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Immunopathology. Path 6266 May 18, 2010 Judy Aronson, M.D. 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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Path 6266

May 18, 2010

Judy Aronson, M.D.

  • 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)


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
  • 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

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



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


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
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
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
  • 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