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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 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 • Lessons from an experimental model of autoimmune diabetes
“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
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
Categories of diseases with immunopathologic components • Infectious • Allergic • Transplant rejection • Graft vs. host disease • Autoimmune
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
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!
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
Clinical diseases • Systemic anaphylaxis • Urticaria (hives), bronchoconstriction, laryngeal edema, hypersecretion of mucus, vomiting, abdominal cramps • Life threatening • Localized reactions—eg urticaria, hay fever • Asthma
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
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)
Overview of complement activation pathways From: Robbins
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
Activation and effector functions of complement Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 2 January 2007 07:24 PM) © 2005 Elsevier
The Lytic Pathway of Complement From: Roitt
Biological Effects of C5a From: Roitt
Opsonization and phagocytosis From: Roitt
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
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)
Autoimmunity • Occurs when hypersensitivity mechanisms are directed against “self” antigens • Breakdown of “tolerance”
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
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)
Downloaded from: StudentConsult (on 10 May 2008 09:33 PM) © 2005 Elsevier
Downloaded from: StudentConsult (on 10 May 2008 09:33 PM) © 2005 Elsevier
Experimental evidence for failure of “homeostatic mechanisms” in autoimmunity: • 1: Failure of AICD • 2: Inappropriate co-stimulatory mol. expression 2 1
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
Adoptive transfer of LCMV-reactive CTL • “insulitis” • No b-cell destruction • No IDDM RIP-LCMV transgenic mouse Transgenic mouse model of IDDM
Variable lag time RIP-LCMV transgenic mouse • Increased glucose • Decreased insulin • Beta cell destruction • Insulin dependent diabetes mellitus Transgenic mouse model of IDDM Trigger: Infect with LCMV
Lessons from LCMV-RIP model of IDDM • Peripheral tolerance can be broken. This requires: • Activation of APC’s and production of co-stimulatory signals for T cell activation and amplification • Interaction between PBL and islet cells • Upregulation of MHC-II and macrophage activation by viral infection
What are the mechanisms of b cell destruction in this model? • CTL, perforin-dependent lysis initiates insulitis, but cannot by itself cause IDDM • Autoreactive CTL cannot lyse -cells without upregulation of MHC-I expression • Interferon- (and other inflammatory cytokines) increase MHC-I • Beta cell destruction and IDDM required additional direct effect of interferon- from infiltrating CD4 and CD8 cells