two platelets at the top left corner. An increase in eosinophils, i.e., the presence of more than 500 eosinophils/microlitre of blood is called an eosinophilia, and is typically seen in people with a parasitic infestation of theintestines, a collagen vascular disease (such as rheumatoid arthritis), malignant diseases such as Hodgkin's disease, extensive skin diseases (such as exfoliative dermatitis), Addison's disease, in the squamous epithelium of the esophagus in the case of reflux esophagitis, eosinophilic esophagitis, and with the use of certain drugs such as penicillin. In 1989, contaminated L-tryptophan supplements caused a deadly form of eosinophilia known as eosinophilia-myalgia syndrome, which was reminiscent of the Toxic Oil Syndrome in Spain in 1981. Eosinophil development, migration and activation Eosinophils develop and mature in bone marrow. They differentiate from myeloid precursor cells in response to the cytokines interleukin 3 (IL-3), interleukin 5 (IL-5), and granulocyte macrophage colony- stimulating factor (GM-CSF). Eosinophils produce and store many secondary granule proteins prior to their exit from the bone marrow. After maturation, eosinophils circulate in blood and migrate to inflammatory sites in tissues, or to sites of helminth infection in response to chemokines like CCL11 (eotaxin-1), CCL24 (eotaxin-2), CCL5 (RANTES), and certain leukotrienes like leukotriene B4 (LTB4) and MCP1/4. At these infectious sites, eosinophils are activated by Type 2 cytokines released from a specific subset ofhelper T cells (Th2); IL-5, GM-CSF, and IL-3 are important for eosinophil activation as well as maturation. There is evidence to suggest that eosinophil granule protein expression is regulated by the non-coding RNA EGOT (gene). Eosinophil granule proteins Following activation by an immune stimulus, eosinophils degranulate to release an array of cytotoxic granule cationic proteins that are capable of inducing tissue damage and dysfunction. These include:  major basic protein (MBP)  eosinophil cationic protein (ECP)  eosinophil peroxidase (EPO)  eosinophil-derived neurotoxin (EDN) Major basic protein, eosinophil peroxidase, and eosinophil cationic protein are toxic to many tissues. Eosinophil cationic protein and eosinophil-derived neurotoxin are ribonucleaseswith antiviral activity. Major basic protein induces mast cell and basophil degranulation,
  • 12. and is implicated in peripheral nerve remodelling. Eosinophil cationic protein creates toxic pores in the membranes of target cells allowing potential entry of other cytotoxic molecules to the cell, can inhibit proliferation of T cells, suppress antibody production by B cells, induce degranulation by mast cells, and stimulate fibroblast cells to secrete mucus and glycosaminoglycan. Eosinophil peroxidase forms reactive oxygen species and reactive nitrogen intermediates that promote oxidative stress in the target, causing cell death by apoptosis and necrosis. Functions of eosinophils Following activation, eosinophils effector functions include production of:  cationic granule proteins and their release by degranulation. reactive oxygen species such as superoxide, peroxide, and hypobromite (hypobromous acid, which is preferentially produced by eosinophil peroxidase).  lipid mediators like the eicosanoids from the leukotriene (e.g., LTC4, LTD4, LTE4) and prostaglandin (e.g., PGE2) families. enzymes, such as elastase.  growth factors such as TGF beta, VEGF, and PDGF.  cytokines such as IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-13, and TNF alpha. In addition, eosinophils play a role in fighting viral infections, which is evident from the abundance of RNAses they contain within their granules, and in fibrin removal during inflammation. Eosinophils along with basophils and mast cells, are important mediators of allergic responses and asthma pathogenesis and are associated with disease severity. They also fighthelminth (worm) colonization and may be slightly elevated in the presence of certain parasites. Eosinophils are also involved in many other biological processes, including postpubertalmammary gland development, oestrus cycling, allograft rejection and neoplasia. They have also recently been implicated in antigen presentation to T cells. Treatment Treatments used to combat autoimmune diseases and conditions caused by eosinophils include:  corticosteroids- promote apoptosis. Numbers of eosinophils in blood are rapidly reduced  monoclonal antibody therapy- e.g., mepoluzimab or reslizumab against IL-5, prevents eosinophilopoiesis  antagonists of leukotriene synthesis or receptors  Gleevec (STI571)- inhibits PDGF-BB in hypereosinophilic leukemia 3.Basophil Basophil granulocytes, sometimes referred to as basophils, are the least common of the granulocytes, representing about 0.01% to 0.3% of circulatingwhite blood cells. The name comes from the fact that these leukocytes are basophilic, i.e., they are susceptible to staining by basic dyes, as shown in the picture. Basophils contain large cytoplasmic granules which obscure the cell nucleus under the microscope. However, when unstained, the nucleus is visible and it usually has 2 lobes. The mast cell,
  • 13. a cell in tissues, has many similar characteristics. For example, both cell types store histamine, a chemical that is secreted by the cells when stimulated in certain ways (histamine causes some of the symptoms of an allergic reaction). Like all circulating granulocytes, basophils can be recruited out of the blood into a tissue when needed. Basophil Basophil granulocyte Basophils of mouse and human have consistent immunophenotypes as follows: FcεRI+, CD123, CD49b(DX-5)+, CD69+, Thy-1.2+, 2B4+, CD11bdull, CD117(c- – – – – – – – – – – kit) , CD24 , CD19 , CD80 ,CD14 , CD23 , Ly49c , CD122 , CD11c , Gr-1 , NK1.1–, B220–, CD3–, γδTCR–, αβTCR–, α4 and β4-integrin negative. Secretions When activated, basophils degranulate to release histamine, proteoglycans (e.g. heparin and chondroitin), and proteolytic enzymes (e.g. elastase and lysophospholipase). They also secrete lipid mediators like leukotrienes, and several cytokines. Histamine and proteoglycans are pre-stored in the cell's granules while the other secreted substances are newly generated. Each of these substances contributes to inflammation. Recent evidence suggests that basophils are an important source of the cytokine, interleukin-4, perhaps more important than T cells. Interleukin-4 is considered one of the critical cytokines in the development of allergies and the production of IgE antibody by the immune system. There are other substances that can activate basophils to secrete which suggests that these cells have other roles in inflammation. Basopenia (a low basophil count) is difficult to demonstrate as the normal basophil count is so low; it has been reported in association with autoimmune urticaria (a chronic itching condition). Basophilia is also uncommon but may be seen in some forms of leukaemia or lymphoma. Function Basophils appear in many specific kinds of inflammatory reactions, particularly those that cause allergic symptoms. Basophils contain anticoagulant heparin, which prevents blood from clotting too quickly. They also contain the vasodilator histamine, which promotes blood flow to tissues. They can be found in unusually high numbers at sites of ectoparasite infection, e.g.,ticks. Like eosinophils, basophils play a role in both parasitic infections and allergies. They are found in tissues where allergic reactions are occurring and probably contribute to the severity of these reactions. Basophils have protein receptors on their cell surface that bindIgE, an immunoglobulin involved in macroparasite defense and allergy. It is the bound IgE antibody that confers a selective response of these cells to environmental substances, for example, pollen proteins or helminth antigens. Recent studies in mice suggest that basophils may also regulate the behavior of T cells and mediate the magnitude of the secondary immune response.
  • 14. 4.Lymphocyt This is under the adaptive immune system. A stained lymphocyte surrounded byred blood cells viewed using a light microscope. A scanning electron microscope(SEM) image of a single human lymphocyte. A particular class of leukocytes known as lymphocyte mostly carry out the specific acquired immune response.Lymphocytes are much more common in the lymphatic system. Lymphocytes are distinguished by having a deeply staining nucleus which may be eccentric in location, and a relatively small amount of cytoplasm.Lymphocytes provide both the specificity and memory which are characteristic of the adaptive immune response. Development Mammalian stem cells differentiate into several kinds of blood cell within the bone marrow. This process is calledhaematopoiesis. All lymphocytes originate, during this process, from a common lymphoid progenitor before differentiating into their distinct lymphocyte types. The differentiation of lymphocytes follows various pathways in a hierarchical fashion as well as in a more plastic fashion. The formation of lymphocytes is known as lymphopoiesis. B cells mature into B lymphocytes in the bone marrow, while T cells migrate to and mature in a distinct organ, called the thymus. Following maturation, the lymphocytes enter the circulation and peripheral lymphoid organs (e.g. the spleen and lymph nodes) where they survey for invading pathogensand/or tumor cells. The lymphocytes involved in adaptive immunity (i.e. B and T cells) differentiate further after exposure to an antigen; they form effector and memory lymphocytes. Effector lymphocytes function to eliminate the antigen, either by releasing antibodies (in the case of B cells), cytotoxic granules (cytotoxic T cells) or by signaling to other cells of the immune system (helper T cells).Memory cells remain in the peripheral tissues and circulation for an extended time ready to respond to the same antigen upon future exposure. Characteristics
  • 15. Microscopically, in a Wright's stained peripheral blood smear, a normal lymphocyte has a large, dark- staining nucleus with little to no eosinophiliccytoplasm. In normal situations, the coarse, dense nucleus of a lymphocyte is approximately the size of a red blood cell (about 7 micrometres in diameter). Some lymphocytes show a clear perinuclear zone (or halo) around the nucleus or could exhibit a small clear zone to one side of the nucleus. Polyribosomes are a prominent feature in the lymphocytes and can be viewed with an electron microscope. The ribosomes are involved in protein synthesis allowing the generation of large quantities of cytokines and immunoglobulins by these cells. It is impossible to distinguish between T cells and B cells in a peripheral blood smear. Normally, flow cytometry testing is used for specific lymphocyte population counts. This can be used to specifically determine the percentage of lymphocytes that contain a particular combination of specific cell surface proteins, such as immunoglobulins or cluster of differentiation (CD) markers or that produce particular proteins (for example,cytokines using intracellular cytokine staining (ICCS)). In order to study the function of a lymphocyte by virtue of the proteins it generates, other scientific techniques like the ELISPOT or secretion assay techniques can be used. Lymphocytes and disease A lymphocyte count is usually part of a peripheral complete blood cell count and is expressed as percentage of lymphocytes to total white blood cells counted. A general increase in the number of lymphocytes is known as lymphocytosis whereas a decrease is lymphocytopenia. High An increase in lymphocyte concentration is usually a sign of a viral infection (in some rare case, leukemias are found through an abnormally raised lymphocyte count in an otherwise normal person). Low A low normal to low absolute lymphocyte concentration is associated with increased rates of infection after surgery or trauma. One basis for low T cell lymphocytes occurs when the human immunodeficiency virus (HIV) infects and destroys T cells (specifically, the CD4+ subgroup of T lymphocytes). Without the key defense that these T cells provide, the body becomes susceptible to opportunistic infections that otherwise would not affect healthy people. The extent of HIV progression is typically determined by measuring the percentage of CD4+ T cells in the patient's blood. The effects of other viruses or lymphocyte disorders can also often be estimated by counting the numbers of lymphocytes present in the blood. Types The blood has three types of lymphocytes:  B cells: B cells make antibodies that bind to pathogens to enable their destruction. (B cells not only make antibodies that bind to pathogens, but after an attack, some B cells will retain the ability to produce an antibody to serve as a 'memory' system.)  T cells:  CD4+ (helper) T cells co-ordinate the immune response and are important in the defense against intracellular bacteria. In acute HIV infection, these T cells are the main index to identify the
  • 16. individual's immune system activity. Research has shown that CD8+ cells are also another index to identify human's immune activity.  CD8+ cytotoxic T cells are able to kill virus-infected and tumor cells.  γδ T cells possess an alternative T cell receptor as opposed to CD4+ and CD8+ αβ T cells and share characteristics of helper T cells, cytotoxic T cells and natural killer cells.  Natural killer cells: Natural killer cells are able to kill cells of the body which are displaying a signal to kill them, as they have been infected by a virus or have become cancerous. T cell Scanning electron micrograph of T lymphocyte (right), a platelet (center) and ared blood cell (left) T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocyte types, such as B cells and natural killer cells (NK cells) by the presence of a special receptor on their cell surface called T cell receptors (TCR). The abbreviation T, in T cell, stands for thymus, since this is the principal organ responsible for the T cell's maturation. Several different subsets of T cells have been discovered, each with a distinct function. Types Helper T helper cell (TH cells) assist other white blood cells in immunologic processes, including maturation of B cells into plasma cells and activation of cytotoxic T cells and macrophages, among other functions. These cells are also known as CD4+ T cells because they express the CD4 protein on their surface. Helper T cells become activated when they are presented with peptide antigens by MHC class II molecules that are expressed on the surface of Antigen Presenting Cells (APCs). Once activated, they divide rapidly and secrete small proteins called cytokines that regulate or assist in the active immune response. These cells can differentiate into one of several subtypes, including TH1, TH2, TH3, TH17, or TFH, which secrete different cytokines to facilitate a different type of immune response. The mechanism by which T cells are directed into a particular subtype is poorly understood, though signalling patterns from the APC are thought to play an important role. Cytotoxic Cytotoxic T cells (TC cells, or CTLs) destroy virally infected cells and tumor cells, and are also implicated in transplant rejection. These cells are also known as CD8+ T cells since they express the CD8 glycoprotein at their surface. These cells recognize their targets by binding to antigen associated with MHC class I, which is present on the surface of nearly every cell of the body. Through IL-10,
  • 17. adenosine and other molecules secreted by regulatory T cells, the CD8+ cells can be inactivated to an anergic state, which prevent autoimmune diseases such as experimental autoimmune encephalomyelitis. Memory Memory T cells are a subset of antigen-specific T cells that persist long-term after an infection has resolved. They quickly expand to large numbers of effector T cells upon re-exposure to their cognate antigen, thus providing the immune system with "memory" against past infections. Memory T cells comprise two subtypes: central memory T cells (TCM cells) and effector memory T cells (TEM cells). Memory cells may be either CD4+ or CD8+. Memory T cells typically express the cell surface protein CD45RO. Regulatory Regulatory T cells (Treg cells), formerly known as suppressor T cells, are crucial for the maintenance of immunological tolerance. Their major role is to shut down T cell-mediated immunity toward the end of an immune reaction and to suppress auto-reactive T cells that escaped the process of negative selection in the thymus. Two major classes of CD4+ regulatory T cells have been described, including the naturally occurring Treg cells and the adaptive Treg cells. Naturally occurring Treg cells (also known as CD4+CD25+FoxP3+ Treg cells) arise in the thymus, whereas the adaptive Treg cells (also known as Tr1 cells or Th3 cells) may originate during a normal immune response. Naturally occurring Treg cells can be distinguished from other T cells by the presence of an intracellular molecule called FoxP3. Mutations of the FOXP3 gene can prevent regulatory T cell development, causing the fatal autoimmune disease IPEX. Natural killer Natural killer T cells (NKT cells) are a special kind of lymphocyte that bridges the adaptive immune system with the innate immune system. Unlike conventional T cells that recognize peptide antigen presented by major histocompatibility complex (MHC) molecules, NKT cells recognize glycolipid antigen presented by a molecule called CD1d. Once activated, these cells can perform functions ascribed to both Th and Tc cells (i.e., cytokine production and release of cytolytic/cell killing molecules). They are also able to recognize and eliminate some tumor cells and cells infected with herpes viruses. γδ γδ T cells (gamma delta T cells) represent a small subset of T cells that possess a distinct T cell receptor (TCR) on their surface. A majority of T cells have a TCR composed of twoglycoprotein chains called α- and β- TCR chains. However, in γδ T cells, the TCR is made up of one γ-chain and one δ-chain. This group of T cells is much less common (2% of total T cells) than the αβ T cells, but are found at their highest abundance in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs). The antigenic molecules that activate γδ T cells are still widely unknown. However, γδ T cells are not MHC restricted and seem to be able to recognize whole proteins rather than requiring peptides to be presented by MHC molecules on antigen presenting cells. Some murine γδ T cells recognize MHC class IB molecules though. Human Vγ9/Vδ2 T cells, which constitute the major γδ T cell population in peripheral blood, are unique in that they specifically and rapidly respond to a set of non- peptidic phosphorylated metabolites precursors of cholesterol, collectively named phosphoantigens. Phosphoantigens are produced by virtually all living cells. The most common phosphoantigens from animal and human cells (including cancer cells) are isopentenyl pyrophosphate (IPP) and its isomer dimethylallyl pyrophosphate (DMAPP), while in microbes the most common phosphoantigens are precursors of eubacterial dimethylallyl pyrophosphate (Hydroxy-DMAPP, also known as HMBPP)and corresponding mononucleotide conjugates. Plant cells produce both types of phosphoantigens. Drugs activating human Vγ9/Vδ2 T cells comprise synthetic phosphoantigens and aminobisphosphonates, which respectively mimick natural phosphoantigens and by up-regulating endogenous IPP/DMAPP.
  • 18. Typical recognition markers for lymphocytes[ CLASS FUNCTION PROPORTION PHENOTYPIC MARKER(S) Lysis of virally infected cells and tumour NK cells 7% (2-13%) CD16 CD56 but not CD3 cells Helper T Release cytokines and growth factors 46% (28-59%) TCRαβ, CD3 and CD4 cells that regulate other immune cells Cytotoxic T Lysis of virally infected cells, tumour 19% (13-32%) TCRαβ, CD3 and CD8 cells cells and allografts γδ T cells Immunoregulation and cytotoxicity TCRγδ and CD3 B cells Secretion of antibodies 23% (18-47%) MHC class II, CD19 and CD21 Development in the thymus All T cells originate from haematopoietic stem cells in the bone marrow. Haematopoietic progenitors derived from haematopoietic stem cells populate the thymus and expand by cell division to generate a large population of immature thymocytes. The earliest thymocytes express neither CD4 nor CD8, and are therefore classed as double-negative (CD4-CD8-) cells. As they progress through their development they become double-positive thymocytes (CD4+CD8+), and finally mature to single-positive (CD4+CD8- or CD4- CD8+) thymocytes that are then released from the thymus to peripheral tissues. About 98% of thymocytes die during the development processes in the thymus by failing either positive selection or negative selection, whereas the other 2% survive and leave the thymus to become mature immunocompetent T cells. The thymus contributes more naive T cells at younger ages. As the thymus shrinks by about 3% a year throughout middle age, there is a corresponding fall in the thymic production of naive T cells, leaving peripheral T cell expansion to play a greater role in protecting older subjects. Positive selection Positive selection "selects for" T-cells capable of interacting with MHC. Double- positive thymocytes (CD4+/CD8+) move deep into the thymic cortex where they are presented with self- antigens (i.e., antigens that are derived from molecules belonging to the host of the T cell) complexed with MHC molecules on the surface of cortical epithelial cells. Only those thymocytes that bind the MHC/antigen complex with adequate affinity will receive a vital "survival signal." The implication of this binding is that all T cells must be able to recognize self antigens to a certain degree. Developing thymocytes that do not have adequate affinity cannot serve useful functions in the body (i.e. the cells must be able to interact with MHC and peptide complexes in order to effect immune responses). Also, the thymocyte must be able to recognize antigens that are self from non-self.). Because of this, the thymocytes with no affinity for self antigens die by apoptosis and are engulfed by macrophages. A thymocyte's fate is also determined during positive selection. Double-positive cells (CD4 +/CD8+) that are positively selected on MHC class II molecules will eventually become CD4+cells, while cells positively selected on MHC class I molecules mature into CD8+ cells. A T cell becomes a CD4+ cell by downregulating expression of its CD8 cell surface receptors. If the cell does not lose its signal through the ITAM pathway, it will continue downregulating CD8 and become a CD4 +, single positive cell. But if there is
  • 19. signal drop, the cell stops downregulating CD8 and switches over to downregulating CD4 molecules instead, eventually becoming a CD8+, single positive cell. This process does not remove thymocytes that may cause autoimmunity. The potentially autoimmune cells are removed by the process of negative selection (discussed below). Negative selection Negative selection removes thymocytes that are capable of strongly binding with "self" peptides presented by MHC. Thymocytes that survive positive selection migrate towards the boundary of the thymic cortex and thymic medulla. While in the medulla, they are again presented with self-antigen in complex with MHC molecules on antigen-presenting cells (APCs) such as dendritic cells and macrophages. Thymocytes that interact too strongly with the antigen receive an apoptotic signal that leads to cell death. The vast majority of all thymocytes end up dying during this process. The remaining cells exit the thymus as mature naive T cells. This process is an important component of immunological tolerance and serves to prevent the formation of self-reactive T cells that are capable of inducing autoimmune diseases in the host. In summary, positive selection selects for T cells that are capable of recognizing self antigens through MHC. Negative selection selects for T cells that bind too strongly to self antigens. These two selection processes allow for Tolerance of self by the immune system. They do not necessarily occur in a chronological order and can occur simultaneously in the thymus. Maturation paradox Positive and negative selection should theoretically kill all developing T cells. The first stage of selection kills all T cells that do not interact with self-MHC, while the second stage selection kills all cells that do. This poses the question: How do we have immunity at all? Currently, two models attempt to explain this: 1. Differential Avidity Hypothesis - the strength of the signal dictates the fate of the T cell. The differential avidity hypothesis (or simply avidity hypothesis) is one of two models that attempt to explain how humans have immunity despite such aggressive selection (positive and negative) to kill developing T cells during their maturation process. The other model is the Differential Signaling Hypothesis. The Avidity hypothesis states that the affinity of the T-cell receptor for the MHC:peptide complex along with the density of the complex provide different signal strength upon binding which in terms dictate the outcome: 1. strong signal leads to negative selection and thus apoptosis. 2. weak signal leads to positive selection and thus rescued from apoptosis. 2. Differential Signaling Hypothesis - the signals that are transduced differ at each stage.
  • 20. The differential avidity hypothesis (or simply avidity hypothesis) is one of two models that attempt to explain how humans have immunity despite such aggressive selection (positive and negative) to kill developing T cells during their maturation process. The other model is the Differential Signaling Hypothesis. The Avidity hypothesis states that the affinity of the T-cell receptor for the MHC:peptide complex along with the density of the complex provide different signal strength upon binding which in terms dictate the outcome: 1. strong signal leads to negative selection and thus apoptosis. 2. weak signal leads to positive selection and thus rescued from apoptosis. Activation Although the specific mechanisms of activation vary slightly between different types of T cells, the "two- signal model" in CD4+ T cells holds true for most. Activation of CD4+ T cells occurs through the engagement of both the T cell receptor and CD28 on the T cell by the Major histocompatibility complex peptide and B7 family members on the APC, respectively. Both are required for production of an effective immune response; in the absence of CD28 co-stimulation, T-cell receptor signalling alone results in anergy. The signalling pathways downstream from both CD28 and the T cell receptor involve many proteins. The first signal is provided by binding of the T cell receptor to a short peptide presented by the major histocompatibility complex (MHC) on another cell. This ensures that only a T cell with a TCR specific to that peptide is activated. The partner cell is usually a professional antigen presenting cell (APC), usually a dendritic cell in the case of naïve responses, although B cells and macrophages can be important APCs. The peptides presented to CD8+ T cells by MHC class I molecules are 8-9 amino acids in length; the peptides presented to CD4+ cells by MHCclass II molecules are longer, as the ends of the binding cleft of the MHC class II molecule are open. The second signal comes from co-stimulation, in which surface receptors on the APC are induced by a relatively small number of stimuli, usually products of pathogens, but sometimes breakdown products of cells, such as necrotic-bodies or heat-shock proteins. The only co-stimulatory receptor expressed constitutively by naïve T cells is CD28, so co-stimulation for these cells comes from the CD80 and CD86proteins, which together constitute the B7 protein, (B7.1 and B7.2 respectively) on the APC. Other receptors are expressed upon activation of the T cell, such as OX40 and ICOS, but these largely depend upon CD28 for their expression. The second signal licenses the T cell to respond to an antigen. Without it, the T cell becomes anergic, and it becomes more difficult for it to activate in future. This mechanism prevents inappropriate responses to self, as self-peptides will not usually be presented with suitable co-stimulation. The T cell receptor exists as a complex of several proteins. The actual T cell receptor is composed of two separate peptide chains, which are produced from the independent T cell receptor alpha and beta (TCRα and TCRβ) genes. The other proteins in the complex are the CD3proteins: CD3εγ and CD3εδ heterodimers and, most important, a CD3ζ homodimer, which has a total of six ITAM motifs. The ITAM motifs on the CD3ζ can be phosphorylated by Lck and in turn recruit ZAP-70. Lck and/or ZAP-70 can also
  • 21. phosphorylate the tyrosines on many other molecules, not least CD28, , LAT and SLP-76, which allows the aggregation of signalling complexes around these proteins. Phosphorylated LAT recruits SLP-76 to the membrane, where it can then bring in PLCγ, VAV1, Itk and potentially PI3K. Both PLCγ and PI3K act on PI(4,5)P2 on the inner leaflet of the membrane to create the active intermediaries diacylglycerol (DAG), inositol-1,4,5-trisphosphate (IP3), and phosphatidlyinositol-3,4,5-trisphosphate (PIP3). DAG binds and activates some PKCs, most important, in T cells PKCθ, a process important for activating the transcription factors NF-κB and AP-1. IP3 is released from the membrane by PLCγ and diffuses rapidly to activate receptors on the ER, which induce the release of calcium. The released calcium then activates calcineurin, and calcineurin activates NFAT, which then translocates to the nucleus. NFAT is a transcription factor, which activates the transcription of a pleiotropic set of genes, most notable, IL-2, a cytokine
  • 22. that promotes long term proliferation of activated T cells. T cell activation B cell B cells are lymphocytes that play a large role in the humoral immune response (as opposed to the cell- mediated immune response, which is governed by T cells). The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells(APCs) and eventually develop into memory B cells after activation by antigen interaction. B cells are an essential component of the adaptive immune system.
  • 23. The abbreviation "B", in B cell, comes from the bursa of Fabricius in birds, where they mature. In mammals, immature B cells are formed in thebone marrow, which is used as a backronym for the cells' name. The cells of the immune system that make antibodies to invading pathogens like viruses. They form memory cells that remember the same pathogen for faster antibody production in future infections. B cells exist as clones. All B cells derive from a particular cell, and thus, the antibodies their differentiated progenies (see below) produce can recognize and/or bind the same components (epitope) of a given antigen. Such clonality has important consequences, as immunogenic memory relies on it. The great diversity in immune response comes about because there are up to 109 clones with specificities for recognizing different antigens. A single B cell or a clone of cells with shared specificity upon encountering its specific antigen divides to produce many B cells. Most of such B cells differentiate into plasma cells that secrete antibodies into blood that bind the same epitope that elicited proliferation in the first place. A small minority survives as memory cells that can recognize only the same epitope. However, with each cycle, the number of surviving memory cells increases. The increase is accompanied by affinity maturation which induces the survival of B cells that bind to the particular antigen with high affinity. This subsequent amplification with improved specificity of immune response is known as secondary immune response. B cells that encounter antigen for the first time are known as naive B cells. Development of B cells Immature B cells are produced in the bone marrow of most mammals. Rabbits are an exception; their B cells develop in the appendix-sacculus rotundus. After reaching the IgM+ immature stage in the bone marrow, these immature B cells migrate to the spleen, where they are called transitional B cells, and some of these cells differentiate into mature B lymphocytes. B cell development occurs through several stages, each stage representing a change in the genome content at the antibody loci. An antibody is composed of two identical light (L) and two identical heavy (H) chains, and the genes specifying them are found in the 'V' (Variable) region and the 'C' (Constant) region. In the heavy-chain 'V' region there are three segments; V, D and J, which recombine randomly, in a process called VDJ recombination, to produce a unique variable domain in the immunoglobulin of each individual B cell. Similar rearrangements occur for light-chain 'V' region except there are only two segments involved; V and J. The list below describes the process of immunoglobulin formation at the different stages of B cell development. When the B cell fails in any step of the maturation process, it will die by a mechanism called apoptosis, here called clonal deletion. B cells are continuously produced in the bone marrow. When B cell receptors on the surface of the cell matches the detected antigens present in the body, the B cell proliferates and
  • 24. secretes a free form of those receptors (antibodies) with identical binding sites as the ones on the original cell surface. After activation, the cell proliferates and B memory cells would form to recognise the same antigen. This information would then be used as a part of the adaptive immune system for a more efficient and more powerful immune response for future encounters with that antigen. B cell membrane receptors evolve and change throughout the B cell life span. TACI, BCMA and BAFF- R are present on both immature B cells and mature B cells. All of these 3 receptors may be inhibited by Belimumab. CD20 is expressed on all stages of B cell development except the first and last; it is present from pre-pre B cells through memory cells, but not on either pro-B cells or plasma cells. Immune Tolerance Like its fellow lymphocyte, the T cell, immature B cells are tested for auto-reactivity by the immune system before leaving the bone marrow. In the bone marrow (the central lymphoid organ), central tolerance is produced. The immature B cells whose B cell Receptors (BCRs) bind too strongly to self antigens will not be allowed to mature. If B cells are found to be highly reactive to self, three mechanisms can occur.  Clonal deletion: the removal, usually by apoptosis, of B cells of a particular self antigen specificity.  Receptor editing: the BCRs of self reactive B cells are given an opportunity to rearrange their conformation. This process occurs via the continued expression of the Recombination activating gene (RAG). Through the help of RAG, receptor editing involves light chain gene rearrangement of the B cell receptor. If receptor editing fails to produce a BCR that is less autoreactive, apoptosis will occur. Note that defects in the RAG-1 and RAG-2 genes are implicated in Severe Combined Immunodeficiency (SCID). The inability to recombine and generate new receptors lead to failure of maturity for both B cells and T cells.  Anergy: B cells enter a state of permanent unresponsiveness when they bind with weakly cross- linking self antigens that are small and soluble. Functions The human body makes millions of different types of B cells each day that circulate in the blood and lymphatic system performing the role of immune surveillance. They do not produceantibodies until they become fully activated. Each B cell has a unique receptor protein (referred to as the B cell receptor (BCR)) on its surface that will bind to one particular antigen. The BCR is a membrane-bound immunoglobulin, and it is this molecule that allows the distinction of B cells from other types of lymphocyte, as well as being the main protein involved in B cell activation. Once a B cell encounters its cognate antigen and receives an additional signal from a T helper cell, it can further differentiate into one of the two types of B cells listed below (plasma B cells and memory B cells). The B cell may either become one of these cell types directly or it may undergo an intermediate differentiation step, the germinal centerreaction, where the B cell will hypermutate the variable region of its immunoglobulin gene ("somatic hypermutation") and possibly undergo class switching. B cell types . Plasma B cells (also known as plasma cells) are large B cells that have been exposed to antigen and produce and secrete large amounts ofantibodies, which assist in the destruction of microbes by binding to them and making them easier targets for phagocytes and activation of thecomplement system. They are sometimes referred to as antibody factories. An electron micrograph of these cells reveals large amounts of rough endoplasmic reticulum, responsible for synthesizing the antibody, in the
  • 25. cell's cytoplasm. These are short lived cells and undergo apoptosis when the inciting agent that induced immune response is eliminated. This occurs because of cessation of continuous exposure to various colony stimulating factors required for survival.  Memory B cells are formed from activated B cells that are specific to the antigen encountered during the primary immune response. These cells are able to live for a long time, and can respond quickly following a second exposure to the same antigen.  B-1 cells express IgM in greater quantities than IgG and their receptors show polyspecificity, meaning that they have low affinities for many different antigens, but have a preference for other immunoglobulins, self antigens and common bacterial polysaccharides. B-1 cells are present in low numbers in the lymph nodes and spleen and are instead found predominantly in the peritoneal and pleural cavities.  B-2 cells are the conventional B cells. Marginal-zone B cells Marginal zone B cells are noncirculating mature B cells that segregate anatomically into the marginal zone (MZ) of the spleen. This region contains multiple subtypes ofmacrophages, dendritic cells, and the MZ B cells; it is not fully formed until 2 to 3 weeks after birth in rodents and 1 to 2 years in humans. The MZ B cells within this region typically express high levels of sIgM, CD21, CD1, CD9 with low to negligible levels of sIgD, CD23, CD5, and CD11b that help to distinguish them phenotypically from FO B cells and B1 B cells. Similar to B1 B cells, MZ B cells can be rapidly recruited into the early adaptive immune responses in a T cell independent manner. The MZ B cells are especially well positioned as a first line of defense against systemic blood-borne antigens that enter the circulation and become trapped in the spleen. MZ B cells also display a lower activation threshold than their FO B cell counterparts with heightened propensity for PC differentiation that contributes further to the accelerated primary antibody response Follicular B Cells Follicular B cells (FO B cells) are a type of B cell that reside in primary and secondary lymphoid follicles (containing germinal centers) of secondary and tertiary lymphoid organs, including spleen and lymph nodes. The mature B cells from the spleen can be divided into two main populations: the FO B cells, which constitute the majority, and the marginal zone B-cells, lining outside the marginal sinus and border the red pulp. FO B cells express high levels of IgM, IgD, and CD23; lower C21; and no CD1 or CD5, readily distinguishing this compartment from B1 B cells andmarginal zone B-cells . FO B cells organize into the primary follicles of B cell zones focused around follicular dendritic cells in the white pulp of the spleen and the cortical areas of peripheral lymph nodes. Multiphoton-based live imaging of lymph nodes indicate continuous movement of FO B cells within these follicular areas at velocites of ~6 µm per min. Recent studies indicate movement along the processes of FDC as a guidance system for mature resting B cells in peripheral lymph nodes. Unlike their MZ counterpart, FO B cells freely recirculate, comprising >95% of the B cells in peripheral lymph nodes. The BCR repertoire of the follicular B cell compartment also appears under positive selection pressures during final maturation in the spleen. However, diversity is substantially broader than B1 B and MZ B cell compartments. More importantly, FO B cells require CD40-CD40L dependent T cell help to promote effective primary immune responses and antibody isotype switch and to establish high-affinity B cell memory.
  • 26. Recognition of antigen by B cells A critical difference between B cells and T cells is how each lymphocyte recognizes its antigen. B cells recognize their cognate antigen in its native form. They recognize free (soluble) antigen in the blood or lymph using their BCR or membrane bound-immunoglobulin. In contrast, T cells recognize their cognate antigen in a processed form, as a peptide fragment presented by anantigen presenting cell's MHC molecule to the T cell receptor. Activation of B cells B cell recognition of antigen is not the only element necessary for B cell activation (a combination of clonal proliferation and terminal differentiation into plasma cells). B cells that have not been exposed to antigen, also known as naïve B cells, can be activated in a T cell-dependent or -independent manner.
  • 27. B cell activation T cell-dependent activation Once a pathogen is ingested by an antigen-presenting cell such as a macrophage or dendritic cell, the pathogen's proteins are then digested to peptides and attached to a class II MHC protein. This complex is then moved to the outside of the cell membrane. The macrophage is now activated to deliver multiple signals to a specific T cell that recognizes the peptide presented. The T cell is then stimulated to produce autocrines (Refer to Autocrine signalling), resulting in the proliferation and differentiation to effector and memory T cells. Helper T cells (i.e. CD4+ T cells) then activate specific B cells through a phenomenon known as an Immunological synapse. Activated B cells subsequently produce antibodies which assist in inhibiting pathogens until phagocytes (i.e. macrophages, neutrophils) or the complement system for example clears the host of the pathogen(s). Most antigens are T-dependent, meaning T cell help is required for maximal antibody production. With a T-dependent antigen, the first signal comes from antigen cross linking the B cell receptor (BCR) and the second signal comes from co-stimulation provided by a T cell. T dependent antigens contain proteins that are presented on B cell Class II MHC to a special subtype of T cell called a Th2 cell. When a B cell
  • 28. processes and presents the same antigen to the primed Th cell, the T cell secretes cytokines that activate the B cell. These cytokines trigger B cell proliferation and differentiation into plasma cells. Isotype switching to IgG, IgA, and IgE and memory cell generation occur in response to T-dependent antigens. This isotype switching is known as Class Switch Recombination (CSR). Once this switch has occurred, that particular B cell will usually no longer make the earlier isotypes, IgM or IgD. T cell-dependent B cell activation, showing a TH2-cell (left), B cell (right), and several interaction molecules T cell-independent activation Many antigens are T cell-independent in that they can deliver both of the signals to the B cell. Mice without a thymus (nude orathymic mice that do not produce any T cells) can respond to T independent antigens. Many bacteria have repeating carbohydrate epitopes that stimulate B cells, by cross-linking the IgM antigen receptors in the B cell, responding with IgM synthesis in the absence of T cell help. There are two types of T cell independent activation; Type 1 T cell-independent(polyclonal) activation, and type 2 T cell-independent activation (in which macrophages present several of the same antigen in a way that causes cross-linking of antibodies on the surface of B cells). The ancestral roots of B cells In an October 2006 issue of Nature Immunology, certain B cells of basal vertebrates (like fish and amphibians) were shown to be capable of phagocytosis, a function usually associated with cells of the innate immune system. The authors postulate that these phagocytic B cells represent the ancestral history shared between macrophages and lymphocytes. B cells may have evolved from macrophage-like cells during the formation of the adaptive immune system.
  • 29. B cells in humans (and other vertebrates) are nevertheless able to endocytose antibody-fixed pathogens, and it is through this route that MHC Class II presentation by B cells is possible, allowing Th2 help and stimulation of B cell proliferation. This is purely for the benefit of MHC Class II presentation, not as a significant method of reducing the pathogen load. B cell-related pathology Aberrant antibody production by B cells is implicated in many autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. 5.Monocyte Monocyte is a type of white blood cell, part of the human body's immune system. Monocytes have several roles in the immune system and this includes: (1) replenish resident macrophages and dendritic cells under normal states, and (2) in response to inflammationsignals, monocytes can move quickly (approx. 8-12 hours) to sites of infection in the tissues and divide/differentiate into macrophages and dendritic cells to elicit an immune response. Half of them are stored in the spleen. Monocytes are usually identified in stained smears by their large bilobate nucleus. Monocytes can be used to generate dendritic cells in vitro by adding cytokines like Granulocyte Monocyte Colony Stimulating Factor (GMCSF) and IL-4. Monocyte Physiology Monocytes are produced by the bone marrow from haematopoietic stem cell precursors called monoblasts. Monocytes circulate in the bloodstream for about one to three days and then typically move into tissues throughout the body. They constitute between three to eight percent of the leukocytes in the blood. Half of them are stored as a reserve in the spleen in clusters in the red pulp's Cords of Billroth. In the tissues monocytes mature into different types of macrophages at different anatomical locations. Monocytes which migrate from the bloodstream to other tissues will then differentiate into tissue resident macrophages or dendritic cells. Macrophages are responsible for protecting tissues from foreign substances but are also suspected to be the predominant cells involved in triggering atherosclerosis. They are cells that possess a large smooth nucleus, a large area of cytoplasm and many internal vesicles for processing foreign material. Monocytes and their macrophage and dendritic cell progeny serve three main functions in the immune system. These are phagocytosis, antigen presentation and cytokine production.Phagocytosis is the process of uptake of microbes and particles followed by digestion and destruction of this material. Monocytes can perform phagocytosis using intermediary (opsonising) proteins such as antibodies or complement that coat the pathogen, as well as by binding to the microbe directly via pattern-recognition receptors that recognize pathogens. Monocytes are also capable of killing infected
  • 30. host cells via antibody, termed antibody-mediated cellular cytotoxicity. Vacuolization may be present in a cell that has recently phagocytized foreign matter. Microbial fragments that remain after such digestion can serve as antigen. The fragments can be incorporated into MHC molecules and then traffic to the cell surface of monocytes (and macrophages and dendritic cells). This process is called antigen presentation and it leads to activation of T lymphocytes, which then mount a specific immune response against the antigen. Other microbial products can directly activate monocytes and this leads to production of pro-inflammatory and with some delay of anti-inflammatory cytokines. Typical cytokines produced by monocytes are TNF tumor necrosis factor, IL-1 interleukin-1and IL-12 interleukin-12. Monocyte subpopulations There are at least three types of monocytes in human blood : a) the classical monocyte is characterized by high level expression of the CD14 cell surface receptor (CD14++ CD16- monocyte) b) the non-classical monocyte shows low level expression of CD14 and with additional co-expression of the CD16 receptor (CD14+CD16++ monocyte). c) the intermediate monocyte with high level expression of CD14 and low level expression of CD16 (CD14++CD16+ monocytes). There appears to be a developmental relationship in that the classical monocytes develop into the intermediate monocytes to then become the non-classical monocytes CD14+CD16+ monocytes. Hence the non-classical monocytes may represent a more mature version. After stimulation with microbial products the CD14+CD16++ monocytes produce high amounts of pro-inflammatory cytokines like tumor necrosis factor and interleukin-12. Diagnostic use A monocyte count is part of a complete blood count and is expressed either as a ratio of monocytes to the total number of white blood cells counted, or by absolute numbers. Both may be useful in determining or refuting a possible diagnosis. Monocytosis Monocytosis is the state of excess monocytes in the peripheral blood. It may be indicative of various disease states. Examples of processes that can increase a monocyte count include:  chronic inflammation  stress response  hyperadrenocorticism  immune-mediated disease  infectious mononucleosis  pyogranulomatous disease  necrosis  red cell regeneration  Viral Fever  sarcoidosis
  • 31. A high count of CD14+CD16+ monocytes is found in severe infection (sepsis) and a very low count of these cells is found after therapy with immuno-suppressive glucocorticoids Monocytopenia Monocytopenia is a form of leukopenia associated with a deficiency of monocytes. (b) Mast cell A mast cell (or mastocyte) is a resident cell of several types of tissues and contains many granules rich in histamine andheparin. Although best known for their role in allergy and anaphylaxis, mast cells play an important protective role as well, being intimately involved in wound healing and defense against pathogens. Mast cells Localization Mast cells are found in connective tissues throughout the body,close to blood vessels and particularly areas of the respiratory ,urogenital and gastrointestinal tracks.It has large characteristic electron-dense granules in their cytoplasm,which are very important for their function.the origin of mast cell is uncertain but they probably also originate in the bone marrow. Classification Two types of mast cells are recognized, those from connective tissue and a distinct set of mucosal mast cells. The activities of the latter are dependent on T-cells. Mast cells are present in most tissues characteristically surrounding blood vessels and nerves, and are especially prominent near the boundaries between the outside world and the internal milieu, such as the skin, mucosa of the lungs and digestive tract, as well as in the mouth, conjunctiva, and nose. Physiology
  • 32. Mast cells play a key role in the inflammatory process. When activated, a mast cell rapidly releases its characteristic granules and various hormonal mediators into the interstitium. Mast cells can be stimulated to degranulate by direct injury (e.g. physical or chemical [such as opioids, alcohols, and certain antibiotics such as polymyxins]), cross-linking of Immunoglobulin E (IgE) receptors, or by activated complement proteins. Mast cells express a high-affinity receptor (FcεRI) for the Fc region of IgE, the least-abundant member of the antibodies. This receptor is of such high affinity that binding of IgE molecules is essentially irreversible. As a result, mast cells are coated with IgE. IgE is produced by Plasma cells (the antibody- producing cells of the immune system). IgE molecules, like all antibodies, are specific to one particular antigen. The role of mast cells in the development of allergy. In allergic reactions, mast cells remain inactive until an allergen binds to IgE already in association with the cell (see above). Other membrane activation events can either prime mast cells for subsequent degranulation or can act in synergy with FceRI signal transduction. Allergens are
  • 33. generally proteins or polysaccharides. The allergen binds to the antigen-binding sites, which are situated on the variable regions of the IgE molecules bound to the mast cell surface. It appears that binding of two or more IgE molecules (cross-linking) is required to activate the mast cell. The clustering of the intracellular domains of the cell-bound Fc receptors, which are associated with the cross-linked IgE molecules, causes a complex sequence of reactions inside the mast cell that lead to its activation. Although this reaction is most well understood in terms of allergy, it appears to have evolved as a defense system against intestinal worm infestations (tapeworms, etc.). The molecules thus released into the extracellular environment include:  preformed mediators (from the granules):  serine proteases, such as tryptase  histamine (2-5 pg/cell)  serotonin  proteoglycans, mainly heparin (active as anticoagulant)  newly formed lipid mediators (eicosanoids):  prostaglandin D2  leukotriene C4  platelet-activating factor  cytokines  Eosinophil chemotactic factor Histamine dilates post capillary venules, activates the endothelium, and increases blood vessel permeability. This leads to local edema(swelling), warmth, redness, and the attraction of other inflammatory cells to the site of release. It also irritates nerve endings (leading to itchingor pain). Cutaneous signs of histamine release are the "flare and wheal"-reaction. The bump and redness immediately following a mosquito bite are a good example of this reaction, which occurs seconds after challenge of the mast cell by an allergen. Structure of histamine The other physiologic activities of mast cells are much less well-understood. Several lines of evidence suggest that mast cells may have a fairly fundamental role in innate immunity – they are capable of elaborating a vast array of important cytokines and other inflammatory mediators such as TNFa, they express multiple "pattern recognition receptors" thought to be involved in recognizing broad classes of pathogens, and mice without mast cells seem to be much more susceptible to a variety of infections.[citation needed] Mast cell granules carry a variety of bioactive chemicals. These granules have been found to be transferred to adjacent cells of the immune system andneurons via transgranulation via their pseudopodia Role in disease
  • 34. Allergic disease Many forms of cutaneous and mucosal allergy are mediated for a large part by mast cells; they play a central role in asthma, eczema, itch (from various causes) and allergic rhinitis andallergic conjunctivitis. Antihistamine drugs act by blocking the action of histamine on nerve endings. Cromoglicate-based drugs (sodium cromoglicate, nedocromil) block a calcium channel essential for mast cell degranulation, stabilizing the cell and preventing release of histamine and related mediators. Leukotriene antagonists (such as montelukast andzafirlukast) block the action of leukotriene mediators, and are being used increasingly in allergic diseases. Anaphylaxis In anaphylaxis (a severe systemic reaction to allergens, such as nuts, bee stings or drugs), body-wide degranulation of mast cells leads to vasodilation and, if severe, symptoms of life-threatening shock.[citation needed] Autoimmunity Mast cells are implicated in the pathology associated with the autoimmune disorders rheumatoid arthritis, bullous pemphigoid, and multiple sclerosis. They have been shown to be involved in the recruitment of inflammatory cells to the joints (e.g. rheumatoid arthritis) and skin (e.g. bullous pemphigoid) and this activity is dependent on antibodies and complement components. Mast cell disorders Mastocytosis is a rare condition featuring proliferation of mast cells. It exists in a cutaneous and systemic form, with the former being limited to the skin and the latter involving multiple organs. Mast cell tumors are often seen in dogs and cats. (c)Phagocyte Phagocytes are the white blood cells that protect the body by ingesting (phagocytosing) harmful foreign particles, bacteria, and dead or dyingcells. Their name comes from the Greek phagein, "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek kutos, "hollow vessel". They are essential for fighting infections and for subsequent immunity. Phagocytes are important throughout the animal kingdom and are highly developed within vertebrates. One litre of human blood contains about six billion phagocytes. Phagocytes were first discovered in 1882 by Ilya Ilyich Mechnikov while he was studying starfish larvae. Mechnikov was awarded the 1908 Nobel Prize in Physiology or Medicine for his discovery. Phagocytes occur in many species; some amoebae behave like macrophage phagocytes, which suggests that phagocytes appeared early in the evolution of life. Phagocytes of humans and other animals are called "professional" or "non-professional" depending on how effective they are atphagocytosis. The professional phagocytes include cells called neutrophils, monocytes, macrophages, dendritic cells, and mast cells.The main difference between professional and non-professional phagocytes is that the professional phagocytes have molecules calledreceptors on their surfaces that can detect harmful objects, such as bacteria, that are not normally found in the body. Phagocytes are crucial in fighting infections, as well as in maintaining healthy tissues by removing dead and dying cells that have reached the end of their lifespan. During an infection, chemical signals attract phagocytes to places where the pathogen has invaded the body. These chemicals may come from bacteria or from other phagocytes already present. The phagocytes move by a method called chemotaxis. When phagocytes come into contact with bacteria, the receptors on the phagocyte's surface will bind to them. This binding will lead to the engulfing of the bacteria by the phagocyte. Some phagocytes kill the ingested pathogen with oxidants and nitric oxide. After phagocytosis, macrophages and dendritic cells can also participate in antigen presentation, a
  • 35. process in which a phagocyte moves parts of the ingested material back to its surface. This material is then displayed to other cells of the immune system. Some phagocytes then travel to the body's lymph nodes and display the material to white blood cells called lymphocytes. This process is important in building immunity. However, many pathogens have evolved methods to evade attacks by phagocytes. Methods of killing The killing of microbes is a critical function of phagocytes that is either performed within the phagocyte (intracellular killing) or outside of the phagocyte (extracellular killing). Simplified diagram of the phagocytosis and destruction of a bacterial cell Oxygen-dependent intracellular When a phagocyte ingests bacteria (or any material), its oxygen consumption increases. The increase in oxygen consumption, called arespiratory burst, produces reactive oxygen-containing molecules that are anti-microbial. The oxygen compounds are toxic to both the invader and the cell itself, so they are kept in compartments inside the cell. This method of killing invading microbes by using the reactive oxygen- containing molecules is referred to as oxygen-dependent intracellular killing, of which there are two types. The first type is the oxygen-dependent production of a superoxide, which is an oxygen-rich bacteria-killing substance. The superoxide is converted to hydrogen peroxide and singlet oxygen by an enzyme called superoxide dismutase. Superoxides also react with the hydrogen peroxide to produce hydroxyl radicals which assist in killing the invading microbe. The second type involves the use of the enzyme myeloperoxidase from neutrophil granules. When granules fuse with a phagosome, myeloperoxidase is released into the phagolysosome, and this enzyme uses hydrogen peroxide and chlorine to create hypochlorite, a substance used in domestic bleach. Hypochlorite is extremely toxic to bacteria.Myeloperoxidase contains a heme pigment, which accounts for the green color of secretions rich in neutrophils, such as pus and infected sputum.
  • 36. Oxygen-independent intracellular Phagocytes can also kill microbes by oxygen-independent methods, but these are not as effective as the oxygen-dependent ones. There are four main types. The first uses electrically charged proteins which damage the bacterium's membrane. The second type uses lysozymes; these enzymes break down the bacterial cell wall. The third type uses lactoferrins, which are present in neutrophil granules and remove essential iron from bacteria. The fourth type uses proteases and hydrolytic enzymes; these enzymes are used to digest the proteins of destroyed bacteria. Extracellular Interferon-gamma—which was once called macrophage activating factor—stimulates macrophages to produce nitric oxide. The source of interferon-gamma can be CD4+ T cells, CD8+ T cells, natural killer cells, B cells, natural killer T cells, monocytes, macrophages, or dendritic cells. Nitric oxide is then released from the macrophage and, because of its toxicity, kills microbes near the macrophage. Activated macrophages produce and secrete tumor necrosis factor. This cytokine—a class of signaling molecule— kills cancer cells and cells infected by viruses, and helps to activate the other cells of the immune system. In some diseases, e.g., the rare chronic granulomatous disease, the efficiency of phagocytes is impaired, and recurrent bacterial infections are a problem. In this disease there is an abnormality affecting different elements of oxygen-dependent killing. Other rare congenital abnormalities, such as Chediak-Higashi syndrome, are also associated with defective killing of ingested microbes. Role in apoptosis Apoptosis (pronounced /ˌæpəˈtoʊsɪs/ or /ˌæpəpˈtoʊsɪs/) is the process of programmed cell death (PCD) that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, loss of cell membrane asymmetry and attachment, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation. (See also Apoptosis DNA fragmentation.) Apoptosis differs from necrosis, in which the cellular debris can damage the organism. In an animal, cells are constantly dying. A balance between cell division and cell death keeps the number of cells relatively constant in adults. There are two different ways a cell can die: by necrosis or by apoptosis. In contrast to necrosis, which often results from disease or trauma, apoptosis—or programmed cell death—is a normal healthy function of cells. The body has to rid itself of millions of dead or dying cells every day, and phagocytes play a crucial role in this process. Dying cells that undergo the final stages of apoptosis display molecules, such as phosphatidylserine, on their cell surface to attract phagocytes. Phosphatidylserine is normally found on the cytosolic surface of the plasma membrane, but is redistributed during apoptosis to the extracellular surface by a hypothetical protein known as scramblase. These molecules mark the cell for phagocytosis by cells that possess the appropriate receptors, such as macrophages. The removal of dying cells by phagocytes occurs in an orderly manner without eliciting an inflammatory response and is an important function of phagocytes.
  • 37. Apoptosis—phagocytes clear fragments of dead cells from the body. Interactions with other cells Phagocytes are usually not bound to any particular organ but move through the body interacting with the other phagocytic and non-phagocytic cells of the immune system. They can communicate with other cells by producing chemicals called cytokines, which recruit other phagocytes to the site of infections or stimulate dormant lymphocytes. Phagocytes form part of the innate immune system which animals, including humans, are born with. Innate immunity is very effective but non-specific in that it does not discriminate between different sorts of invaders. On the other hand, the adaptive immune system of jawed vertebrates—the basis of acquired immunity—is highly specialized and can protect against almost any type of invader. The adaptive immune system is dependent on lymphocytes, which are not phagocytes but produce protective proteins called antibodies which tag invaders for destruction and prevent viruses from infecting cells. Phagocytes, in particular dendritic cells and macrophages, stimulate lymphocytes to produce antibodies by an important process called antigen presentation. What is opsonization? This is the process of making a microbes easier to phagocytose.Opsonization is a process in which pathogens are coated with a substance called an opsonin, marking the pathogen out for destruction by the immune system. Once a pathogen has been opsonized, it is killed via one of two mechanisms. The pathogen may be ingested and killed by an immune cell, or killed directly withoutingestion.
  • 38. The process of killing and ingesting a pathogen is called phagocytosis. Cells called phagocytes ingest the pathogens and then kill them by exposing them to toxic chemicals. The chemicals are stored in small membrane-bound parcels within the phagocytes, and these parcels are triggered to open when a phagocyte ingests a pathogen. Opsonization also leads to pathogen death in a second mechanism called antibody-dependent cellular cytotoxicity, in which immune cells directly kill pathogens without ingesting them. In this process, antibodiesact as opsonins, and then trigger immune cells called granulocytes. These cells then release toxic chemicals into the environment around the pathogens to kill them. In addition to killing pathogens, this process also causes tissue damage via inflammation. There are several different substances which may act as opsonins; all of these are proteins which are active in the immune system. Two antibody types called IgG and IgA are both opsonins. IgG is active in blood and tissues, and IgA is active in mucosal surfaces such as the airways, urogenital system, and gut. Several proteins which act in the complement system are also opsonins. The complement system is a cascade of reactions between a number of different proteins. The end result of the cascade is opsonization of pathogens, as well as direct pathogen killing via the formation of a protein complex which punctures holes in bacterial cell walls. Phagocytosis Phagocytosis (from Greek phago, meaning eating, cyte, meaning vessel, and osis meaning process) is the cellular process of engulfing solid particles by the cell membrane to form an internal phagosome by phagocytes and protists. Phagocytosis is a specific form ofendocytosis involving the vesicular internalization of solid particles, such as bacteria, and is, therefore, distinct from other forms of endocytosis such as the vesicular internalization of various liquids. Phagocytosis is involved in the acquisition of nutrients for some cells, and, in the immune system, it is a major mechanism used to remove pathogens and cell debris. Bacteria, dead tissue cells, and small mineral particles are all examples of objects that may be phagocytosed. The process is homologous to eating only at the level of single-celled organisms; in multicellular animals, the process has been adapted to eliminate debris and pathogens, as opposed to taking in fuel for cellular processes, except in the case of the Trichoplax.
  • 39. Phagocytosis in three steps: 1. Unbound phagocyte surface receptors do not trigger phagocytosis. 2. Binding of receptors causes them to cluster. 3. Phagocytosis is triggered and the particle is taken up by the phagocyte. In immune system Phagocytosis in mammalian immune cells is activated by attachment to Pathogen-associated molecular patterns (PAMPS), which leads toNF-κB activation. Opsonins such as C3b and antibodies can act as attachment sites and aid phagocytosis of pathogens. Engulfment of material is facilitated by the actin-myosin contractile system. The phagosome of ingested material is then fused with the lysosome, leading to degradation. Degradation can be oxygen-dependent or oxygen-independent.  Oxygen-dependent degradation depends on NADPH and the production of reactive oxygen species. Hydrogen peroxide andmyeloperoxidase activate a halogenating system, which leads to the destruction of bacteria.  Oxygen-independent degradation depends on the release of granules, containing proteolytic enzymes such as defensins, lysozyme, and cationic proteins. Other antimicrobial peptides are present in these granules, including lactoferrin, which sequesters iron to provide unfavourable growth conditions for bacteria. It is possible for cells other than dedicated phagocytes (such as dendritic cells) to engage in phagocytosis. In apoptosis Following apoptosis, the dying cells need to be taken up into the surrounding tissues by macrophages in a process called Efferocytosis. One of the features of an apoptotic cell is the presentation of a variety of intracellular molecules on the cell surface, such as Calreticulin, Phosphatidylserine (From the inner layer of the plasma membrane), Annexin A1, and oxidisedLDL. These molecules are recognised by receptors