Failures against ‘self’ (Principles of Autoimmunity) marshnes@yahoo.com

Mechanisms of autoimmunity Individual’s immune system reacts to autologous antigens  pathologic tissue injury “Horror autotoxicus” (P. Ehrlich, 1900s): immunity against self Autoreactive lymphocytes: B cells  autoantibodies Autoreactive T cells Breakdown/failure for maintaining self tolerance

Paul Ehrlich (1854-1915) : Horror autotoxicus, Nobel Prize 1908 Autoantigens Autoreactive effector cells, Autoantibodies 5% population 3

Self tolerance of lymphocytes Clonal deletion Most effective mechanism Deletion of self-recognizing B-and T cells prior to their maturation Clonal anergy Induced by encounter with self antigens Self reactive B/T cells can survive, but not react to self antigens

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Negative selection 6

Negative selection AIRE (Autoimmune Regulator) is a transcription factor that regulates the negative selection of autoreactive T cells by leading the transcription of tissue-specific antigens in the thymus. AIRE mutations and polymorphisms have been found in different autoimmune manifestations such as autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) with a semidominant effect. 7

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Cellular inactivation by weak signaling without co-stimulus 9

Supression of cytokines, intercellular signaling 10

Cytokine deviation Differentiation of Th2 cells limiting inflammatory cytokine secretion 11

Elimination of B cells in germinal centers 12

Pathogenesis of autoimmunity Studies by using animal models: Occurs spontaneously or induced by particular immunization General properties: Caused by multiple interacting factors There are systemic and organ-specific autoimmune diseases

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Multiple interacting factors Immunologic abnormalities Genetic backgrounds Predispose to autoimmunity: MHC/HLA genes Microbial infections: virus, bacteria Anatomic alterations Sequestered/privilege sites of antigens Hormonal influences Systemic lupus erythematosus (SLE): affects females about 10 x as frequently as males

Role of MHC genes Some HLA alleles occur at high frequency in patients with particular diseases Estimation of the “relative risk”, exp: Ankylosing spondylitis with HLA-B27 is 90 Rheumatoid arthritis with HLA-DR4 is 6 Insulin-dependent diabetes mellitus with HLA-DR3, DQw8 is 100

Table 1. HLA-linked immunologic diseases HLA allele Relative Risk Rheumatoid arthritis DR4 6 IDDM DR3, DQw8 100 Pemphigus vulgaris 24 Chronic active hepatitis DR3 14 Sjorgen’s syndrome 10 Celiac disease 12 Ankylosing spondylitis B27 90

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Concluding remarks Autoimmunity is an immunity against ‘self’ molecules/proteins/antigens. Basically, this is due to a breakdown of self tolerance that normally occurs within the body Multiple interacting factors are documented to be the causes of autoimmunity/autoimmune diseases There are organ-specific and/or systemic manifestations of the autoimmune diseases