AUTOTOLERANCE AND AUTOIMMUNITY

1. AUTOTOLERANCE AND AUTOIMMUNITY

2. The problem of self-nonself discrimination • The immune system responds to many foreign (microbial) antigens but not to self antigens • Developing lymphocytes express a large number of antigen receptors, not biased by specificity • Therefore, all individuals produce lymphocytes with the ability to recognize self antigens • Self antigens have access to the immune system • Therefore, self-reactive lymphocytes must be selected against (eliminated or inactivated) to prevent autoimmunity

3. Immunological tolerance • Definition: • specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen (implies antigen specificity, in contrast to “non-specific immunosuppression”) • Significance: • All individuals are tolerant of their own antigens (self-tolerance); breakdown of self-tolerance results in autoimmunity • Therapeutic potential: Inducing tolerance may be exploited to prevent graft rejection, treat autoimmune and allergic diseases, and prevent immune responses in gene therapy, perhaps stem cell transplantation

4. Central and peripheral tolerance The principal fate of lymphocytes that recognize self antigens in the generative organs is death (deletion), BUT: Some B cells may change their specificity (called “receptor editing”) Some T cells may differentiate into regulatory (suppressor) T lymphocytes

5. Mechanisms of unresponsiveness to self antigens • Central tolerance: Immature self-reactive lymphocytes that recognize self antigens in generative (“central”) lymphoid organs die by apoptosis; other fates • Peripheral tolerance: Mature self-reactive lymphocytes that recognize self antigens in peripheral tissues are inactivated (anergy), killed (deletion) or suppressed • “Clonal ignorance”: Mature self-reactive lymphocyte clones do not encounter or respond to self antigens • In normal individuals it is not known which self antigens induce tolerance by which mechanism

6. Central T cell tolerance

7. Deletion of self-reactive T cells in the thymus: how are self antigens expressed in the thymus? AIRE (autoimmune regulator) is a putative transcription factor that stimulates thymic expression of many self antigens, which were thought to be restricted to peripheral tissues Discovered as the genetic cause of a human autoimmune disease (APS-1)

8. Consequences of AIRE mutation • Human disease: autoimmune polyendocrinopathy with candidiasis and ectodermal dysplasia (APECED), also called autoimmune polyendocrine syndrome (APS-1) • Associated gene identified by positional cloning, named AIRE (“autoimmune regulator”)

9. Central tolerance: fates of immature self-reactive lymphocytes • Induced by antigen in generative lymphoid organs (thymus for T cells, bone marrow for B cells), and high-affinity (“strong”) recognition of the antigens (dangerous lymphocytes) • Immature lymphocytes undergo apoptosis upon encounter with antigens (negative selection) • Eliminates high-affinity self-reactive (potentially most dangerous) lymphocytes • Some self-reactive T cells that encounter self antigens in the thymus develop into regulatory T cells and immature B cells in the bone marrow change their receptors (rendered harmless)

10. APC APC APC APC Peripheral tolerance T cell CD28 Normal T cell response Activated T cells TCR Functional unresponsiveness Anergy Off signals TCR Activated T cell Apoptosis (activation-induced cell death) Deletion Block in activation Suppression Regulatory T cell

11. T cell anergy From Abbas, Lichtman and Pillai. Cellular and Molecular Immunology 6th ed, 2007

12. “Activation-induced cell death”: death of mature T cells upon recognition of self antigens ALPS

13. Regulatory T cells From Abbas, Lichtman and Pillai. Cellular and Molecular Immunology 6th ed, 2007

14. Tolerance in B lymphocytes • Central tolerance: • Deletion of immature cells by high-affinity antigen recognition in the bone marrow • Some immature cells may change their antigen receptors when they encounter antigens in the bone marrow (“receptor editing”) • Peripheral tolerance: • Anergy • Exclusion from lymphoid follicles, death because of loss of survival signals

15. AUTOIMMUNE DISEASES Frequency: 5% of population The most Reumatoid arthritis frequent Graves disease diseases Type I diabetes mellitus Pernicious anemia Systemic lupus erithematosus Multiple sclerosis

16. Autoimmunity • Definition: immune response against self (auto-) antigen, by implication pathologic • General principles: • Pathogenesis: The development of autoimmunity reflects a combination of susceptibility genes and environmental triggers (usually infections) • Different autoimmune diseases may be systemic or organ-specific; may be caused by different types of immune reactions (antibody- or T cell-mediated) • Problems in understanding pathogenesis of human autoimmune diseases: • Failure to identify target antigens, heterogeneous disease manifestations, disease may present long after initiation

17. GENETIC PREDISPOSITION - MHC genes - non MHC genes Environmental factors - infection - drugs AUTOIMMUNITY

18. Genetic basis of autoimmunity -- 1 • Genetic predisposition of autoimmune diseases • Increased incidence in twins (more in monozygotic) • Identification of disease-associated genes by breeding and genomic approaches • Multiple genes are associated with autoimmunity • Most human autoimmune diseases are multigenic • Single gene mutations and mouse knockouts reveal critical pathways

19. Genetic basis of autoimmunity -- 2 • MHC genes • Major genetic association with autoimmune diseases (relative risk of disease in individuals with particular HLA haplotypes) • Disease-associated alleles are present in normal individuals • Non-MHC genes: • Many loci identified by whole genome association and linkage studies • Most are chromosomal locations; actual genes and roles in disease are largely unknown

20. Genetic basis of autoimmunity -- 3 • Genome wide association studies are being done to define genes • Crohn’s disease: • NOD-2: microbial sensor in intestinal epithelial and other cells • IL-23 receptor: involved in TH17 responses • Rheumatoid arthritis, others: • PTPN-22 (tyrosine phosphatase): may control kinase-dependent lymphocyte activation • Multiple sclerosis: • CD25 (IL-2 receptor): required for maintenance of regulatory T cells • Difficult to define pathways and target them for therapies

21. Infections predispose to autoimmunity Genes encoding antigen receptor specific for a myelin antigen Transgenic mouse with myelin-specific T cells Pathogen-free mouse colony Normal mouse colony CNS disease No disease

22. Infections and autoimmunity • Infections trigger autoimmune reactions • Clinical prodromes, animal models • Autoimmunity may develop after infection is eradicated (i.e. the autoimmune disease is precipitated by infection but is not directly caused by the infection) • Some autoimmune diseases are prevented by infections (type 1 diabetes, multiple sclerosis, others? -- increasing incidence in developed countries): mechanism unknown; similar protection suggested for asthma • The “hygiene hypothesis”

24. Immune-mediated inflammatory diseases • Immune-mediated inflammatory diseases develop because the normal controls on immune responses fail • These diseases often become self-perpetuating • The phenotype of the disease is determined by the nature of the immune response