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Lecture 22 Autoimmunity

Lecture 22 Autoimmunity. Autoimmune Disease. Self tolerance is lost Specific adaptive immune responses mounted against self antigens Inability to eliminate antigen leads to chronic inflammatory process Ehrlich termed this horror autotoxicus.

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Lecture 22 Autoimmunity

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  1. Lecture 22Autoimmunity

  2. Autoimmune Disease • Self tolerance is lost • Specific adaptive immune responses mounted against self antigens • Inability to eliminate antigen leads to chronic inflammatory process • Ehrlich termed this horror autotoxicus

  3. Autoimmune diseases mediated by cytotoxic antibodies (Type II)

  4. Autoimmune diseases mediated by immune complexes (Type III)

  5. Autoimmune diseases mediated by T-cells (Type IV)

  6. Autoimmune disease susceptibility • Genetic predisposition • Twin studies (Diabetes: 20% monozygotic vs. 5% dizigotic) • Family studies • Association with MHC genotype • HLA genotyping

  7. Genetic organization of the MHC in humans and the mouse

  8. Detailed map of the human MHC region

  9. Association between HLA and susceptibility to autoimmune disease

  10. Population studies show association of susceptibility to insulin-dependent diabetes mellitus (IDDM) with HLA genotype

  11. Family studies show strong linkage of susceptibility to insulin-dependent diabetes mellitus (IDDM) with HLA genotype

  12. Autoimmunity involves T cells • Ability of a T cell to respond is determined by MHC genotype • It has been hypothesized that susceptibility to an autoimmune disease is determined by differences in the ability of allelic variants of MHC molecules to present autoantigenic peptides • Alternatively, self peptides may drive the positive selection of developing thymocytes that are specific for particular autoantigens.

  13. Levels of autoantigens may drive T cell selection • If antigens are expressed at too low a level, they may not drive negative intrathymic selection, but sufficient to drive positive selection • Insulin genes transcribed at high level in thymus protect against diabetes

  14. Peripheral B-cell anergy

  15. Elimination of autoreactive B cells in germinal centers

  16. Several ways in which infectious agents could break self tolerance

  17. Association of infection with autoimmune disease

  18. Some body sites are immunologically priviledged

  19. Damage to an immunologically privileged site can induce an autoimmune response

  20. Sjögren’s Syndrome Chronic autoimmune disorder Major clinical manifestations resulting from changes in exocrine glands

  21. Forms of Sjögren’s Syndrome Primary Sjögren’s is characterized by inflammatory cell involvement of both the salivary and lacrimal glands Secondary Sjögren’s includes other defined connective tissue disease Causes are unknown

  22. Features of Sjögren’s Syndrome Glandular epithelial cells participate in the autoimmune disease process Epithelial cells produce a number of immunologically active mediators May serve as antigen-presenting cells Epithelial cell responses modulate mechanisms occurring in the salivary glands

  23. Is Sjögren’s Syndrome an Autoimmune Disorder? Described as an autoimmune exocrinopathy (Strand and Talal, 1980) Grouped with other connective tissue diseases Rheumatoid arthritis Systemic lupus erythematosis (SLE) What is the evidence that it is an autoimmune disease?

  24. Evidence that Sjögren’s Syndrome is an Autoimmune Disease A specific auto-immunogen and pathogenic antibodies have not been identified Autoantibodies that have been found have not been shown to have any direct pathogenic effects on exocrine tissues There is substantial circumstantial evidence that tissue damage is the result of autoimmunity

  25. Polyclonal Hypergammaglobulinemia B-cell hyper-responsiveness Marked elevations of IgG Production of rheumatoid factors Presence of anti-nuclear antibodies Extractable nuclear antigens Anti-SS-A (Ro) and anti-SS-B (La) Antibodies are found directed against salivary duct cells (90% of patients) Primarily against extractable nuclear antigens Concentration does not correlate with gland destruction

  26. Other Characteristics Elevated sedimentation rates and decreased WBC counts, as seen in other autoimmune connective tissue diseases Specific extended MHC haplotype at a higher frequency than controls MHC-encoded proteins Induction of tolerance to self proteins Selection of the T-cell repertoire Binding and presentation of antigen to T-cells

  27. Histopathology Mononuclear infiltrate consisting primarily of T-cells (primarily CD4+) Host of mediators Altered cell adhesion molecules expression Increased HLA class II antigens expression Immunosuppressive therapy often effective

  28. Classical Histopathological Lesion Lympho-epithelial lesion affecting the parotid gland Progressive replacement of the salivary tissue by dense lymphoid infiltrates Formation of proliferating islands of ductal epithelial cells Creates well-formed lymphoid follicles typical of MALT and may give rise to lymphomas of the MALT type as an expansion of monoclonal B-cells

  29. Salivary Gland Structure

  30. Conclusion Numerous changes in immune factors in Sjögren’s Syndrome Salivary glands appears as a highly active, immune-mediated inflammatory sites Salivary epithelial cells are immunologically-active participants in the disease process

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