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Failures against ‘self’ ( Principles of Autoimmunity )

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:

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Failures against ‘self’ ( Principles of Autoimmunity )

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

  2. 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

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

  4. 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

  5. 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. Cellular inactivation by weak signaling without co-stimulus

  8. Supression of cytokines, intercellular signaling

  9. Cytokine deviation Differentiation of Th2 cells limiting inflammatory cytokine secretion

  10. Elimination of B cells in germinal centers

  11. 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

  12. 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

  13. 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

  14. Table 1. HLA-linked immunologic diseases

  15. 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

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