This document discusses immunological tolerance and autoimmunity. It defines central and peripheral tolerance as mechanisms by which the immune system learns to distinguish self from non-self. Central tolerance involves deletion of self-reactive lymphocytes in the thymus and bone marrow. Peripheral tolerance mechanisms include clonal deletion, anergy, and suppression. Failure of tolerance can lead to autoimmune diseases, which are influenced by genetic, hormonal, and environmental factors. Common triggers include molecular mimicry between microbial and self-antigens.

1. AUTOIMMUNITY FE A. BARTOLOME, MD, FPASMAP Department of Microbiology Our Lady of Fatima University

2. IMMUNOLOGICAL TOLERANCE State in which the individual is incapable of developing an immune response to a specific antigen Self-tolerance  lack of responsiveness to an individual’s antigens Central tolerance & peripheral tolerance

3. CENTRAL TOLERANCE Clonal deletion of self-reactive T and B lymphocytes during their maturation in the central lymphoid organs

4. CENTRAL TOLERANCE T cells T lymphocytes that bear high-affinity receptors for self-antigens are negatively selected or deleted  undergo apoptosis occur during fetal development

5. CENTRAL TOLERANCE B cells Also undergo clonal deletion Developing B cells encounter a membrane-bound antigen within the bone marrow  B cells undergo apoptosis Occur throughout life

6. PERIPHERAL TOLERANCE Self-reactive T cells that escape intrathymic negative selection are deleted or muzzled in the peripheral tissues

7. PERIPHERAL TOLERANCE MECHANISMS: Clonal deletion by activation-induced cell death Clonal anergy Peripheral suppression by T cells

8. PERIPHERAL TOLERANCE Clonal deletion by activation-induced cell death Apoptotic death of activated T cells by the Fas-FasL system Self-antigens abundant in peripheral tissue (e.g. collagen, thyroglobulin)  repeated & persistent stimulation of self-antigen-specific T cells  activation of Fas-mediated apoptosis

9. Clonal deletion in thymus A A A Cell death B B B Antigen Two immature T cells (A and B) with different antigen receptors Binding of self antigen to T-cell A in thymus but not to T-cell B Death of self-reacting T-cell A; survival of T-cell B that reacts against foreign antigen

11. PERIPHERAL TOLERANCE Clonal anergy Prolonged or irreversible functional inactivation of lymphocytes Induced by encounter with antigens T cells – due to absence of co-stimulatory molecules on APCs, such as B7-1 & B7-2 B cells – due to lack of T cell help for antibody synthesis (T cell anergy or down-regulation of surface IgM)

12. PERIPHERAL TOLERANCE APC Helper T cell Class II MHC Antigen TCR B7 protein CD28 protein CD4 protein APC Helper T cell Class II MHC Antigen TCR CD28 protein CD4 protein B7 protein on APC interacts with CD28 on helper T cells. Full activation of helper T cells occur. B7 protein on APC is not produced. CD28 on helper T cell does not give a co-stimulatory signal. Anergy occurs.

14. PERIPHERAL TOLERANCE Peripheral suppression by T cells Suppressor T cells – with ability to down-regulate the function of other autoreactive T cells Shift immune response from T H 1 to T H 2 T H 2 generally immunosuppressive  down-modulate T H 1 response

16. Factors Affecting Artificially-Induced Tolerance Form, dose & route of administration Very simple molecules induce tolerance more readily than a complex one Very high or very low doses of an antigen may result in tolerance instead of an immune response Purified polysaccharides or amino acid co-polymers injected in very large doses result in “ immune paralysis ”

17. Factors Affecting Artificially-Induced Tolerance Immunologic “maturity” of the host E.g. neonates  immunologically immature  do not respond well to foreign antigens Chimerism Tolerance induced by inoculation of allogeneic cells into hosts that lack immune competence Antibodies to CD4 and CD8 Tolerance of transplanted tissues by inoculating graft recipient with monoclonal antibodies against CD4 and CD8

18. Factors Affecting Artificially-Induced Tolerance Clonal exhaustion Repeated antigenic challenge Stimulate B and T cell to differentiate into short-lived end cells

19. Factors Affecting Artificially-Induced Tolerance Clonal anergy induced by anti-idiotypic antibodies & antagonistic peptides Antibody combining site (idiotype) act as antigen  induce formation of anti-idiotypic antibodies  cross-link on B cells  prevent interaction with Ag Antagonistic peptides  fit into Ag-binding site of MHC  no activation of T cells

20. Other aspects of induction/maintenance of tolerance T cells become tolerant more readily and remain tolerant longer than B cells. Administration of a cross-reacting antigen tends to terminate tolerance. Administration of immunosuppressive drugs enhances tolerance. Tolerance is maintained best if the antigen to which the immune system is tolerant continues to be present.

21. AUTOIMMUNITY Immune reaction against self-antigens Requirements: Presence of an autoimmune reaction Clinical or experimental evidence that reaction is not secondary to tissue damage but is of primary pathogenetic significance Absence of another well-defined cause of the disease

22. AUTOIMMUNITY Most important step in production of autoimmune disease: activation of self-reactive CD4 T cells Most are antibody-mediated

23. AUTOIMMUNITY GENETIC FACTORS (+) genetic predisposition Strong association with HLA specificities, especially class II genes Class I MHC-related: ankylosing spondylitis & Reiter’s syndrome; more common in men Class II MHC-related: RA, Grave’s disease, SLE; more common in women

24. AUTOIMMUNITY HORMONAL FACTORS Approximately 90% occur in women Estrogen  can alter the B-cell repertoire and enhance formation of antibody to DNA

25. AUTOIMMUNITY ENVIRONMENTAL FACTORS Exposure to an environmental agent can trigger a cross-reacting immune response against some component of normal tissue Example: S. pyogenes & rheumatic fever

26. AUTOIMMUNITY: Mechanisms Defects in clonal deletion mechanisms Thymic defects that lead to proliferation of self-reactive T cells Failure of central tolerance

27. AUTOIMMUNITY: Mechanisms Polyclonal lymphocyte activation Microorganism-derived mitogens stimulate lymphocytes Microbial products (e.g. LPS)  act as superantigens  activate a large pool of T and B cells

28. AUTOIMMUNITY: Mechanisms Molecular mimicry Microbial antigens with similar structure to self-antigens  activate autoreactive T cells Cross-reactivity-induced immune response Example: M protein of S. pyogenes and myosin of cardiac muscle

29. AUTOIMMUNITY: Mechanisms Release of sequestered antigens Immunologically privileged sites ( brain, ant. eye chamber, ovary, placenta, testis, pregnant uterus )  not exposed to immune system Damage  release of antigens  elicit immune response

30. AUTOIMMUNITY: Mechanisms Defects in the regulation of TH 1 and TH 2 cells Impaired T suppressor cell immunoregulation

31. Microbial infections associated with autoimmune diseases Microbe Autoimmune disease BACTERIA Streptococcus pyogenes Campylobacter jejuni Escherichia coli Chlamydia trachomatis Shigella sp. Yersinia enterocolitica Borrelia burgdorferi Rheumatic fever Guillain-Barre syndrome Primary biliary cirrhosis Reiter’s syndrome Reiter’s syndrome Grave’s disease Lyme arthritis VIRUSES Hepatitis B virus Hepatitis C virus Measles virus Cytomegalovirus Multiple sclerosis Mixed cryoglobulinemia Allergic encephalitis Scleroderma

32. ORGAN-SPECIFIC AUTOIMMUNE DISEASES Type of Immune Response Autoimmune Disease Target of Immune Response Antibody to receptors Myasthenia gravis Grave’s disease Acetylcholine receptor TSH receptor Antibody to cell components other than receptors Pernicious anemia Goodpasture’s synd. IDDM Addison’s disease Male infertility Pemphigus Hashimoto’s Primary myxedema Intrinsic factor and parietal cells BM of kidney & lung Islet cell Adrenal cortex Sperm Desmoglein in tight junctions of skin Thyroglobulin Thyroid peroxidase

33. NON-ORGAN SPECIFIC AUTOIMMUNE DISEASES Type of Immune Response Autoimmune Disease Target of Immune Response Antibody to cell components other than receptors Rheumatoid arthritis SLE Sjogren’s syndrome (Sicca syndrome) Guillain-Barre synd. IgG in joints dsDNA, histones RNP antigens (SS-A/Ro and SS-B/La) Myelin protein