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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

Immunopathology

Path 6266

May 18, 2010

Judy Aronson, M.D.

Jaronson@utmb.edu

outline
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
the double edged sword of immune responses

“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
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
Categories of diseases with immunopathologic components
  • Infectious
  • Allergic
  • Transplant rejection
  • Graft vs. host disease
  • Autoimmune
hypersensitivity reactions1
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
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!
mast cell mediators
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
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
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
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)
complement effector functions
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
slide18

Activation and effector functions of complement

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 2 January 2007 07:24 PM)

© 2005 Elsevier

type iii hypersensitivity
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
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
Autoimmunity
  • Occurs when hypersensitivity mechanisms are directed against “self” antigens
  • Breakdown of “tolerance”
requirements for categorization as autoimmune disorder
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
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)
slide45
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
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

slide47

Adoptive transfer of LCMV-reactive CTL

  • “insulitis”
  • No b-cell destruction
  • No IDDM

RIP-LCMV transgenic mouse

Transgenic mouse model of IDDM

slide48

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
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
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
slide51
Why does LCMV infection cause IDDM in this model, while adoptive transfer of LCMV-reactive T cells does not?
  • LCMV infects islets and leads to antigen-presenting cell activation (MHC-II expression) before arrival of T lymphocytes
    • Expansion of infiltrating CD4 and CD8 T cells
    • Continued T cell attack against b cells even after virus is cleared
  • Lessons possibly generalizable to humans?
    • An “inflammatory environment” facilitates propagation of autoreactive T cells
    • “Hit and run” model for human autoimmune diseases—disease may be triggered by infection, but continues after agent is cleared
t regs
T regs
  • “Natural” and “induced” populations
  • Inhibit sustained T cell responses and prevent immunopathology (but do not inhibit initial T cell activation)
  • Lack characteristics of Th1 or Th2 cells
  • Selectively express Foxp3, (forkhead/winged helix family transcription factors)
  • CD25 is an activation marker (IL-2R); operationally, a marker for Treg
    • Transfer of CD25 depleted T cells from normal mice into syngeneic nude mice>autoimmune diseases
natural cd25 cd4 t reg cells
Natural CD25+CD4+Treg cells
  • Subpopulation of T cells generated in thymus
  • Recognize discrete set of antigens (?tissue specific antigens of thymic epithelia)
  • Capable of suppression of immune responses in periphery

Nat Immunol 6(4):345-352 (2005)

some mechanisms of autoimmune disease
Some mechanisms of autoimmune disease
  • Failure of activation-induced cell death
    • Fas or FasL null mice
  • Breakdown of T cell anergy
    • Increased co-stimulatory molecules in RA synovium, MS, experimental IDDM
  • Molecular mimicry
    • Streptococcal M protein and cardiac proteins: acute rheumatic fever
  • Polyclonal lymphocyte activation
    • Superantigen activation of autoreactive T cells
  • Release of sequestered antigens
    • Post-traumatic uveitis or orchitis
  • Decreased Treg activity
summary
Summary
  • Four general mechanisms have been described by which the immune response can damage host cells and tissues
    • (type I-IV hypersensitivity reactions)
  • Hypersensitivity mechanisms are important in the pathogenesis of allergic, autoimmune, and some infectious diseases
  • The pathogenesis of autoimmune diseases involves failure of peripheral tolerance
  • Inflammation and inflammatory cytokines play important roles in propagating autoimmune reactions