Diseases of immunity By Dr. Tareni Das, Scientist, ICAR.pdf

DISEASES OF IMMUNITY
Dr. Tareni Das, Scientist, Division of Pathology, ICAR-IVRI, Izatnagar

Introduction
 Immune system is like a two-edged sword
 The various diseases of immunity are described under three headings
 (1) hypersensitivity reactions
 (2) autoimmune diseases
 (3) immunodeficiency diseases
Dr. Tareni Das, Scientist, Pathology, ICAR-IVRI, Izatnagar

Immune system

Mechanism
Barrier
Anatomic
• Mechanical barrier retards entry of microbes
• Acidic environment (pH 3–5) retards growth of microbes
Skin
• Normal flora compete with microbes for attachment sites
• Mucous entraps foreign microbes
• Cilia propel microbes out of body
Mucous membrane
Physiologic
• Body temperature/fever response inhibits growth of some pathogens
Temperature
• Acidic pH of stomach kills most undigested microbes
Low pH
• Lysozyme cleaves bacterial cell wall
• Interferon induces antiviral defences in uninfected cells
• Complement lyses microbes or facilitates phagocytosis
Chemical mediators
Phagocytic/endocytic barriers
• Various cells internalize (endocytosis) and break down foreign macromolecules
• Specialized cells (blood monocytes, neutrophils, tissue macrophages) internalize
(phagocytose), kill and digest whole organisms
Inflammatory barriers
• Tissue damage and infection induce leakage of vascular fluid containing serum protein
with antibacterial activity, leading to influx of phagocytic cells into the affected area
Summary of non-specific host-defense mechanisms for barriers of innate immunity

.
Humoral immunity, mediated by soluble antibody proteins
 Antibodies participate in immunity
 by directly neutralizing extracellular microbes
 by activating complement and certain effector cells (neutrophils and macrophages) to kill
microorganisms
Cellular immunity, mediated by lymphocytes
 T -lymphocytes or T -cells
 directly lyse (destroy) targets (achieved by cytotoxic T-cells)
 Arrange for the antimicrobial immune response of other cells by producing soluble protein
mediators called cytokines

.
 B-cells and their antibodies can
recognize and bind to intact
antigens (e.g., bacteria)
 T-cells can recognize only those
antigens which have been
processed (i.e., enzymatically
broken into smaller pieces) and
presented by antigen-presenting
cells such as macrophages and
dendritic cells to T -cells with
major histocompatibility complex
(MHC) molecules
 Natural killer (NK) cells are a
separate class of lymphocytes
that act as a first line of defense

T-Lymphocytes
 Thymus-derived, or T-cells mediate cellular immunity
 Essential for inducing the B-cell-derived humoral immunity
 T -cells constitute between 60% and 70% of the lymphocytes in circulating
blood
 Each T -cell is genetically programmed to recognize a specific processed
antigen (a peptide fragment) by means of a T-cell receptor (TCR)
 Expresses signalling proteins (CD3 proteins and zeta chains)
 CD4 is expressed on about 60% of mature T-cells (known as 'helper T-cells’)-
secrete soluble molecules (cytokines) that influence almost all other cells
 CD8 is expressed on about 30% of T-cells (known as 'cytotoxic T-cells’)-directly
killing virus-infected or tumour cells
 In humans, in normal healthy individuals, the CD4/CD8 ratio is 2:1

.
 CD4 T -cells are of two types with different functions determined by their
cytokines.
 Th1 CD4+ cells secrete cytokines that direct cell-mediated immune
responses, including macrophage and natural killer cell activation.
 These Th1 cytokines – interleukin-2 (IL-2) and interferon-gamma (IFN-gamma)
 Th2 (helper T 2) CD4+ cells secrete cytokines IL-4, IL-5, and IL-10 that
antagonize Th1 effects and/or promote certain aspects of humoral immunity

B-Cells
 B-Iymphocytes constitute 10% to 20% of the lymphocytes in human
blood, and 15% to 40% in domestic animals
 Stimulation by local infection leads to the formation of a central
zone of large, activated B-cells in follicles called a 'germinal
center
 After anti genic stimulation, B-cells form plasma cells that secrete
immunoglobulins (antibodies)
 B-cells recognize antigen through monomeric surface IgM (i.e.,
IgM consisting of only one subunit)-B-celI receptor (BCR)
 B-cell CD40 molecule binds to CD154 on activated T –cells:
essential for B-cell maturation and secretion of IgG, IgA, or IgE
 CD21 (also known as CR2 complement receptor) - another
important B-cell-associated co-stimulatory molecule

Macrophage
 Macrophages along with dendritic cells express class II MHC molecules
 Central role in the processing and presentation of antigen to CD4+ helper T-
cells
 Macrophages produce a large number of cytokines
 Macrophages phagocytose and ultimately kill microbes coated by antibody
and/ or complement
 Macrophages kill tumour cells by producing reactive oxygen metabolites (free
radicals), or by secretion of tumour necrosis factor (TNF)

Dendritic Cell
 Cells with dendritic morphology, having free dendritic (branching like a tree)
cytoplasmic processes
Dendritic cells (interdigitating dendritic cells)
 Non-phagocytic cells and express high levels of MHC class II and co-stimulatory
molecules (B7 - CD80, CD86),
 Widely distributed and occur in lymphoid tissues and in the interstitium of
 Many non-lymphoid organs, such as the heart and lungs
 Similar cells within the epidermis are called langerhans cells
 Best suited for presenting antigens to CD4+ T –cells
Follicular dendritic cells
 Present in the germinal centres of lymphoid follicles in the spleen and lymph
nodes
 Possess Fc receptors for IgG and effectively trap antigen bound to antibodies

Natural Killer (NK) Cells
 NK cells are larger granular lymphocytes
 Comprise 10% to 15% of peripheral blood lymphocytes
 Contain abundant azurophilic granules and can lyse (destroy) a variety of tumour
cells, virally infected cells, and some normal cells, without prior sensitization
 First line of defence
 NK cells do not have antigen-specific receptors; they have receptors that bind self
carbohydrates onto host cells to activate NK killing and other receptors that
recognize self MHC alleles to inhibit the killing of normal cells
 Morphologically, NK cells have the appearance of large granular lymphocytes with
neither T cell nor B cell antigen receptors
 NK cells do express CD16 (an Fc receptor for IgG) and CD56 (an NK-specific
adhesion molecule)
 NK cells are involved in a variety of immune reactions in the recognition and
killing of target cells utilizing direct and antibody-dependent cellular cytotoxicity
(ADCC) mechanisms
 NK cells also secrete cytokines and are an important source of interferon-gamma
(IFN-gamma)

Cytokines
 Cytokines are low molecular weight polypeptides (10 to 40 kD) that
are secreted by lymphocytes as well as by effector cells and APCs
 Short-acting soluble mediators
 Cytokines mediate their effects by binding to specific high affinity
receptors on target cells. For example, interIeukin-2 (IL-2) activates
T -cells by binding to IL-2 receptors (IL-2R)
 Cytokines produce their effects in three ways:
 Autocrine Effect: cytokines act on the same cell that produces them
i.e. IL-2 produced by activated T-cells promotes T-cell growth
 Paracrine Effect: cytokines affect other cells in their vicinity i.e IL-7
produced by marrow stromal cells promotes the differentiation of B-
cell progenitors (ancestors) in the bone marrow
 Endocrine Effect: cytokines affect cells systemically. i.e. IL-l and TNF
that produce the acute phase response during inflammation

.
 Cytokines can act in amplifying sequences i.e. TNF induces IL-l production,
which in turn drives IL-6 synthesis
 Same cytokines are produced by different cell types i.e. IL-l and TNF can be
produced by virtually any cell
 The effects of cytokines are pleiotropic-IL-2 -T-cell growth factor and
regulates the growth and differentiation of B-cells and NK cells
 Many cytokines may produce similar effects- IL-1 and TNF
 Cytokines may be antagonistic-interferon-gamma activates macrophages
while IL-10 prevents macrophage activation

General Classes of Cytokines
 Cytokines that mediate innate immunity: IL-I, TNF, IL-6, and type I interferons
Macrophages are the major source of these cytokines
 Cytokines that regulate lymphocyte growth, activation, and differentiation:IL-2,
IL-4, IL-5, IL-12, IL-15, and transforming growth factor-alpha (TGF-alpha)
 Cytokines that activate inflammatory cells: Interferon-gamma (a Th1 cytokine),
TNF lymphotoxin (TNF-beta), and migration inhibitory factor
Most of these cytokines are derived from T –cells
 Chemokines are cytokines that recruit inflammatory cells to sites of injury:
interleukin-8 a, monocyte chemoattractant protein I (MCP-I) and monocyte
inflammatory protein I alpha (MIP-I alpha)
 Cytokines that stimulate hematopoiesis: colony stimulating factors (CSFs)

Histocompatibility Molecules
 Main role of histocompatibility molecules is to bind peptide fragments of
foreign proteins (i.e., Antigens) for presentation to appropriate antigen-
specific T –cells
 Engaging KIRs on natural killer cells, MHC class I molecules prevent lysis of
normal cells by NK cells
 First detected on blood leukocytes

MHC-I
 MHC-I is composed of two different molecules: alpha chain and beta-
macroglobulin
 The extracellular portion of the alpha chain contains a cleft where foreign
peptides (i.e., antigens) bind to MHC molecules for presentation to CD8+ T-
cells
 MHC I molecules bind to antigens derived from proteins synthesized within the
cells (e.g., viral antigens)
 Because MHC I molecules are present on virtually all nucleated cells, virally
infected cells can be detected and lysed (destroyed) by cytotoxic T-cells

MHC-II
 Composed of two different molecules alpha and beta subunits
 Expressed mainly on antigen-presenting cells (monocytes,
macrophages, dendritic cells) and B-cells
 Vascular endothelial cells, fibroblasts, and renal tubular
epithelial cells, are induced to express MHC II by interferon-
alpha (IFN-alpha)
 MHC molecules bind to antigens derived from proteins
synthesized outside the cell, for example, those derived from
extracellular bacteria
 This allows CD4+ T -cells to recognize the presence of
extracellular pathogens and to organize a protective
cytokine-mediated response

Overview of humoral and cell-mediated arms of adaptive immunity

Cross regulation of
immunity

Hypersensitivity reaction
 A hypersensitivity reaction is defined as the altered reactivity to a specific
antigen that results in pathologic reactions upon the exposure of a sensitized
host to that specific antigen

Immediate hypersensitivity reaction/ TYPE-1
 This is a rapidly occurring reaction (within
minutes).
 It follows interaction of allergen (antigen)
with IgE antibody previously bound to the
surface of mast cells and basophils in a
sensitized host.
 Depending on the route of entry of
allergen, type I hypersensitivity may
occur as a local reaction or may end in a
fatal systemic disorder (anaphylaxis)

CD4+ cells (Th2)
play an extremely
important role
because the
cytokines secreted
by them (IL-4 and
IL-5 in particular)
cause Ig E
production by B-
cells, act as growth
factor for mast
cells, and recruit
and activate
eosinophils

MAST
CELL
 Mast cell-derived cytokines (TNF, IL-l, IL-4, IL-5,
and IL-6) and chemokines play an important role in
type I hypersensitivity reaction.
 They recruit and activate a variety of
inflammatory cells.
 TNF is an extremely powerful mediator for
leukocyte adhesion, emigration, and activation.
 IL-4 is also a mast cell growth factor and is
required for IgE synthesis by B-cells

Eosinophils in type 1 hypersensitivity
 Eosinophils are recruited by Eotaxin and other chemokines released from TNF-
activated epithelium
 Important effectors of tissue injury (i.e., Cells that carry out), in the late-
phase response. For example, eosinophils produce major basic protein and
eosinophil cationic protein, which are toxic to epithelial cells
 Leukotriene C4 and platelet-activating factor produced by eosinophils directly
activate mast cell mediator release
 The recruited cells increase and sustain the inflammatory response in the
absence of any additional antigen exposure

Clinical Manifestations
 Type I reaction may occur as a systemic disorder, or as a local reaction
 Within minutes of an exposure in a sensitized host pruritus (itchiness),
urticaria, and skin erythema appear
 Followed by profound respiratory difficulty caused by pulmonary
bronchoconstriction and aggravated by hypersecretion of mucus
 Musculature of the entire gastrointestinal tract may be affected. This may
cause vomiting, abdominal cramps, and diarrhoea
 Local reactions occur when antigen is confined to a particular site
 Susceptibility is genetically controlled
 Atopy is used to indicate familial predisposition to such localized
hypersensitivity reactions

TYPE-2 HYPERSENSITIVITY
 Type 2 hypersensitivity is mediated by
antibodies.
 These antibodies are directed against target
antigens on the surface of cells or other
tissue components.
 The antigens may be normal molecules
intrinsic to (i.e., part of) cell membranes or
extracellular matrix, or they may be
adsorbed (adhered) exogenous antigens,
such as a drug metabolite penicillin
 Transfusion reactions
 Haemolytic disease of the newborn
 Drug reactions
 Hypersensitivity to infectious diseases (
EIA, anaplasma, trypanosomes and babesia)
 Antibody-mediated cellular dysfunction-
myasthenia gravis

Transfusion reactions

Hemolytic disease of the newborn Human

Hemolytic disease of Foal

Type III hypersensitivity reactions
 Type III hypersensitivity is mediated by
the deposition of antigen-antibody
(immune) complexes.
 This is followed by complement
activation and accumulation of
neutrophils.
 Immune complexes can involve
exogenous antigens such as bacteria
and viruses, or endogenous antigens
such as DNA
 Pathogenic immune complexes either
form in the circulation, or form at
extravascular sites when antigen has
been deposited
 Systemic (Acute serum sickness or
Local (Arthus reaction)
 The most pathogenic complexes are
formed during antigen excess and are
small or of intermediate size.
 Status of the mononuclear phagocytic
system

 The ARTHUS REACTION is a localized area of tissue
necrosis that results from acute immune complex
vasculitis
 The reaction is produced experimentally by injecting
an antigen into the skin of a previously immunized
animal
 Antibodies against the antigen are therefore already
present in the circulation.
 Because of the excess of antibodies, immune
complexes are formed as antigen diffuses into the
vascular wall.
 These are precipitated at the site of injection,
especially within vessel walls, and trigger the
inflammatory reaction
 Accumulated neutrophils results in the release, or
generation of a variety of additional pro-inflammatory
substances like prostaglandins, vasodilator peptides, and
chemotactic substances as well as lysosomal enzymes
capable of digesting basement membrane, collagen,
elastin, and cartilage
 Tissue damage is also mediated by oxygen free radicals
produced

 Type IV hypersensitivity is mediated by
specifically sensitized T-cells rather
than antibodies
 It is of two basic types: (1) delayed
type hypersensitivity, initiated by CD4+
helper T -cells, and (2) direct cell
cytotoxicity, mediated by CD8+
cytotoxic T –cells
 Delayed hypersensitivity, Th1 type
CD4+ T -cells secrete cytokines which
recruit macrophages, the major
effector cells
 Cell-mediated cytotoxicity, cytotoxic
CD8+ T -cells themselves perform the
effector function

 Cytotoxic T -lymphocytes kill virus-infected cells
by two mechanisms: (1) perforin-granzyme-
dependent killing, and (2) Fas-Fas ligand-
dependent killing
 Perforins and granzymes are soluble mediators
contained in the lysosome-like granules of CTLs.
perforin makes holes in the plasma membrane of
target cells.
 First, a number of perforin molecules (between 12
and 18) combine and form a large molecule
through polymerization.
 This large molecule (membrane attack complex)
then inserts itself into the target cell and makes a
pore (a tiny opening).
 These pores allow water to enter into the cell,
resulting in osmotic lysis
 The lymphocyte granules also contain a variety of
proteases (proteolytic enzymes) called granzymes.
 These are delivered into the target cells through
the perforin pores. Once inside the cell,
granzymes activate target cell apoptosis
 Activated cytotoxic T -lymphocytes also express
Fas ligand (a molecule similar to TNF), which binds
to Fas on target cells which leads to apoptosis

Delayed
hypersensitivity

Tuberculin hypersensitivity reaction

Granulomatous inflammation
 It is a special form of delayed-type hypersensitivity.
 It is characterized by the formation of a granuloma (a
granular nodule), which occurs in response to persistent
and/or non-degradable antigens.
 The early perivascular CD4+ T -cell infiltrate is replaced
by macrophages within 2 to 3 weeks. These accumulated
macrophages show features of activation, that is, they
become large, flat, and eosinophilic and resemble
epithelial cells known as 'epithelioid cells’.
 The epithelial cells sometimes fuse under the influence
of certain cytokines (mainly interferon-gamma) to form
multi-nucleated giant cells
 A microscopic aggregate of epithelial cells,
characteristically surrounded by a collar (circular band)
of lymphocytes is called a 'granuloma'

TB GRANULOMA

 Foam cell formation in the
granuloma during the infection
with Mycobacterium tuberculosis
 Bacilli that reside within
macrophages overproduce lipids
such as trehalose dimycolates
(TDM) that consolidate as multi-
vesicular bodies and are
subsequently exocytosed to the
extracellular milieu
 Through the SRs and TLRs
exocytosed bodies are taken up
by macrophages that then
become foam cells

 Direct pathway is mediated by
antigen-presenting cells within
the graft recognizing major
histocompatibility complex
(MHC) molecules of the
recipient and are recognized by
CD4+ and CD8+ T lymphocytes.
 The indirect pathway is
mediated by graft antigens
presented by antigen-presenting
cells of the recipient that
activate CD4+ and CD8+ T
lymphocytes, resulting in a type
IV hypersensitivity reaction

Autoimmunity
 Autoimmunity is by definition a specific immune response to self-antigens.
 Autoimmunity reflects a loss of immunologic tolerance to self-tissue or cellular
antigens and is characterized by abnormal or excessive activity of self-reactive
immune effector cells.
 Autoimmunity can be organ specific, localized, or systemic.
 Autoimmunity can be mediated by both autoantibodies and by self-reactive T
lymphocytes.
 The etiology of most autoimmune diseases remains elusive, as they are often
multifactorial and have a genetic and an environmental component

Criteria for diagnosing an autoimmune
disease
 Direct proof such as the fact that the disease can be transferred through cells or
autoantibodies
 Indirect proof as in identifying the antigen, then isolating the homologous
antigen in an animal model, and reproducing the disease through administration
of the antigen
 Isolating self-reactive antibodies or T lymphocytes
 Circumstantial evidence such as familial occurrence, lymphocyte infiltrate, MHC
associations, and clinical improvement with immunosuppressive therapy.
 The complexity of autoimmune diseases is also supported by the fact that non
pathologic autoreactive T lymphocytes and antibodies can be found in normal
individuals.

IMMUNOLOGIC TOLERANCE
 Immunologic tolerance is defined as a failure of the immune system to respond to a specific antigen
after previous exposure to that antigen.
 It is an absence of a functional response rather than a lack of any response at all.
 The development of autoimmunity can be simply described as an escape from the mechanism by
which self-tolerance is maintained
 Central tolerance: deletion (removal) of $elf-reactive T-and B-lymphocytes during their maturation
in central lymphoid organs (thymus for T-cells; bone marrow for B-cells in mammals and bursa of
Fabricius in birds
 The killing of T-or B-cells that have the potential to react to self-antigen is called 'negative
selection' or 'clonal deletion'. It has been observed that up to 99% self-reactive B-cells are
destroyed through apoptosis in the bursa of Fabricius.
 The increased proliferation of cells that respond to foreign antigen is called positive selection
 Peripheral tolerance- Anergy, Regulatory T- cell, Activation induced cell death

Peripheral tolerance
 Anergy: Prolonged or irreversible inactivation of lymphocytes (not apoptosis)
 Activation of T -cells requires two signals. First is recognition by T -cells of antigen in association
with self-MHC molecules on APCs
 Second is a set of co-stimulatory signals (via B7 molecules) provided by the APCs
 If the second co-stimulatory signals are not delivered, the T -cell becomes anergic (unreactive)
 B-cells can also become anergic, if they encounter antigen in the absence of specific helper T –
cells
 Activation-induced cell death: Fas ligand is a membrane protein and is expressed mainly on
activated T -lymphocytes.
 Lymphocytes also express Fas, and Fas expression is markedly increased on activated T -cells.
 Binding of Fas by Fas ligand co-expressed (expressed together) on activated T -cells, suppresses
the immune response by inducing apoptosis
 Peripheral suppression by regulatory T-cells: IL-10 and transforming growth factor-beta (TGF-beta)

Mechanisms of Autoimmune Disease
 Breakdown of one or more mechanisms of self-tolerance can result in an
immunological attack on tissues and development of auto immune diseases
 Failure of activation-induced cell death-genetic defects in Fas or Fas ligand
 Breakdown of T-cell anergy-normal cells that do not usually express co stimulatory
molecules can be induced to do so. Such induction may occur after infections, or
where there is tissue necrosis and local inflammation
 Bypass of B-cell requirement for T-cell help- recognition of the modified self-antigens
(autoantigens) by helper T-cells that were not deleted. Such helper T -cells could then
cooperate with the B-cells, leading to the formation of autoantibodies
 Failure of T-cell-mediated suppression
 Molecular mimicry (resemblance): Antibodies to streptococcal M protein cross-react
with cardiac glycoproteins
 Polyclonal lymphocyte activation: Anergic (unreactive) clones are stimulated by
antigen-independent mechanisms i.e. bacterial lipopolysaccharide (endotoxin)
 Release of sequestered antigens (exposure of hidden antigens): Spermatozoa and ocular
antigens
 Exposure of cryptic (hidden) self-epitopes

Infection and Autoimmunity
 1. Viruses and other microbes, particularly certain bacteria like streptococci,
may share cross-reacting epitopes with self-antigens.
 2. Microbial antigens and autoantigens may become associated to form
immunogenic units and bypass T -cell tolerance, as described earlier.
 3. Some viruses and bacterial products are non-specific polyclonal B-cell or T-
cell mitogens and thus may induce formation of autoantibodies and/or break T-
cell anergy.
 4. Microbial infections with resulting tissue necrosis and inflammation can cause
up-regulation (increased expression) of co. stimulatory molecules on resting APCs
in tissue. This favor's a breakdown of T-cell anergy.
 5. Local inflammatory response may facilitate presentation of cryptic antigens.

Autoimmune diseases of domestic animals
 Auto immune thyroiditis-autoantibodies against thyroglobulin and a thyroid colloid
antigen
 Affected thyroids are infiltrated with plasma cells and lymphocytes to such an
extent that germinal centre formation may occur
 The infiltrating cells probably cause epithelial cell destruction through antibody-
dependent cell-mediated cytotoxicity (ADCC) and T-cell cytotoxicity
 Experimental allergic encephalomyelitis (EAE)-after administration of rabies
vaccines containing phenolized brain tissue to humans
 Equine recurrent uveitis or periodic ophthalmia-Leptospira interrogans
 Autoimmune Reproductive Disease- Autoantibodies to sperm may also be detected
in the serum of some animals following injury to the testes.
 Male dogs infected with Brucella canis
 Autoantibodies agglutinate and immobilize sperm

 Auto immune Skin Disease-autoantibodies against intercellular cement (desmoglein-3 )
in the skin
 (i) Pemphigus vulgaris- development of bullae (vesicles or blisters) around the
mucocutaneous junctions
 (ii) Pemphigus vegetans
 (iii) Pemphigus foliaceous,
 (iv) Pemphigus erythematosus

Auto immune Nephritis
 There are two immunopathogenic types of glomerulonephritis.
 In the immune-complex type (type III hypersensitivity), immune complexes
containing complement are deposited in a lumpy, granular fashion on
glomerular basement membranes (GBMs)
 Autoantibodies are produced against GBM antigens-deposited in a smooth,
linear fashion.
 Goodpasture's syndrome in humans

Auto immune Haemolytic Anaemia
 Autoantibodies to antigens on red blood cells cause their destruction and thus
induce autoimmune haemolytic anaemia (AIHA)
 The affected dogs show pallor (paleness), weakness, and lethargy accompanied by
fever, jaundice, and hepatomegaly.
 The destruction of red cells is due either to intravascular haemolysis through
complement, or more commonly, to removal of antibody-coated red cells by
macro phages in the spleen and liver
 In the dog, the disease is more common in females by a 2:1 ratio. The average
age of onset is around 4 to 5 years

Classification

Auto immune thrombocytopaenia
 Due to the development of antiplatelet
autoantibodies, has been reported in horses, dogs,
and cats.
 Affected animals show many petechiae in the skin,
gingiva, other mucous membranes and conjunctiva
 Epistaxis (nose bleeding) may occur and the dog
may show melena (blood in faeces) and haematuria
 Blood examination shows a severe
thrombocytopaenia.
 The main cause of death in these dogs is severe
gastrointestinal haemorrhage

Myasthenia gravis
 Myasthenia gravis (MC) in humans, dogs, and cats is a disease of skeletal
muscle characterized by abnormal fatigue and weakness after even mild
exercise.
 Failure of transmission of nerve impulses across the motor end plate of
striated muscle due to a deficiency of acetylcholine receptors.

Systemic Lupus Erythematosus
 Systemic lupus erythematosus (SLE) is a generalized immunological disorder that
has been described in humans, horses, dogs, and cats.
 SLE results from a loss of contact over the B-celI response. This leads to
polyclonal gammopathy and the production of autoantibodies against a great
range of normal organs or tissues which initiate a wide spectrum of pathological
lesions and clinical manifestations.
 Development of autoantibodies against antigens in the cell nucleus/ HISTONES
 Cause membranous glomerulonephritis, fibrinoid necrosis, arthritis etc.
 ANAs also bind to the nuclei of degenerating cells producing round or oval bodies
of DNA bound to antibody known as haematoxylin bodies. They are found in the
skin, kidney, lung, lymph nodes, spleen, and heart.
 Within the bone marrow these opsonized nuclei may be phagocytosed, giving rise
to lupus erythematosus (LE) cells

.
 Autoantibodies against red cells that cause haemolytic anaemia
 Antibodies against platelets that cause thrombocytopaenia
 Anti-lymphocytic antibodies interfere with immune regulation
 Anti-muscle antibodies cause myositis
 Anti myocardial antibodies cause myocarditis or endocarditis
 Antibodies against skin components cause dermatitis.

SLE
 Presentation of unknown antigens by MHC molecules leads
to priming of CD4 + T cells.
 These cells then help B cells in autoreactive germinal
centers undergo class switching, affinity maturation and
differentiation into plasma cells that secrete high levels of
soluble autoantibodies of the IgG isotype.
 These autoantibodies form immune complexes by binding
autoantigens, and fix complement or engage Fcγ receptors
on several different cell types.
 This can support inflammation and tissue destruction
through the recruitment of inflammatory cells to tissues.
 Apoptotic cells from damaged tissues can be taken up by
phagocytes, which present novel autoantigens, supporting
further priming and autoreactivity.
 Engagement of TLRs by environmental triggers such as viral
infection or DNA damage by UV rays contribute to the
process by inducing the secretion of IFN-I and other
cytokines, supporting lymphocyte autoreactivity as well as
tissue destruction.

SJogren’s Syndrome
 Autoimmune attack on salivary and lachrymal glands leads to the
conjunctival dryness (kerato-conjunctivitis sicca) and mouth dryness
(xerostomia)

Dermatomyositis
 Dermatomyositis is an inflammatory disease of the skin, muscles, and vasculature
affecting primarily young dogs
 Characterized by alopecia and erythematous dermatitis that involve the face,
ears, and bony prominences of the distal extremities.
 Erosions and ulcers are common early in the disease and scarring and pigmentary
changes are seen in chronic case
 Histopathologically, degeneration and necrosis of basal cells of the epidermis and
follicular epithelium are characteristic. Frequently, vacuolation of the basal
epithelium leads to subepidermal cleft formation.
 Infiltration of the superficial dermis is often composed of lymphocytes, plasma
cells, and macrophages with fewer mast cells and neutrophils.
 Follicular atrophy and secondary ulceration and fibrosis can also be noted.
 The skeletal muscle manifestations of the disease are a myositis composed of a
variable infiltrate of primarily mononuclear inflammatory cells and occasional
neutrophils.
 There are varying degrees of myofiber degeneration characterized by myofiber
fragmentation, vacuolation, and hyalinization.
 In chronic cases, there may be fibrosis and evidence of myofiber regeneration

Immune vasculitis
 Vasculitis is inflammation of the walls of blood vessels.
 In these instances, the pathogenesis involves a type III hypersensitivity
reaction with the formation of immune complexes that are either formed in
the vessel wall or formed in the circulation and lodge in the vessel wall

Rheumatoid Arthritis
 This is the commonest immune-mediated erosive polyarthritis.
 Its major symptoms are systemic joint swelling, pain, and disability.
 RA is characterized by proliferative synovitis causing cartilage and bone
destruction.
 Two autoantigens involved may be IgG and TYPE-II collagen. The
development of autoantibodies against IgG is characteristic of RA. These
autoantibodies are called 'rheumatoid factors, RFs'. They can belong to any
immunoglobulin class including IgE, but IgG RFs are the most common
 During the active phase of RA, pannus forms at the site where synovial cells
have proliferated.
 The inflamed synovium comprises T-cells, synovial fibroblasts, and
macrophages that produce inflammatory cytokines, such as TNF-α, IL-1, IL-6,
IL-17, and macrophage colony-stimulating factor (M-CSF).
 These inflammatory cytokines activate osteoclasts, leading to bone
destruction

.
 In RA, there is an excessive immune response of T-cells. CD4+ T-cells consist
of T-helper (Th) cells that promote the immune responses and regulatory T-
cells (Treg) that regulate these immune responses.
 Th cells have subsets such as Th1, Th2, and Th17 cells. Th17 cells play an
important functional role in phlogistic action.
 Naive T-cells differentiate into Th17 cells through IL-1β, IL-6, IL-21, and
transforming growth factor-β (TGF-β).
 IL-17 produced by Th17 activates inflammation by acting on various immune
cells and activates osteoclasts by inducing the receptor activator of nuclear
factor kappa B ligand (RANKL) in synovial fibroblasts.

Pathology of rheumatoid arthritis (RA) and the
mechanism of cartilage and bone destruction
 RA is characterized by proliferative synovium (pannus) and an excessive immune response of T-cells.
Pannus comprises T-cells, synovial fibroblasts, and macrophages that produce inflammatory cytokines,
such as tumor necrosis factor (TNF)-α, interleukin-1 (IL-1), IL-6, and IL-17.
 These inflammatory cytokines activate osteoclasts, leading to bone destruction. T-helper (Th) cells
have subsets such as Th1, Th2, and Th17 cells. Naive T-cells differentiate into Th17 cells through IL1β,
IL-6, IL-21, and transforming growth factor-β (TGF-β).
 Th17 cells produce IL-17 that activates inflammation by acting on various immune cells and activates
osteoclasts by inducing the receptor activator of nuclear factor kappa B ligand (RANKL) in synovial
fibroblasts. IFN-γ, IL-4, and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), produced by Th1,
Th2, and Treg, respectively, regulate osteoclast differentiation.
 Cartilage destruction is caused by matrix metalloproteinase (MMP) and a disintegrin and
metalloproteinase with thrombospondin motifs (ADAMTS) produced by chondrocytes, synovial
fibroblasts, and synovial macrophages.

Primary immunodeficiency
diseases
 Most primary immunodeficiency diseases are the
result of a genetic defect (inherited or congenital)
and affect specific (i.e.,humoral and cell-mediated
arms of the adaptive immune response) or
nonspecific immunity (i.e.,components of innate
immune responses, such as complement,
phagocytosis, NK cells, etc.).
 Specific defects in adaptive immune responses
can be divided into those affecting T lymphocytes
or B lymphocytes or both

SEVERE COMBINED IMMUNODEFICIENCY DISEASE
 Severe combined immunodeficiency disease (SCID) is a family of genetic defects that have in
common deficiencies in both humoral and cell-mediated immunity.
 In its extreme form, SCID results from a defect in the common lymphoid stem cell that results in
defective cell-mediated and humoral immune responses.
 More commonly, SCID defects affect either T lymphocytes or B and T lymphocytes and are best
characterized in humans, mice, dogs, and horses.
 T-Iymphocyte defects often clinically have a combined immunodeficiency because there is a
secondary impairment of humoral immunity that is the result of an inability of the T lymphocyte
to provide the necessary signals for B-Iymphocyte activation.
 These defects result in an inability to generate a specific immune response and can have an
autosomal recessive, X-linked, or sporadic inheritance pattern

.
 Often the most common infectious manifestation of SCID is a viral or fungal
infection.
 Immunity to viral and fungal infections is largely dependent on cell-mediated
immunity.
 Immunity to most bacterial infections (especially extracellular bacteria) are
largely dependent on humoral immunity, and neonates have adequate
humoral immunity from the passive transfer of maternal antibodies that
protect them.
 SCID in horses is an autosomal recessive disorder described in the Arabian or
Arabian-cross breed results in a severe lymphopenia (less than lOOO/mm3)
attributed to an inability to produce functional T and B lymphocyte
 Recurrent infections are typical and death is commonly the result of infection
with equine adenovirus, Pneumocystis carinii, Cryptosporidium parvum

.
 Grossly the thymus is small and maybe undetectable.
 Microscopically, there is profound lymphoid hypoplasia of primary and
secondary lymphoid tissue.
 Thymuses contain small lobules with no corticomedullary differentiation, few
lymphocytes, Hassall’s corpuscles, and occasional cysts.
 Spleens are characterized as having no lymphoid follicles, peri arteriolar
lymphoid sheaths, or plasma cells.
 Additionally, it has been noted that the lymphoid follicle sites in the spleen
lack connective tissue stroma, and this characteristic can be used to
differentiate hypoplasia from atrophy.
 Lymph nodes lack lymphoid follicles, plasma cells, and corticomedullary
differentiation.
 DNA-dependant protein kinase (DNA-PK) is required for the recombination of
immunoglobulin heavy chain and TCR genes during development, which when
defective results in an inability to form functional V regions

XSCID
 SCID in dogs was first described in Basset hounds as an X-linked defect (XSCID)
characterized by lymphopenia, with increased numbers of B lymphocytes and few
to no T lymphocytes.
 Decrease in the number of circulating CD8+ lymphocytes
 Hypogammaglobulinemia with normal serum IgM concentrations and decreased
concentrations of IgG and IgA
 At necropsy, lymph nodes, tonsils, Peyer’s patches, and the thymus are extremely
small
 Thymuses of affected puppies are small (approximately 10%the weight of age-
matched controls) and are characterized by a lack of corticomedullary
demarcation and small lobules with few to no lymphocytes
 Canine XSCID is due to a mutation in the common gamma (y-subunit of the IL-2, IL-
4, IL-7, IL-9, and IL-15 receptors
 T lymphocytes are nonfunctional due to an inability to express a functional IL-2
receptor
 An autosomal recessive form of SCID has been described in Jack Russell terriers
that is the result of a mutation in DNA-PKcs

COMMON VARIABLE IMMUNODEFICIENCY
 Onset of hypogammaglobulinemia attributed to an intrinsic B-Iymphocyte
defect, which results in an inability to produce much of the antibody in a
litter of miniature Dachshund dogs
 Absence of B lymphocytes in lymphoid tissues and little to no serum
immunoglobulins. At necropsy, the affected animals had lesions characterized
as atrophy of lymphoid tissue and pneumonia.
 Lymph nodes were further characterized as lacking lymphoid follicles.
 The pneumonia was caused by Pneumocystis carinii, a common opportunistic
pathogen in immunocompromised animals and humans.

AGAMMAGLOBULINEMIA
 Agammaglobulinemia is a primary immunodeficiency characterized by an
inability to produce immunoglobulins and an absence of mature B
lymphocytes and plasma cells.
 Microscopically, there was an absence of plasma cells, primary follicles, and
germinal centers in lymph nodes.
 In humans there is a mutation of the BTK (Bruton's tyrosine kinase) gene
located on the X chromosome that encodes a tyrosine kinase that results in an
arrest of B-Iymphocyte development at the pre-B stage.
 The disease in humans is referred to as X-linked agammaglobulinemia (XIA)

SELECTIVE IMMUNOGLOBULIN DEFICIENCY
 Selective IgM deficiency and selective IgA deficiency, characterized by a
serum level of IgM or IgA, respectively, that is at least 2 standard deviations
below normal
 Serum concentrations of other classes of immunoglobulin are normal, and B
lymphocyte numbers are normal

Thymic hypoplasia
 Thymic hypoplasia represents a number of immunodeficiency diseases
characterized by a failure to develop a functional thymus, resulting in a T-
Iymphocyte deficiency.
 Mice homozygous for the genetic trait nu (nu/nu) are hairless, and this
athymic strain is commonly referred to as the nude mouse.
 Nude mice have defective cell-mediated immune responses and are unable to
develop antibody responses. The immunologic abnormalities are attributed to
a deficiency of T-lymphocyte responses
 The few circulating T lymphocytes in affected mice have TCRs of the "γ/δtype
rather than the α/β type

DiGeorge syndrome
 DiGeorge syndrome is a T lymphocyte deficiency resulting from an
embryologic defect affecting the development of the third and fourth
pharyngeal pouches.
 Affected humans have thymic (fourth pharyngeal pouch) and parathyroid
(third pharyngeal pouch) defects.
 They have decreased circulating T lymphocytes, and T-Iymphocyte areas of
lymphoid tissue

DEFICIENCIES OF THE COMPLEMENT
SYSTEM
 Although a deficiency of C2 is the most common, humans with deficiencies in
components of the classical pathway have little to no increased risk for
infections, suggesting that the alternative and lectin pathways of activation
are sufficient for controlling infections.
 Deficiencies of the classical pathway components are associated with an
increased incidence of SLE-like autoimmune disease, which has been
attributed to impaired clearance of immune complexes by the monocyte-
macrophage system
 A deficiency of C3, which is required for all three pathways of complement, is
the most serious deficiency and results in serious recurrent infection

Porcine dense deposit disease
 An autosomal recessive trait resulting in a deficiency of factor H, a component of the
alternative pathway of complement, has been described in the Norwegian Yorkshire
breed of pig.
 Factor H is a regulator of complement activation that blocks the formation ofC3
convertase and is a cofactor for cleavage of C3b by factor I.
 Deficiencies of factor H result in unregulated elaboration of C3b upon activation of the
alternative pathway.
 The most common clinical manifestation is renal disease.
 Affected pigs develop a type II membranoproliferative glomerulonephritis
characterized by glomerular changes consisting of thickened capillary walls,
proliferation of mesangial cells, dense intramembranous deposits, and glomerular
deposits of C3 components.

CI inhibitor deficiency
 C1 inhibitor deficiency is an autosomal dominant trait that causes hereditary
angioedema.
 C1 inhibitor is a protease inhibitor that targets C1r and C1s enzymes of the
classical pathway of complement, Hageman factor (factor XII) of the
coagulation pathway, and the kallikrein system.
 These three pathways are closely linked and result in the elaboration of
vasoactive amines, notably bradykinin.
 Affected human patients develop episodes of edema involving the skin and
mucosal membranes, such as those of the larynx and gastrointestinal system

CHEDIAK-HIGASHI SYNDROME
 Chediak-Higashi syndrome is an inherited disease caused by defective lysosomes,
melanosomes, platelet dense granules, and cytolytic granules
 The hallmark of the disease is the presence of enlarged granules within melanocytes,
neutrophils, eosinophils, and monocytes.
 The enlarged granules are melanosomes (melanocytes), lysosomes (many cell types), or
cytoplasmic granules (e.g., fused primary and secondary granules of neutrophils).
 Neutrophils containing giant granules have impaired functions, such as defective
chemotaxis and intracellular killing. NK cells are also defective
 The hypopigmentation is the result of an inability of melanocytes, containing
abnormally large melanosomes, to migrate and release their contents, resulting in a
deficiency of pigment most commonly evident in the skin, hair, and eye.
 The bleeding tendency is a coagulopathy resulting from defective platelets.
 Platelet counts are generally normal. In most species studied, most recently cattle,
there is insufficient platelet aggregation because of a decreased response to collagen
 Mutation of the Lyst gene/ lysosomal trafficking regulator
 The Lyst gene encodes a membrane-associated protein, which is thought to regulate
intracellular protein trafficking

Leukocyte adhesion deficiency (LAD)
 Leukocyte adhesion deficiency (LAD) is a primary immunodeficiency disease
characterized by the inability of leukocytes to migrate from circulation into sites of
inflammation, resulting in recurrent bacterial infections
 Profound leukocytes is characterized by a marked neutrophilia
 The molecular basis for the disease is a defective expression of the β 2 integrin
subunit of a large group of heterodimeric (α and β-subunits) leukocyte adhesion
molecules
 In LAD type~l, there is a defect in the biosynthesis of the beta chain shared by LFA~l
and Mac~l integrins that mediate leukocyte endothelial adhesion (
 LAD type-2 is caused by the absence of sialyl-Lewis X, the ligand for .E-selectin, due
to a generalized defect in fucose metabolism.

SECONDARY IMMUNODEFICIENCIES
 Viral diseases
 Infectious bursal disease
 HIV-productive infection of T-cells is the mechanism by which HIV causes CD4+ T -
cell depletion
 Macrophages are quite resistant to cytopathic effects of HIV
 Initial infection of macrophages (or dendritic cells) is critical for HIV transmission
 When CD4+ T -cells are massively lost, macrophages remain a major site of
continued viral replication
 CD
 ASF
 BVD
 EQUINE HERPESVIRUS
 FELINE PANLEUKOPAENIA
 FELINE LEUKAEMIA
 FID, BIV, CIV

.
 Microbial and parasitic infections: Toxoplasma, trypanosomes, Trichinella spiralis,
Demodex, Pasteurella haemolytica
 Toxin-induced immunosuppression:dieldrin, iodine, lead, cadmium, methyl mercury,
and DDT, T -2 toxin, Aflatoxins, Ochratoxins
 Malnutrition and the immune response:
 Starvation rapidly induces thymic atrophy and a reduction in the level of thymic
hormones
 Reduce T -cell function and therefore impair cell-mediated responses
 Depressed complement levels and impairment of neutrophil and macrophage
chemotaxis, the respiratory burst, release of lysosomal enzymes, and microbicidal
activity
 Some B vitamins, vitamin A, and polyunsaturated fatty acids -depress
immunoglobulin levels through effects on regulatory T –cells
D Tareni Das, Scientist, Pathology, ICAR-IVRI, Izatnaga

. Magnesium deficiency-B-Cell
 Vitamin E deficiency- decreased lymphocyte blastogenesis
 Deficiencies of vitamin A, vitamin B12, and folic acid -depress cell-mediated
immune responses
 Vitamin D –macrophage development
 Zinc-deficient pigs - reduced thymus weight, depressed cytotoxic T-cell
activity, depressed B-cell activity, and depressed NK cell activity
 Copper deficiency -reduce neutrophil numbers and function, reduce
responsiveness to mitogens, reduce T and NK cell numbers, and increase
mast cell histamine release
 Selenium deficiency- reduces neutrophil activity, T-cell blastogenesis, and
IgM production
 Chromium supplementation - increase immune function

.
 Exercise and the Immune Response
 Regular moderate exercise increases immune function
 Strenuous exercise is stressful due to raised steroid levels due to stress
 Trauma and the Immune Response
 Corticosteroids, prostaglandins from damaged tissues, and a small protein
called suppressive active peptide-immunosuppressive properties
 Age and the Immune Response
 Both cell-mediated and humoral immune responses decrease with advancing
age
 Animal ages- significant drop in the numbers of CD4+ cells as a result of
thymic involution
 Aged macrophages show reduced cytokine production and responses to
activating agents such as interferon-gamma
 Young animals- immaturity of the immune system

Diseases of immunity By Dr. Tareni Das, Scientist, ICAR.pdf

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