This document provides an overview of basic immunology. It begins with an introduction to immunity, the immune system, and immunology. It then discusses the history of immunology, types of immunity including innate and acquired immunity. It describes the tissues and cells involved in immunity. It covers basic aspects like antigens, antibodies, antigen-antibody reactions, and the complement system. It also discusses major histocompatibility complex, cytokines, immune disorders, and immune responses in periodontal pathogenesis.
2. ⢠Introduction
⢠History
⢠Types of immunity
⢠Tissues of immunity
⢠Cells of immunity
⢠Basic aspects of immunology
⢠Major histocompatibility complex
⢠Cytokines
⢠Disorders of immune system
⢠Immune responses in periodontal pathogenesis
⢠Periodontal vaccine
⢠Host modulation
⢠Conclusion
⢠References
CONTENTS
3. INTRODUCTION
ďź Immunity: resistance to disease, specifically infectious disease.
ďź Immune system: The collection of cells, tissues, and molecules that
mediate resistance to infections.
ďź Immune response: the coordinated reaction of these cells and
molecules to infectious microbes.
ďź Immunology: the study of the immune system, including its
responses to microbial pathogens and damaged tissues and its role
in disease.
4. Traditional concept:
Immunity refers to protection against infectious
diseases.
Modern concept:
Immunity is a function of which an individual
recognizes and excludes antigenic foreign substances.
It is normally beneficial, but sometimes, it is injurious.
5. â˘1796 â First demonstration of smallpox vaccination (Edward Jenner)
â˘1862 â Phagocytosis (Ernst Haeckel)
â˘1877 â Mast cells (Paul Ehrlich)
â˘1883 â 1905 â Cellular theory of immunity via phagocytosis by
macrophages and microphages (polymorphonuclear leukocytes) (Elie
Metchnikoff)
â˘1890 â Demonstration of antibody activity against diphtheria and tetanus
toxins. Beginning of humoral theory of immunity - Emil von Behring and
Kitasato ShibasaburĹ
â˘1900 â Antibody formation theory (Paul Ehrlich)
HISTORY
6. ⢠1965 â Discovery of "immune interferon" (gamma interferon) (E.F.
Wheelock)
⢠1971 â Peter Perlmann and Eva Engvall at Stockholm University
invented ELISA
⢠1973 â Dendritic Cells first described by Ralph M. Steinman
⢠1975 - Discovery of Natural Killer cells (Rolf Kiessling, Eva Klein,
Hans Wigzell)
⢠1980-1983 â Discovery and characterization of interleukins (IL-1 IL-
2 ) (Robert Gallo, Kendall A. Smith, Tadatsugu Taniguchi)
⢠1985 â Identification of Toll-like receptors (Christiane Nusslein
Volhard)
⢠2000 - Characterization of M1 and M2 macrophage subsets
by Charles Mills
8. TYPES OF IMMUNITY
INNATE IMMUNITY:
Non-specific:
⢠Species
⢠Racial
⢠Individual
Specific:
⢠Species
⢠Racial
⢠Individual
ACQUIRED IMMUNITY:
Active immunity:
⢠Natural
⢠Artificial
Passive immunity:
⢠Natural
⢠Artificial
9. ⢠Resistance to infections which, an individual possesses by virtue
of his genetic and constitutional make-up.
⢠Not affected by prior contact with microorganisms or
immunization.
⢠Nonspecific - when it indicates a degree of resistance to
infections in general.
⢠Specific - where resistance to a particular pathogen is
concerned.
Innate or native immunity:
10. ⢠Species immunity:
refers to the total or relative refractoriness, to a pathogen,
shown by all members of a species.
⢠Racial immunity:
Within a species, different races may show differences in
susceptibility to infections. Such racial differences are
known to be genetic in origin,
⢠Individual immunity:
The differences in innate immunity exhibited by different
individual in a race.
11. Factors influencing the level of innate immunity:
Innate
Immunity
Age
Hormonal
influence
Nutrition
12. Mechanisms of innate immunity:
ď Epithelial surfaces:
ď Antibacterial substances in blood and tissues:
⢠Complement system
⢠Beta-lysine
⢠Basic polypeptides- leukins, plakins
⢠Acidic substances like lactic acid
⢠Enzymes - lactoperoxidase, lysozymes
⢠Interferons
14. ď Inflammation:
ď Fever:
A rise of temperature following infection is a natural defense
mechanism.
Accelerates the physiological processes and destroy the infecting
pathogens.
Stimulates the production of interferon. and aids recovery from
viral infections.
15. ď Acute phase proteins:
⢠Infection or injury leads to a sudden increase in plasma
concentrations of certain proteins.
⢠These include:
ďź C reactive protein (CRP),
ďź Mannose binding protein,
ďź Alpha-1-acid glycoprotein,
ďź Serum amyloid P component etc.,
⢠Activate the alternative pathway of complement.
⢠Enhance host resistance, prevent tissue injury and promote
repair of inflammatory lesions.
16. Acquired Immunity:
⢠The resistance that an individual acquires during life is known as
acquired Immunity.
⢠also known as adaptive immunity as it represents an adaptive
response of the host to a specific pathogen or other antigen.
⢠Types:
17. Comparison of active and passive immunity:
Active immunity: Passive immunity:
Produced actively by host's immune
system.
Received passively. No active host
participation.
Induced by infection or by
immunogens.
Readymade antibody treatment.
Durable effective protection. Transient, less effective.
Immunity effective only after lag
period.
Immediate immunity.
Immunological memory present. No memory.
Booster effect on subsequent dose. Subsequent dose less effective.
Negative phase may occur. No negative phase.
Not applicable in the
immunodeficient.
Applicable in immunodeficient.
21. TISSUES OF IMMUNE SYSTEM
⢠The tissues of the lymphoid organs can be classified into:
1. Central / primary lymphoid organs
2. Peripheral / secondary lymphoid organs
⢠Central lymphoid organs:
Lymphoepithelial structures in which the precursor lymphocytes
proliferate, develop and acquire immunological capability.
A. Thymus
B. Bone marrow
⢠Peripheral lymphoid organs:
After acquiring immunocompetence, the lymphocytes migrate
along blood and lymph streams, accumulate in the peripheral
lymphoid organs and following antigenic stimulus, effect the
appropriate immune response.
A. Lymph nodes
B. Spleen
C. Mucosa associated lymphoid tissue (MALT)
23. Lymph nodes:
⢠Encapsulated nodular aggregates of
lymphoid tissues.
⢠Lymph: tissues ď lymphatic
vessels ď lymph node ď blood
circulation.
⢠APCs :- pick up antigens of
microbes from epithelia and other
tissues and transport these
antigens to the lymph nodes.
⢠On antigenic stimulation: primary
lymphoid follicles ď germinal
centers
⢠T cell zone: inbetween cortex and
medulla which has t lymphocytes
29. Cell Life span
T cells Weeks to months
Memory cells - years
B cells 5-6 weeks
Macrophages 6-16 days
Monocytes 2-5 days
Neutrophils 2-5 days
Dendritic cells Few months
30. Lymphocytes:
⢠Circulate through lymphoid organs and nonlymphoid tissues.
⢠Recognize foreign antigens and initiate adaptive immune
responses.
⢠O.5 â 1 x 1012 Lymphocytes.
⢠Arise from stem cells in bone marrow.
⢠Types:
1. B-lymphocytes:
⢠B1
⢠B2
2. T-lymphocytes:
⢠CD4+ T cells â Helper T cells
⢠Special subset of CD4+ T cells â Regulatory T
lymphocytes.
⢠CD8+ T cells â Cytotoxic T lymphocytes.
3. Null cells/large granular lymphocytes
34. Natural killer cells:
Natural killer (NK) cells recognize infected and stressed cells and
respond by killing these cells by secreting the macrophage-activating
cytokine IFN-Îł
35. Dendritic cells:
⢠Leucocytes with cytoplasmic processes.
⢠Dermal dendrocytes are also known as histiocytes.
⢠Langerhans cells ď peripheral dendritic cells
⢠Possess receptors for C3a
⢠Express MHC class II, ICAM Molecules.
⢠Bridge between innate and adaptive immune response.
⢠Can express MMP in response to bacterial challenge and can
contribute to periodontal destruction.
36. Mast cells:
⢠Important in immediate inflammation
⢠Has receptors for complement components (C3a, C5a) and Fc portion of
IgE and IgG (Fcxr and Fcyr).
⢠Express Toll like receptors
⢠Stimulation of receptors causes activation of vasoactive substances
leading to inflammatory process.
⢠Contain lysozymes, histamine, neutrophil chemotactic factor, heparin.
⢠They can synthesize slow reactive substances like SRS-A, TNFa and IL6.
37.
38. Neutrophils:
⢠First cells to arrive at the site of
inflammation
⢠Possess receptors for c1,c3,c4 & c5
⢠Primary granules:
Beta glucoronidases,
betagalactosidase,
Elastase,
Myeloperoxidase,
Lysozyme
⢠Secondary granules:
Lactoferrin,
Lysozyme,
Antimicrobial peptides
Beta defensins
Cathelicidins
cystatins
39. Macrophages:
⢠Monocytes enter tissue and differentiate into macrophages
⢠Antigen presenting cells
⢠Ingest antigens and coat with MHC molecules and present to T cell
receptor
⢠Secrete variety of cytokines like IL1, IL6, TNFA, IFN, Complements
and growth factors and can phagocytose antigens.
42. BASIC ASPECTS OF IMMUNOLOGY
ďą Antigens
ďą Antibodies
ďą Antigen-antibody reactions
ďą Complement system
43. ANTIGENS
⢠Antigen has been defined as any substance which when
introduced parenterally into the body, stimulates the production
of an antibody with which it reacts specifically and in an
observable manner.
⢠Attributes of antigenicity:
1. Immunogenicity â induction of an immune response
2. Immunological reactivity â specific reaction with antibodies
44. ⢠Based on the ability of antigens to carry out these two functions,
they are classified as :
1. Complete antigen â able to induce antibody formation and
produce a specific and observable reaction with the produced
antibody.
2. Haptens: substances incapable of inducing antibody formation
on their own.
⢠Complex haptens â can precipitate with specific antibodies
⢠Simple haptens - nonprecipitating.
⢠Biological classes of antigens:
1. T cell dependent antigens (TD)
2. T cell independent antigens (TI)
47. ďSynthesized by plasma cells & to some extent by lymphocytes.
ďImmunoglobulins are glycoproteins, each molecule consisting of
two pairs of polypeptide chains, the light (L) & heavy (H) chains.
ANTIBODIES
48.
49. ABNORMAL IMMUNOGLOBULINS:
â˘Bence jones proteins in multiple myeloma.
â˘IgM in waldenstromâs macroglobulinemia.
â˘Cryoglobulinemia
â˘A different disorder is found in â heavy chain diseaseâ, a
lymphoid neoplasia characterized by over production of Fc
parts of heavy chains.
50. ANTIGEN â ANTIBODY REACTIONS
ďThey serve several functions. In the body, they form the basis of
humoral immunity.
ď In the laboratory, they help in the diagnosis of infections, in
epidemiological surveys, in the identification of infectious agents.
ď The reaction occur in 3 stages
1. Primary reactions
2. Secondary reactions
3. Tertiary reactions
51. When an antigen is bound by an antibody, any of four
actions may occur:
⢠Antigen may no longer function properly (inactivation by antibody)
⢠Complement may be activated
⢠antigen and/or attached microorganism may clump (agglutination)
or even precipitate out of solution
⢠Antibody-dependent cell-mediated cytotoxicity may occur.
52. GENERAL FEATURES:
⢠Reaction is specific.
⢠Entire molecule react & not fragments.
⢠No denaturation during the reaction.
⢠Combination occurs at the surface.
⢠Combination is firm but reversible.
AFFINITYâ intensity of attraction
AVIDITYâ strength of the bond
55. RADIO IMMUNOASSAY (RIA)
ENZYME IMMUNOASSAY
A technique for determining antibody levels by introducing an
antigen labelled with a radioisotope and measuring the
subsequent radioactivity of the antibody component.
57. THE COMPLEMENT SYSTEM
ďcoined by Ehrlich.
ď Refers to a system of factors which occur in normal serum & are activated
by Ag- Ab reaction & subsequently mediate a number of biologically
significant consequences.
ď Acts as mediator & amplifier of many immune responses & inflammation.
ď The complement system belong to a group of biologic effector
mechanisms called Triggered enzyme mechanisms.
ď Only IgM & IgG1,2,3 fixes the complement.
ďComplement as a whole is heat labile.
58. COMPONENTS:
ď A complex 9 different fractions called C1- C9.
ď C1 is present in serum as a calcium dependant ion which chelates with
EDTA.
COMPLEMENT ACTIVATION:
ď C cascade is a series of reactions in which the preceding components act
as enzymes on the succeeding components, cleaving them into dissimilar
components.
ď Larger fragment join the cascade, smaller fragments often possess the
biologic effects which contribute to defense mechanisms by various
mechanisms.
59. ď C cascade can be activated by
1. Classical pathway
2. Alternative pathway
3. lectin pathway
62. REGULATION OF C- ACTIVATION:
ďź Unchecked C-activity can cause not only exhaustion of the C-
system but also serious damage to tissues.
ďź Two different type of regulators are
A) Inhibitors
B) Inactivators
ďź Various inhibitors include inhibitor of C1a esterase. This does not
prevent normal C-cascade but checks itâs autocatalytic prolongation.
ďź The S protein binds to C567a & modulates the cytolytic action of
the MAC.
64. MAJOR HISTOCOMPATIBILITY COMPLEX
(MHC)
⢠MHC is a locus in the short arm of Chromosome 6 that encodes
for MHC classI, II & III molecules which are involved with antigen
uptake and presentation.
⢠Class I â present in all cells in association with self derived
antigens (intracellular) presented to CD8 & NK cells
⢠Class II â Antigens from Extracellular sources are presented by
APCS (peripheral DCs, monocyte derivitives & B cells) in
association with Class II molecules â HLA- DR, DP, DQ
⢠Class III â complement factors B, C2and C4
65.
66. Genes Of MHC Organized In 3 Classes
ď Class I MHC genes
ď Glycoproteins expressed on all nucleated cells
ď Major function to present processed Ags to TC
ď Class II MHC genes
ď Glycoproteins expressed on B-cells, dendritic cells.
ď Major function to present processed Ags to TH
ď Class III MHC genes
ď Products that include secreted proteins that have immune
functions.
Ex. Complement system, inflammatory molecules.
67. DEFENSINS
⢠Endogenous, small, cysteine-rich antimicrobial peptides that are
produced by leukocytes and epithelial cells.
⢠Multifunctional and, by interacting with host cell receptor(s),
participate in both immune responses.
⢠Contain cysteine residues that form characteristic disulfide
bridges.
⢠Human defensins are classified into two subgroups:
⢠Six alpha-defensins (hND-1 to hND-6) ď PMNs
⢠Four beta-defensins (hBD-1 to hBD-4) ď Mucosal epitheial
cells
68. CYTOKINES
â˘Low molecular wt. proteins secreted by many cells (previously
known as Lymphokines)
â˘Assist in the regulation and development of Immune effector cells
â˘Cell to Cell communication
â˘Direct effector function
â˘Autocrine, Paracrine or endocrine
â˘Pleiotrophic
69.
70.
71. CELLULAR RECEPTORS FOR MICROBES AND DAMAGED CELLS
Receptors used to detect microbes and damaged cells are expressed on
phagocytes, dendritic cells and many other cell types.
Based on their location, they are of 3 types:
72. These receptors for PAMP and DAMP belong to several protein families.
1. Toll-like receptors
2. NOD-like receptors and the inflammasome
3. Others: the RIG-like receptor
Cytosloic DNA sensors
lectin receptors
76. IMMUNODEFICIENCY DISEASES
⢠Conditions where the defense mechanisms, of the body are impaired,
leading to repeated microbial infections of varying severity and
sometimes enhanced susceptibility to malignancies.
⢠Deficiencies of defence mechanisms may involve:
⢠Specific immune functions - humoral immunity, cell mediated
immunity or both
⢠Nonspecific mechanisms - such as phagocytosis and complement.
⢠Immunodeficiencies may be classified as:
⢠Primary or Secondary.
⢠Primary immunodeficiencies: from abnormalities in the development
of the immune mechanisms.
⢠Secondary immunodeficiencies: are consequences of disease, drugs,
nutritional inadequacies and other processes that interfere with the
proper functioning of the mature Immune system.
77. Classification of primary Immunodeficiency syndromes:
A. Disorders of specific immunity:
â˘I. Humoral immunodeficiencies {B cell defects):
â˘a. X-linked agammaglobulinemia
â˘b. Transient hypogammaglobulinemia of infancy
â˘c. Common variable immunodeficiency (late onset hypogammaglobuilnemia)
â˘d. Selective immunoglobulin deficiencies (IgA, IgM or IgC subclasses)
â˘e. Immunodeficiencies with hyper-IgM
â˘f. Transcobalamin II deficiency
â˘II. Cellular immunodeficiencies. (T cell defects):
â˘a. Thymic hypoplasia (Digeorge's syndrome)
â˘b. Chronic mucocutaneous candidiasis
â˘c. Purine nucleoside phosphorylase (PNP) deficiency.
â˘III. Combined immunodeficiencies (B and T cell defects):
â˘a. Cellular immunodeficiency with abnormal immunoglobulin -synthesis
â˘b. Ataxia telangiectasia
â˘c. Wiskott-Aldrich syndrome
â˘d. Immunodeficiency with thymoma
â˘e. Immunodeficiency with short-limbed dwarfism
â˘f. Episodic lymphopenia with lymphocytotoxin.
â˘g. Severe combined immunodeficiencies
â˘'Swiss typeâ agammaglobulinemia
â˘Reticular dysgenesis of de Vaal
â˘Adenosine deaminase (ADA) deficiency
78. B. Disorders of complement:
⢠a. Complement component deficiencies
⢠b. Complement inhibitor deficiencies
C. Disorders of phagocytosis:
⢠Chronic granulomatous disease
⢠Myeloperoxidase deficiency
⢠Chediak-Higashi syndrome
⢠Leucocyte G6PD deficiency
⢠Jobsâs syndrome
⢠Tuftsin deficiency
⢠Lazy Leucocyte syndrome
⢠Hyper-IgE syndrome
⢠Actin-bindlng protein deficiency
⢠Shwachman's disease
79. AUTOIMMUNITY
⢠Condition in which structural or functional damage is produced by
the action of immunologically competent cells or antibodies against
the normal components of the body.
⢠Pathogenesis :
ďą Autoantibody formation may be a result of tissue injury
ďą They may cause damage by the cytotoxic (type II) or by toxic
complex (type III) reactions
ďą Sensitized T-lymphocytes may also result in autoimmune
diseases through type IV reactions.
ďą Humoral and cellular responses may act synergistically in the
production of some autoimmune diseases.
80. ⢠Autoimmune hemolytic anemias
⢠Autoimmune thrombocytopenia
⢠Autoimmune leucopenia
Hemolytic autoimmune diseases:
⢠Autoimmune diseases of thyroid gland
⢠Addisons disease
⢠Pernicious anemia
⢠Myasthenia gravis
⢠Autoimmune orchitis
⢠Autoimmune diseases of the eye
⢠Autoimmune diseases of the nervous system
⢠Autoimmune diseases of the skin.
Localized autoimmune diseases:
⢠Sjogrens syndrome
⢠Systemic lupus erythematosus
⢠Rheumatoid arthritis
⢠Polyarteritis nodosa
Systemic autoimmune diseases:
Classification of autoimmune diseases:
81. HYPERSENSITIVITY
⢠The term hypersensitivity refers to the injurious consequences in
the sensitized host, following contact with specific antigens.
⢠Traditionally they are classified into:
1. Immediate hypersensitivity:
⢠Anaphylaxis
⢠Atopy
⢠Antibody mediated cell damage
⢠Serum sickness
2. Delayed hypersensitivity:
⢠Infection (tuberculin) type
⢠Contact dermatitis
82. Coombs and Gell (1963) classification:
1. Type I reactions (IgE dependent):
cytotropic IgE antibodies fixed on the surface of tissue cells (mast
and basophils) in sensitized individuals binds to Ag.
Occurs in two forms:
a. Anaphylaxis â acute, fatal and systemic
b. Atopy â chronic, recurrent, nonfatal, localized form
Tissues involved - target tissues or shock organs.
84. Type II reaction: cytolytic and cytotoxic:
Antibodies bind with the antigenic determinants on the surface
of cells leading to cytotoxic or lytic effects
Ex:
⢠Autoimmune anemias and hemolytic disease of new born
⢠Long acting throid stimulators (LATS) in graves disease.
⢠Myasthenia gravis
85. Type III reactions: Immune complex diseases:
1. Arthus reaction:
⢠Local manifestation of generalized hypersensitivity.
⢠Seen as an intense local reaction with edema,induration and
hemmorhagic necrosis.
2. Serum sickness:
⢠Systemic form of type III hypersensitivity.
⢠The clinical syndrome consists of fever, lymphadenopathy,
splenomegaly, arthritis, glomerulonephritis, endocarditis,
vasculitis,urticarial rashes, abdominal pain, nausea and vomiting.
86. Type IV reactions: Delayed hypersensitivity:
Induced by sensitized t cells (Tdth, Th1,Th2,Tc), which on contact with
specific antigens causes biological effects on leucocytes, macrophages and
tissue cells
1. Tuberculin type (infection):
Small dose of tuberculin when injected intradermally in an sensitized
individual, an indurated inflammatory reaction develops at the site
within 48-72 hours.
2. Contact dermatitis type:
DH develops from skin (esp. inflamed area)contact with chemicals.
Contact with the allergen in sensitized individuals.
Varies from macules, papules to vesicles.
88. PERIODONTAL DISEASE IMMUNOLOGY
Initiated by small subset of
endogenous gram-negative
periodontal bacteria.
Trigger innate, inflammatory, and
adaptive immune responses.
Destruction of the
PERIODONTIUM
89. ⢠First line of defense.
⢠Includes:
ďź Saliva
ďź GCF
ďź Epithelial barrier
ďź Commensals
⢠Orchestrated by a broad
range of cytokines,
chemokines, cell surface
receptors.
Innate immunity in periodontal diseases:
90. The PRRâs
⢠The primary response to pathogens in the innate immune
system is triggered by Pattern Recognition Receptors (PRRs)
that bind Pathogen-Associated Molecular Patterns (PAMPs),
found in a broad type of organisms.
⢠These receptor types include:
ďź toll-like receptors (TLR),
ďź nucleotide-binding oligomerization domain (NOD)
proteins,
ďź cluster of differentiation 14 (CD14),
ďź complement receptor-3,
ďź lectins and scavenger receptors.
91. TOLL LIKE RECEPTORS
⢠10 TLRs are identified so far.
⢠Among them TLR-2 and TLR-4 are most defined members.
⢠TLR 2 responds to lipoteichoic acid and microbial lipoproteins
⢠TLR 4 responds to LPS
⢠TLR 5 responds to Flagellin
⢠TLR 9 responds to bacterial DNA
⢠Porphyromonas gingivalis LPS stimulates TLR-2, and not TLR-4
⢠Only Aggregatibacter actinomycetemcomitans and Veillonella
parvula were capable of stimulating both TLR-2 and TLR-4.
⢠Chronic stimulation of TLRs results in over-production of pro-
inflammatory cytokines and may lead to tissue destruction.
92. Adaptive immunity in periodontal disease:
⢠The importance of adaptive immunity in periodontal diseases is
endorsed by the histologic studies of established lesions, which
revealed:
ďź B cells and plasma cells in progressive lesions.
ďź T cells especially T-helper subset (CD4) in stable lesions.
⢠Antigen presenting cells â Generate Ag specific response
⢠T cells â alterations in th1 and th2 balance leads to tissue destruction
⢠B cells â control extracellular antigens.
⢠Antibodies â mainly IgG, but also IgM and A.
⢠Complement system - Provide barrier against spread of bacterial
infections.
94. The MMPs
⢠Family of proteolytic enzymes that degrade extracellular matrix molecules.
⢠Produced by variety of cells like PMN, macrophages, fibroblast, epithelial cells.,
Key inhibitors of mmps: glycoprotein, antitrypsin, macroglobulin.
95. PERIODONTAL DISEASE OSTEOIMMUNOLOGY
tnfa, il1a, 1b, 6, 11,15, 17 stimulate bone resorption
Il 4,5,10,13,18,tgfb inhibit bone resorption.
Th2 cells: inhibit ocl by il 4,10
Th17 cells: promote ocl by il 23,17 and RANKL.
96. IMMUNOLOGIC CONSIDERATIONS OF:
1. Gingivitis:
⢠Initial lesion - PMNs
⢠Early lesion â T Lymphocyte
⢠Established lesion - Plasma cells & B lymphocytes
⢠Advanced lesion - Plasma cells
2. Chronic periodontitis:
⢠Involves mainly alternative pathway of complement
⢠P gingivalis produces an enzyme that can cleave C5
⢠MMP-8 is elevated & TIMP-1 are not
⢠Chymotrypsin released by T denticola activates MMPs
⢠Most of the collagenase activity of C.P is due to the MMP-8 released
by PMNs.
3. Aggressive periodontitis:
⢠75% of LAP patients have dysfunctional neutrophils.
⢠Elevated levels of MMP-1 & TIMP-1 are present.
⢠Demonstrate elevated IgG2 antibodies against Aa.
⢠GAP is often characterized by defects in either PMNs/monocytes.
97. Immunological differences between chronic and aggressive
periodontitis
⢠Clinically the gingival lesion is often absent in aggressive
periodontitis suggesting that it may not follow the same sequence of
initiation and progression as chronic periodontitis (from gingival T-
cell lesion to progressive B-cell lesion).
⢠Ford et al. ď Examined the possibility of subtle immunological
differences.
⢠There are differences between these two forms of periodontitis with
⢠respect to the synthesis of b-defensins by host cells.
⢠In components of the adaptive immune system
98. ⢠Differences in neutrophil function:
⢠Patients with localized aggressive periodontitis had an inherited
trait characterized, by lower than normal chemotaxis
phagocytosis and intracellular microbial killing responses.
⢠Ryder ď believed that some of the differential functions of
neutrophils in aggressive forms of periodontitis may be due to a
combination of inherited and acquired characteristics.
⢠At present it is not possible to identify real differences in the
immunopathology of the two diseases.
⢠This may be because there are no differences, or because the
differences only reflect variations in the degree of severity or
susceptibility rather than actual different immunopathologies.
99. Periodontal vaccine
⢠The complexity of periodontopathic bacteria might be a problem
in developing a periodontal vaccine.
⢠The vaccine development program involves identifying the
bacterial peptides and proteins that trigger the immune
response, and using these as the basis of vaccines.
⢠The vaccines are being trialed in mouse models of periodontal
disease and following a positive response, a vaccine will progress
to clinical trials.
⢠Administering the vaccine, in early adolescent age before there is
any sign of periodontitis, helps in prolonging the healthy life of
the periodontium and risk of any inflammation is reduced.
100.
101. Host Modulation
⢠Modulation of Arachidonic Acid metabolites (NSAIDS)
⢠Modulation of MMPs â SDD (Doxycline - 20 mg twice daily)
⢠Modulation of bone remodeling (Bisphosphanates)
⢠Inhibit Inflammatory cytokines (IL1 & TNFι) through
recombinant human IL11 (rhIL-11)
⢠Inhibition of Nitric Oxides by MEG (Mercaptoalkylguanidines)
102. CONCLUSION
⢠Immunity is a war between pathogens and host defense
system which ends in the âSURVIVAL OF FITTESTâ.
⢠The immune responses team in unique ways, depending upon
host, microbial and environmental controls, to maintain or re-
establish homeostasis.
⢠However, these inherent good guys if went rogue would result
in collateral damage of the periodontium.
⢠Immune system, thus could be a
103. REFERENCES
⢠Text book of microbiology-R .AnanthanarayAan, 6th edition.
⢠Carranzaâs Clinical periodontology-11th edition.
⢠Clinical periodontology and implant dentistry-Jan Lindhe.
⢠Mimâs medical microbiology-4th edition.
⢠Basic Immunology - Functions and disorders of the immune
system 5e - Abbas (2016)
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Editor's Notes
Edward jenner father of immunology
What types of immune responses protect individuals from infections?
EX OF species imm. all human being are totally unsusceptible to plant pathogens. RACIAL : the people of Negroid origin in the USA are more susceptible than the Caucasians to tuberculosis.
AGE:
The two extremes of life carry higher susceptibility to infectious diseases as compared with adults.
Newborns - related to the immaturity of its immune apparatus.
Old age - are highly susceptible to infections due to the waning of their immune responses.
Hormonal influence:
Endocrine disorders such as diabetes mellitus, hypothyroidism and adrenal dysfunction are associated with an enhanced susceptibility to infections.
Corticosteroids - depress the hostâs resistance by their antiinflammatory and antiphagocytic effects and by the suppression of antibody formation and hypersensitivity.
nutrition:
The interaction between malnutrition and immunity Is complex but, in general, both humoral and cell mediated immune processes are reduced when there is malnutrition.
Epithelial surfaces:
The intact skin and mucous membrane covering the body protect it considerably against invasion by microorganisms. They provide much more than a mechanical barrier as the healthy skin posses bactericidal activity.
Antibacterial substances in blood and tissues:
Several substances possessing antibacterial properties have been described in blood and tissues, These include complement system-bactericidal activity (1) beta lysm, a relatively thermostable substance active against anthrax, and related bacilli; (2) basic polypeptides such as teutons extracted from leucocytes and plakins from platelets; {3} acidic substances* such as lactic acid found in muscle tissue and In the inflammatory zones; and (4) lactuperoxidase in milk.
Innate lymphoid cells (ILCs) are lymphocyte-like cells that produce cytokines and perform functions similar to those of T lymphocytes but do not express T cell antigen receptors (TCRs).
Microbial antagonisms: The skin and mucous surfaces have resident bacterial flora which prevent colonisation by pathogens. Alteration of normal resident flora may lead to invasion by extraneous microbes, causing serious diseases.
Inllammntinn: Tissue injury or irritation, initiated by die entryofpathogens or other irritants, leads to inflammation, which is an important, nonspecific defence mechanism.
In humoral immunity, B lymphocytes secrete antibodies that eliminate extracellular microbes. In cell-mediated immunity, different types of T lymphocytes recruit and activate phagocytes to destroy ingested microbes and kill infected cells.
An adaptive immune response consists of distinct phases; the first three are recognition of antigen, activation of lymphocytes, and elimination of antigen (effector phase). The response declines as antigen-stimulated lymphocytes die by apoptosis, restoring the baseline steady state called homeostasis, and the antigen-specific cells that survive are responsible for memory. The duration of each phase may vary in different immune responses. These principles apply to both humoral immunity (mediated by B lymphocytes) and cell-mediated immunity (mediated by T lymphocytes).
Congenital aplasia of thymus results in DIGEORGES syndrome which is characterized by deficient CMI
Thymectomy also affects CMI
located along lymphatic channels throughout the body.
Filter for lymph
OUTER CORTEX and INNER MEDULLA
T cell zone: inbetween cortex and medulla which has t lymphocytes
Largest
White pulp of spleen
Malphigian corpuscles or follicles
Graveyard of red blood cells
Encapsulated with trabeculae
Branches of splenic artery travel along the trabeculae and branches out into central arterioles ď white pulp of spleen
Periarterial lymphoid collections in the white pulp of the spleenď malphigian corpuscles
THE MUCOSA lining diff tracts of our body are endowed with a rich collection of lymphoid cells, either as special aggregates like the peyers patches or scattered isolated lymphoid follicles â collectively called the MALT.
Such lymphoid tissues in gut ,from the adenoids and tonsils to the follicles in the colon called gut assc lymphoid tissue GALT.
MALT has both B and T cells.
Ringed arrangement of lympjoid tissue in the pharynx
The cells of the immune system are located in different tissues and serve different roles in host defense
Myeloid cells : neutrophils monocyte peripheral dendritic cell eosinophil basophil mast cell
Lymphoid cells : CD4+ cells CD8+ cells B cell Nk cells
These cells posses receptors on their surfaces they are identified as CD (cluster of differentiation)
A, Naive lymphocytes recognize foreign antigens to initiate adaptive immune responses. Naive lymphocytes need signals in addition to antigens to proliferate and differentiate into effector cells; these additional signals are not shown. Effector cells, which develop from naive cells, function to eliminate antigens. The effector cells of the B lymphocyte lineage are antibody-secreting plasma cells (some of which are long-lived). The effector cells of the CD4 T lymphocyte lineage produce cytokines. (The effector cells of the CD8 lineage are CTLs; these are not shown.) Other progeny of the antigen-stimulated lymphocytes differentiate into long-lived memory cells. B, The important characteristics of naive, effector, and memory cells in the B and T lymphocyte lineages are summarized. The generation and functions of effector cells, including changes in migration patterns and types of immunoglobulin produced, are described in later chapters.
Clonal selection. Mature lymphocytes with receptors for many antigens develop before encountering these antigens. A clone refers to a population of lymphocytes with identical antigen receptors and therefore specificities; all of these cells are presumably derived from one precursor cell. Each antigen (e.g., X and Y) selects a preexisting clone of specific lymphocytes and stimulates the proliferation and differentiation of that clone. The diagram shows only B lymphocytes giving rise to antibody-secreting cells, but the same principle applies to T lymphocytes. The antigens shown are surface molecules of microbes, but clonal selection also is true for extracellular soluble and intracellular antigens.
Functions of natural killer (NK) cells. A, NK cells kill host cells infected by intracellular microbes, thus eliminating reservoirs of infection. B, NK cells respond to interleukin-12 (IL-12) produced by macrophages and secrete interferon-Îł (IFN-Îł), which activates the macrophages to kill phagocytosed microbes.
Capture antigens and present them to the T lymphocytes.
Produced in bm and released into peripheral blood
Circulate in blood fr 7 hrs and then migrate into tissues where they live for a few days
Process by which inflammatory cells ingest antigens to contain or kill them
Microbes engulfed by neutrophils are contained with in a membrane and are known as phagosomes
On inflammatory response selectins are expressed on neutrophils and vascular wall, pmn attaches to wall and sheds selectin expressing integrins. zipper effect, trans endothelial migration. Chemotaxis and then phagocytosis
Phagocytosis mechanisms:
Nonoxidative: granules release Lysosomal enzymes and other antibacterial subs. Which kill bacteria
Oxidative: act by formation of reduced oxygen metabolites such as super oxide anions in the presence of nadph catalase these have bactericidal potency
Immunogenicity induction of an immune response
Immunological reactivity-specific reaction with antibodies are sensitized cells
Complete antigen is able to induce antibody formation and produce a specific and observable reaction with the ntibody so produced
Haptens are substances which are incapable of inducing antibody formation by themselves but can react specifically with antibodies.
They become immunogenic on combining with larger molecule carrier.
Epitope and paratope determine the specificity of immunological reactions.
An antibody molecule is composed of
four polypeptide chainsâtwo identical
heavy (H) chains and two identical light
(L) chainsâwith each chain containing a
variable region and a constant region
Monoclonal ab
Cryoglobulins are ig which are insoluble at low temperatures
Principal of immunochromatography is the same as ELISA sandwich method, only difference is in that immunological reaction is carried out on the chromatographic paper by capillary action. For this system, two kinds of specific antibodies against antigen are used.One of the antibodies is immobilized on the chromatographic paper, and the other is labeled with colloidal gold and infiltrated into sample pad. An immunochromatographic unit is completed by attaching the sample pad at the end of the membrane.
4. Principal of Immunochromatography kit: When the liquid sample is dropped on the sample pad, the antigen in the sample forms an immunocomplex with the antibody labeled with colloidal gold. Its complex moves along with the liquid sample, and makes a contact with the antibody immobilized on the membrane, followed by forming an immunocomplex with the immobilized antibody, resulting in generating a colored red purple line. Appearance of red purple line on the membrane indicates the presence of antigen of interest in the sample. Since the liquid of the sample migrates through the membrane very fast, it makes it possible to detect the presence or absence of antigen within 15 minutes.
Sandwich uses two antibodies where they capture the antigens and then detect
Competitive: in this an-ab mixture is added to immobilized antigen, and a secondary ab is further added to it.
liquid sample is dropped on the sample pad, the antigen in the sample forms an immunocomplex with the antibody labeled with colloidal gold. Its complex moves along with the liquid sample, and makes a contact with the antibody immobilized on the membrane, followed by forming an immunocomplex with the immobilized antibody, resulting in generating a colored red purple line. Appearance of red purple line on the membrane indicates the presence of antigen of interest in the sample. Since the liquid of the sample migrates through the membrane very fast, it makes it possible to detect the presence or absence of antigen within 15 minutes.
Signaling functions of Toll-like receptors. TLRs activate similar signaling mechanisms, which involve adaptor proteins and lead to the activation of transcription factors. These transcription factors stimulate the production of proteins that mediate inflammation and antiviral defense. NF-ÎşB, Nuclear factor ÎşB.
The inflammasome. Shown is the activation of the NLRP-3 inflammasome, which processes proâ interleukin-1β (proâIL-1β) to active IL-1. The synthesis of proâIL-1β is induced by various PAMPs or DAMPs through pattern recognition receptor signaling. Subsequent production of biologically active IL-1β is mediated by the inflammasome. Note that the inflammasome consists of several molecules of NLRP-3, an adaptor protein, and caspase-1 Other forms of the inflammasome exist which contain sensors other than NLRP-3, including NLRP1, NLRC4, or AIM2. ATP, Adenosine triphosphate; NLRP-3, NOD-like receptor family, pyrin domain containing 3; TLRs, Toll-like receptors.
Type1 : cytotrpic ige antibodies fixed on the surface of tissue cells (mast and basophils) in sensitized individuals
Antigens binds wih these ab and causes the release of vasoactive amines which are responsible for the clinical reactions developed in this reaction.
Histamine: by mast cells,basophils,platelets. Stimulates sensory nerves causing burning and itching. Vasodilation. Smooth muscle contraction. Stimulates secretions.
Serotonin (5HT): platelets. Smooth muscle contraction, vasoconstriction,increased cap. Permea.
Chemotactic factors: eosinophil chemo factr. From mast cells. Chemotaxis of eosinophils
Heparin: anaphylaxis in dogs not in humans
Enzymes from mast cells
Pg: affect secretions, platelet adhesion, permeablty, cap. Dilation and pain threshold
Leukotrienes: LTB4,C4,D4,E4: sustained contraction of smooth muscles and so known as Slow reacting substance of anaphylaxis (SRS-A).
Platelet activating factor:frm basophils. Aggregates platelets and release of vasoactive amines frm them
Ig m and ig g mediated immune response, where these antibodies bind with the antigenic determinants on the surface of cells leading to cytotoxic or lytic effects
Ag-ab complexes cause activation of complement and release of inflamm. Mediators.
Self-limited.
Serum sickness differs frm others, wherein a single dose can serve as a sensitizing and shocking dose.
Provoked by intracellular microbial infections or haptens.
Induced by sensitized t cells (Tdth, Th1,Th2,Tc), which on contact with specific antigens cuases biological effects on leucocytes, macrophages and tissue cells
Cant be transferred by serum, bt by lymphocytes or the transfer factors.
SKIN PRICK TEST AND INTRADEMAL TEST ARE BASED ON TYPE 1 HYPERSENSITIVITY REACTIONS
PATCH TEST IS BASED ON TYPE 4 H.R WHERE THE CD8 CELLS ARE SENSITIZED TO THE ALLERGEN AND PRODUCE AN IMMUNE RESPONSE
Saliva: prevents bacterial attachment, has numerous molecular components like (table),
Gcf: has a flushing action, brings the blood components like pmns,ab etc into the sulcus and aids in the bac. Elimination
Ep. : initial interaction occurs here, also the site of invasion, acts as a barrier to microbial entry. Bt in j.e which is permeable and nonkeratinized, there is inward movement of microbes and outward movement of gcf along with ceels of immune sys. The ep. Cells also secrete antimicrobial peptides like defensins which are small polycationic peptides that disrupt bacterial membranes and kill them.
Commensal also provide protection by competing with pathogens for resources
APC: sentinel cells in tissues which capture antigens and present them to the t cells in lymph nodes, thereby generating antigen specific immune response
T cells: cd 4 t cells are predominantly seen in stable lesions and alterations in the balance of th1 and th2 subsets may lead to destructive changes in tissues.
B cells: help to control extracellular antigens, recognize them through B cell antigen receptor. They ingest the antigens and degrade them and sometimes also present them to t cells and b cells which further differentiate and form specific immune response
Antibodies: antibodies to periodontal pathogens are primarily Ig G, few IgM and IgA. Auto antibodies produced can cause tissue destruction.
Complement system: they link innate and adaptive immunity systems. Provide barrier against spread of bacterial infections . Facilitate clotting mechanism. Mobilize hemopoeitic stem cells from bone marrow. Help replenish new leucocytes. Activate differentiation of specific tcell subsets.
Apart from their protective role, dysregulation of complement system amplifies inflammatory tissue damage.
Collagenases: degrades interstitial collagen, digests ECM and non-ECM molecules.
Stromyelysins: degrades ECM molecules,
Gelatinases: osteoclastic activation, degrades dentured collagen and gelatins,
matrilysins: disrupted cell aggregation, increased cell invasion
Membrane type MMP: digest ECM molecules
Key inhibitors of mmps: glycoprotein,antitrypsin,macroglobulin (found in serum)
Tissue inhibitors of metallo proteinases (TIMP)found in tissues
Tetracyclines also inhibit mmps and hence sdd is being used as a systemic adjunctive to treat periodontitis.
Cytokines like tnfa, il1a, 1b, 6, 11,15, 17 stimulate bone resorption
Il 4,5,10,13,18,tgfb inhibit bone resorption.
RANK, RANKL and OPG are the key modulators of bone resorption.
In periodontal health, the resorption and formation is kept In a balance.
In disease conditions, the immune cells effect bone resorption by increased expression of RANKL and interleukins causing differentiation of pre ocl to ocl resulting in pathologic resorption.
Th2 cells: inhibit ocl by il 4,10
Th17 cells: promote ocl by il 23,17 and RANKL.