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Immunopathology

Immunopathology. Path 6266 May 18, 2010 Judy Aronson, M.D. Jaronson@utmb.edu. Outline. How does the immune response damage tissues? Hypersensitivity mechanisms Examples of immunopathologic disease Autoimmune diseases How does autoimmunity occur? Mechanisms of peripheral tolerance

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Immunopathology

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  1. Immunopathology Path 6266 May 18, 2010 Judy Aronson, M.D. Jaronson@utmb.edu

  2. Outline • How does the immune response damage tissues? • Hypersensitivity mechanisms • Examples of immunopathologic disease • Autoimmune diseases • How does autoimmunity occur? • Mechanisms of peripheral tolerance • Lessons from an experimental model of autoimmune diabetes

  3. “Immunitas”: Freedom from disease Protective responses against infectious agents Host tissue damage by immune response “Pathos”: Suffering/disease The double edged sword of immune responses

  4. Hypersensitivity reactions • Mechanisms of immune-mediated injury • Classified into 4 types (I-IV) • Imperfect correlation between hypersensitivity reaction and disease syndrome • In some diseases, all 4 types may contribute • Humoral and cell-mediated mechanisms may co-exist

  5. Categories of diseases with immunopathologic components • Infectious • Allergic • Transplant rejection • Graft vs. host disease • Autoimmune

  6. Hypersensitivity Reactions • Type I: anaphylactic • allergy, asthma • Type II: antibody-mediated • transfusion reaction • Type III: immune complex-mediated • post-strep glomerulonephritis • Type IV: cell-mediated, delayed type • tuberculosis

  7. Type I hypersensitivity • Immunoglobulin E (IgE) • made by plasma cells, specific for allergen • Mast cells, basophils • Have receptors for Fc portion of IgE molecule • When antigen binds IgE variable regions, degranulation of cells occurs • Histamine and other vasoactive substances are released • Severe reactions can be life-threatening!

  8. Type I hypersensitivity

  9. Primary mediators Histamine: vasodilation and increased permeability, bronchoconstriction, mucus secretion Tryptase: generate kinins, activate complement Eosinophil chemotactic factor Neutrophil chemotactic factor Secondary mediators Lipid mediators (result from PLA2 activation) PAF LTC4, LTD4: vaso-dilation, bronchospasm LTB4: chemotactic factor PGD2: increased mucus, bronchospasm Cytokines: TNF, IL-1, IL-4, IL-5, IL-6) Mast cell mediators

  10. Clinical diseases • Systemic anaphylaxis • Urticaria (hives), bronchoconstriction, laryngeal edema, hypersecretion of mucus, vomiting, abdominal cramps • Life threatening • Localized reactions—eg urticaria, hay fever • Asthma

  11. Urticaria (hives)

  12. Asthma

  13. Type II hypersensitivity • Involves IgG or IgM antibodies that react with fixed antigen on cells or tissue components • Mechanisms of damage: • cell lysis (complement, MAC) • inflammation (complement activation) • block normal cell function • stimulate excessive cell function

  14. Complement • A system of about 20 serum proteins • Activation is by a proteolytic cascade mechanism • Classical pathway: initiated by Ag-Ab complexes • Alternative pathway: initiated by microbial surface • Important products are formed at activating cell surface (opsonins, MAC) and in aqueous environment (anaphylatoxins)

  15. Overview of complement activation pathways From: Robbins

  16. Complement:Effector functions • Formation of membrane attack complex, lysis of target cell • Generation of C3a and C5a “anaphylatoxins” • Chemotactic factors for phagocytes, esp. pmn • Leukocyte activation • Mast cell degranulation • Bronchoconstriction • Opsonization—coating surface of target cell with C fragments (esp. C3), promoting phagocytosis

  17. Activation and effector functions of complement Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 2 January 2007 07:24 PM) © 2005 Elsevier

  18. The Lytic Pathway of Complement From: Roitt

  19. Biological Effects of C5a From: Roitt

  20. Opsonization and phagocytosis From: Roitt

  21. Type II Hypersensitivity

  22. ABO antigens and transfusion

  23. Type III hypersensitivity • Caused by immune complexes (antigen-antibody) that are soluble and formed in antigen excess • Circulating immune complexes deposited according to size, charge, local hemodynamics, etc. (e.g. glomeruli of kidney, joints, skin, small vessels) • Complement is activated, inflammation ensues

  24. Type III (Immune complex) Hypersensitivity

  25. Normal glomerulus

  26. Immune complex glomerulonephritis

  27. HBV: Immune complex GN

  28. Question to consider, buzz group • In a patient with ongoing or active type III hypersensitivity reaction, would you expect the following components in the systemic circulation to be increased, decreased, or unchanged, compared to baseline for the patient? • C3 • C4 • Total complement (CH50)

  29. Type IV hypersensitivity • T lymphocytes and macrophages are effector cells (cell-mediated immune reactions) • Macrophages activated by T cell cytokines (interferon gamma) make granulomas • TB is classic example of delayed type hypersensitivity (DTH)

  30. T cells have multiple effector functions

  31. Non-cytopathic virus interactions with host Zinkernagel, 1997

  32. Effects of antiviral T cells

  33. Effects of antiviral T cells(from Zinkernagel, 1997)

  34. Autoimmunity • Occurs when hypersensitivity mechanisms are directed against “self” antigens • Breakdown of “tolerance”

  35. Requirements for categorization as autoimmune disorder • The presence of an autoimmune reaction • Clinical or experimental evidence that such a reaction is of primary pathogenetic significance, not secondary to tissue damage from another cause • The absence of another well-defined cause of the disease

  36. Autoimmune diseases • Systemic • SLE (lupus): anti-nuclear antibodies (ANA) are characteristic • joints, skin, kidneys, blood, heart, and brain can be involved (type III hypersensitivity) • Rheumatoid arthritis • Organ-specific • Graves disease (thyroid) • Multiple sclerosis (brain)

  37. Central and peripheral tolerance

  38. Downloaded from: StudentConsult (on 10 May 2008 09:33 PM) © 2005 Elsevier

  39. Downloaded from: StudentConsult (on 10 May 2008 09:33 PM) © 2005 Elsevier

  40. Experimental evidence for failure of “homeostatic mechanisms” in autoimmunity: • 1: Failure of AICD • 2: Inappropriate co-stimulatory mol. expression 2 1

  41. Transgenic mouse model of IDDM No spontaneous diabetes mellitus Transgene is LCMV antigen under the control of rat insulin promoter (RIP-LCMV) Expression of transgene in b cells Islets Exocrine pancreas Von Herrath 2002

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