Lecture outline
• Types of hypersensitivity reactions
• Immediate hypersensitivity, allergy
• Antibody-mediated diseases
• T cell-mediated diseases
• Therapeutic approaches
Immunological (hypersensitivity) diseases
• Diseases caused by aberrant (excessive or
uncontrolled) immune reactions
– Reactions against self antigens (autoimmunity)
– Uncontrolled or excessive reactions against foreign antigens
• Underlying problem may be failure of self-tolerance
and control mechanisms
• The nature of the disease is determined by the
type of immune response
– Diseases are classified based on immune mechanisms:
useful for understanding pathogenesis, but many diseases
involve multiple mechanisms
Types of hypersensitivity disease
Pathogenic immune
Mechanism of
tissue injury
Immediate hypersensitivity (Type I)
IgE antibody,
mast cells
Mast cell mediators
Antibody mediated
(Type II)
IgM and IgG antibodies
against cell and matrix
•Interference with
cell functions
Complexes of circulating
Immune complex
antigens and IgM or
mediated (Type III)
IgG antibodies
Complement and Fc
receptor mediated
T cell mediated
(Type IV)
•Killing by CTLs
Type of hypersensitivity
CD4 and CD8 T cells
Immediate hypersensitivity reaction
Stages of immediate hypersensitivity reactions
Sequence of events in immediate hypersensitivity
Actions of mast cell mediators
Mast cell products are responsible for the manifestations of
immediate hypersensitivity
Clinical manifestations of immediate hypersensitivity
Treatment of immediate hypersensitivity disorders
Genetic susceptibility for immediate
• Allergic diseases run in families
– Different members of the same family may
show different manifestations of immediate
hypersensitivity (“atopy”)
• Multiple susceptibility genes have been
identified by gene mapping and family
– Genes may influence TH2 responses, IgE production,
mast cell activation, end-organ sensitivity
– Susceptibility loci identified include: HLA (immune
responsiveness); cytokine gene cluster; others
How antibodies deposit in tissues
Antibody is
specific for
tissue antigen
(typically self):
disease is
specific for
target tissue
Antibody reacts
with circulating
antigen (self
or foreign), and
complexes tend
to deposit in
small vessels; not
specific for
any tissue
How antibodies cause disease -- 1
Neutrophils (and monocytes) are recruited by complement
products (generated by the classical pathway) and binding to Fc
tails of deposited antibodies, and are activated.
Leukocyte recruitment and activation are part of inflammation.
Experimental models of immune complex
• Serum sickness
– Systemic immunization with large dose of
protein antigen --> circulating immune
complexes --> complexes deposit in vessels
and cause inflammation (Fc receptor and
– Arthritis, vasculitis, glomerulonephritis
• Arthus reaction
– Subcutaneous administration of antigen in
previously immunized individual --> formation
and deposition of local immune complexes
– Cutaneous vasculitis
Immune complex-mediated glomerulonephritis
Anti-basement membrane antibodymediated glomerulonephritis
How antibodies cause disease -- 2
Antibody and/or complement (C3b) are deposited on cell and
are recognized by receptors for Fc or C3b on phagocytes -->
coated (opsonized) cell is ingested and destroyed.
Basis of autoantibody-mediated depletion of RBCs, platelets
How antibodies cause disease -- 3
Causes of antibody-mediated diseases
• Autoimmunity (production of autoantibodies)
– May be due to failure of self-tolerance in
autoreactive B cells or helper T cells
• Antibody responses to foreign antigens
– Antibodies against hepatitis B form immune
complexes --> vasculitis (polyarteritis nodosa)
– Post-streptococcal glomerulonephritis: immune
complexes of Strep antigen + anti-Strep
antibodies; formed in circulation or GBM
– Not known why immune complex diseases
develop in rare individuals after common
How T cells injure tissues -- 1
CD4+ T cells respond to self (or microbial) antigens, produce
cytokines that recruit and activate macrophages and neutrophils,
and the products of these leukocytes damage tissues.
Recall that the same reaction destroys phagocytosed microbes
(cell-mediated immunity, one arm of host defense)
Delayed type hypersensitivity (DTH) reaction
Detectable reaction to an antigen in a
sensitized (previously exposed) individual
Caused mainly by CD4+ T cells  cytokine
secretion  inflammation, macrophage
Morphology of a delayed type hypersensitivity
(DTH) reaction
Classically attributed to Th1 response; may include Th17.
How T cells injure tissues -- 2
Cytotoxic T lymphocytes (CTLs) react against antigens
in host tissues and kill (“lyse”) the host cells.
Causes of T cell-mediated
hypersensitivity diseases
• Autoimmunity
– Type 1 diabetes, multiple sclerosis, rheumatoid
arthritis, psoriasis
• Reaction to microbes and other foreign
– Contact sensitivity (DTH) to chemicals (poison ivy)
– Tuberculosis (granulomatous inflammation in
response to a persistent microbe: chronic DTH)
– Crohn’s disease (excessive Th1 and Th17
responses to gut commensals?)
– Viral hepatitis (CTLs kill virus-infected
hepatocytes); not considered an example of
Immune-mediated inflammatory diseases
• Chronic diseases in which inflammation is a
prominent component and the immune
system reacts excessively against one or
more tissues
- Major role of CD4+ T cells and cytokines;
antibodies may contribute to disease
- Same therapies work in many of these diseases
• These diseases develop because the normal
controls on immune responses fail; typically
due to autoimmunity but may be excessive
reactions to microbes
– MS, type 1 diabetes, RA: autoimmunity
– Crohn’s: reaction against gut microbes?
Chronicity of immune-mediated
inflammatory diseases
• Many of these hypersensitivity diseases
are chronic and even self-perpetuating
– The initiating stimuli cannot be removed (self
or environmental antigens, persistent
– The immune response tends to amplify itself
(normally, enables few antigen-specific
lymphocytes to deal with infections)
Amplification loop in DTH reactions
Cytokines are
amplifiers of
immune reactions
Therapy of immune diseases:
the current way
• Block the production or counteract the actions
of effector molecules that cause tissue injury
– Anti-inflammatory drugs, e.g. steroids
– Block T cell activation (immunosuppressive
drugs, e.g. cyclosporine)
– Deplete pathogenic antibodies
(plasmapheresis), B or T lymphocytes
(depleting antibodies)
• Empirical
– Desensitization for allergy
– Intravenous IgG (IVIg): engages inhibitory
FcR on B cells?
Therapy of immune disorders: rational approaches target
lymphocyte activation and subsequent inflammation
Inhibitors of calcineurin,
(block costimulation)
various kinases
(inhibit signaling)
T cell
(block cytokine
IL-12, IL-23
TNF, IL-1,
TNF, IL-1,
IL-6 Anti-p40
(block cytokines)
(block adhesion)
Molecularly targeted therapies for
immunological diseases: the rational approach
• Target the molecular basis of lymphocyte
activation and effector functions:
rationally designed therapies
– Based on understanding of lymphocyte biology
– Risks -- reactivation of infections
• Induce antigen-specific immunological
tolerance: requires identification of target
– Being tried in MS, type 1 diabetes (in which
the major autoantigens are known)

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