Transcript Immunopathology

Immunopathology
Path 6266
May 18, 2010
Judy Aronson, M.D.
[email protected]
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
“Pathos”:
Suffering/
disease
Protective responses against
infectious agents
Host tissue damage
by immune response
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 coexist
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!
Type I hypersensitivity
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: vasodilation, bronchospasm
• LTB4: chemotactic
factor
• PGD2: increased
mucus, bronchospasm
– Cytokines: TNF, IL-1, IL4, IL-5, IL-6)
Clinical diseases
• Systemic anaphylaxis
– Urticaria (hives), bronchoconstriction,
laryngeal edema, hypersecretion of mucus,
vomiting, abdominal cramps
– Life threatening
• Localized reactions—eg urticaria, hay
fever
• Asthma
Urticaria (hives)
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 II Hypersensitivity
ABO antigens and transfusion
Blood type
Natural Abs Can donate
present
to:
Can receive
from:
A
Anti-B
A, AB
A, O
B
Anti-A
B, AB
B, O
AB
none
AB
A,B,AB,O
O
Anti-A
Anti-B
All
O
Type III hypersensitivity
• Caused by immune complexes (antigenantibody) 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 III (Immune
complex)
Hypersensitivity
Normal glomerulus
Immune complex glomerulonephritis
HBV: Immune complex GN
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)
T cells have multiple effector functions
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)
Central and
peripheral
tolerance
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© 2005 Elsevier
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© 2005 Elsevier
• Experimental
evidence for failure
of “homeostatic
mechanisms” in
autoimmunity:
– 1: Failure of AICD
– 2: Inappropriate costimulatory 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)
Islets
Exocrine pancreas
Expression
of transgene
in b cells
Von Herrath 2002
Transgenic mouse model of IDDM
Adoptive transfer of
LCMV-reactive CTL
•“insulitis”
RIP-LCMV
transgenic
mouse
•No b-cell
destruction
•No IDDM
Transgenic mouse model of IDDM
Trigger:
Infect with
LCMV
RIP-LCMV
transgenic
mouse
Variable lag time
• Increased glucose
• Decreased insulin
• Beta cell destruction
•Insulin dependent
diabetes mellitus
Lessons from LCMV-RIP model of IDDM
• Peripheral tolerance can be broken.
This requires:
– Activation of APC’s and production of costimulatory 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 b-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
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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+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
1.
2.
3.
4.
5.
6.
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
• 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