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
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)
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
Non-cytopathic virus interactions with host
Zinkernagel,
1997
Effects of antiviral T cells
Virus feature
Protection
Immunopathology
Cytopathic
+++
Not noticeable
Noncytopathic
With limited
spread
Widespread or
involving
essential organs
Putative
(unknown) noncytopathic
Effects of antiviral T cells
(from Zinkernagel, 1997)
Virus feature
Protection
Immunopathology
Cytopathic
+++
Not noticeable
++
+/-
+
+++
Not
noticeable
+++
Noncytopathic
With limited
spread
Widespread or
involving
essential organs
Putative
(unknown) noncytopathic
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
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 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
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