Transcript 10 Hypersensitivity.

Hypersensitivity.
Transplantation and tumor
immunity.
M. S. Tvorko
Immunopathology
Hypersensitivity
Autoimmunity
Immunodeficiency
ALLERGY
Peter Gell and Robert Coombs developed a classification
system for reactions responsible for hypersensitivities in 1963. Their
system correlates clinical symptoms with information about
immunologic events that occur during hypersensitivity reaction.
The Gell-Coombs classification system divides hypersensitivity into
four types:
Type I (Anaphylaxis) Hypersensitivity
Type II (Cytotoxic) Hypersensitivity
Type III (Immune Complex)
Hypersensitivity
Type IV (Cell-Mediated) Hypersensitivity
Allergic reactions are subdivided into two groups: (1)
immediate and (2) delayed reactions, although it is difficult to
draw a strict distinction between them.
Allergic reactions of immediate action are associated with Blymphocytes and antibodies circulating in the blood, allergic
reactions of delayed action with T-lymphocytes.
TYPE I: IMMEDIATE (ANAPHYLACTIC) HYPERSENSITIVITY
Mast cells display a high
affinity receptor for IgE
IgE is synthesised in
response to certain
antigens (allergens)
Allergens are deposited on
mucous membranes and
taken up and processed
by antigen presenting cells
(e.g. Dendritic cells or B
cells)
Allergen presented to TH2
cells which provide cytokine
signals to B cells to
produce IgE Ig E binds to
mast cells
Cross linking of IgE by
subsequent exposure to
allergen causes mast cell
degranulation
Mast cell degranulation is the major initiation of the acute
allergic reaction
Mast cell mediators include histamine, heparin and other
factors
These cause, mucus secretion, vasodilation and oedema
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Mast cell mediators include pre-formed and newly formed
mediators
Pre-formed mediators include : histamine, heparin and
neutral protease
Newly formed mediators include leukotrienes, prostaglandin
D2 and platelet activating factor
Skin testing can be useed for
identify
the
allergen
responsible for allergies.
These
tests
involve
inoculating small amounts
of suspect allergen into the
skin. Sensitivity to the
allergen is shown by a rapid
inflammatory
reaction
characterizide by redness,
swelling, and itching at the
site of inoculation
Stages of
reaction and
mechanism
Prevention
therapy
Allergen penetrates
into individual
Avoid meeting
allergen
IgE antibody is
induced by allergen
and binds to mast
cells and basophils
Desensitization
When exposed to the
allergen again, the
allergen cross-links
the bound IgE,which
induces degranulation
Stabilization of mast
cells (chromolyn
sodium, theocine,
caffeine)
Release of mediators
Antagonists of
mediators,
Antihistamine drugs
Local manifistations:
rhinitis, asthma,
urticaria
Inhibitors of late
stage.
Corticosteroides,
indometacin
Desensitization. Major manifestations of anaphylaxis
occur when large amounts of mediators are suddenly
released as a result of a massive dose of antigen
abruptly combining with IgE on many mast cells. This is
systemic anaphylaxis, which is potentially fatal.
Desensitization can prevent systemic anaphylaxis.
Acute desensitization involves the administration of
very small amounts of antigen at 15-minute intervals.
Antigen-IgE complexes form on a small scale, and not
enough mediator is released to produce a major
reaction. This permits the administration of a drug or
foreign protein to a hypersensitive person, but
hypersensitivity is restored days or weeks later.
involves the long-term
weekly administration of the antigen to which the
person is hypersensitive. This stimulates the production
of IgG-blocking antibodies in the serum, which can
prevent subsequent antigen from reaching IgE on mast
cells, thus preventing a reaction.
Chronic
desensitization
Type II Mechanism
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Antibody mediated
hypersensitivity
Antibody directed against
membrane and cell surface
antigens (autoantibodies)
Antigen-antibody reactions
activate complement
producing membrane damage
Examples include: transfusion
reactions and haemolytic
disease of the newborn
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Antibodies bind to cell surface
Phagocytes bind to the antibody
via their Fc receptor
Phagocytosis of target cell
Antibody binding also activates
complement via the classical
pathway
Complement mediated cell lysis
Type III Hypersensitivity
Immune complex mediated
Excessive formation of immune
complexes e.g. persistent
low-grade infection, repeated
inhalation of antigens
Examples of Type III
hypersensitivity include:
Farmers lung, immune
complex glomerulonephritis
Normally immune complexes are
degraded by phagocytosis,
particularly in the liver and
spleen
Excessive immune complex
formation results in deposition in
the tissues, particularly
arterioles, kidney and joints
Complexes induce platelet
aggregation and complement
activation
Attempted phagocytosis causes
enzyme release and results in
tissue damage
Type III Hypersensitivity
RF is capable of selfassociating into immune
complexes
These immune complexes
may fix complement and
activate additional
inflammatory processes
Small immune complexes may
directly activate
macrophages to produce
proinflammatory cytokines
by binding to macrophagesurface receptors
Type IV Hypersensitivity
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Delayed type hypersensitivity
Takes more than 12 hrs to develop after
antigenic challenge
Examples include: contact dermatitis and
tuberculin reaction
Antigens include large molecules or small
molecules (haptens) linked to carrier
molecules
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APC resident in the
skin process antigen
and migrate to
regional lymph nodes
where they activate T
cells
Sensitised T cells
migrate back to the the
skin where they
produce cytokines
which attract
macrophages which
cause tissue damage
Type IV Mechanism
Type IV Reaction – Contact Dermatitis
Autoimmunity
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Autoimmunity is a reaction of the immune
system to the bodies own tissues
Self molecules are recognised as antigens
due to a breakdown of self-tolerance
Antibodies (autoantibodies) react against
these components
Includes organ-specific and non-organ
specific diseases
CLASSIFICATION OF
AUTOIMMUNE DISEASES
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Organ Specific
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Insulin dependent diabetes mellitus (IDDM) / Type I)
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Grave’s disease
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Goodpasture’s syndrome
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Myasthenia gravis
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Systemic
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Systemic lupus erythematosus
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Rheumatoid arthritis
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Multiple sclerosis
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Sjogren’s syndrome
Autoantibodies
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ANA (antinuclear antibodies): SLE Anti-ds DNA: SLE
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Anti-histone: drug-induced SLE
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Anti-IgM (rheumatoid factor): part of RA
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Anti-neutrophil: vasculitis
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Anti-centromere: CREST - scleroderma
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Anti-mitochondrial: primary biliary cirrhosis
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Anti-basement membrane: Goodpasture’s (renal, lung)
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Anti-epithelial cell: pemphigus vulgaris
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Anti-gliadin (not an autoantibody): celiac disease,
dermatitis herpetiformis
Systemic Lupus Erythematosus
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Chronic, systemic inflammatory disease caused by
immune complex formation.
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The word "systemic" means the disease can affect many
parts of the body.
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Pathophysiology associated with clinical features
secondary to immune complexes depositing in tissues
resulting in inflammation.
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Parts of the body affected include: the joints, skin,
kidneys, heart, lungs, blood vessels, and brain.
SLE Butterfly Rash
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The source of the name
"lupus" is unclear. All
explanations originate with
the characteristic butterflyshaped malar rash that the
disease classically exhibits
across the nose and
cheeks.
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Stranger still, is the
account that the term
"Lupus" didn't come from
latin at all, but from the
term for a French style of
mask which women
reportedly wore to conceal
the rash on their faces
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Effector mechanisms
 Autoantibodies to many autoantigens
 Most common autoantibody is to ds-DNA
 Immune complex deposition on basement
membranes with complement activation and
inflammation
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Laboratory diagnosis
 Anti-nuclear antibody (ANA)
 HEp-2 cells
 Homogeneous pattern and titer > 1:160
 Anti ds-DNA
 Crithidia lucilliae
 C3 level
RHEUMATOID ARTHRITIS
(RA)
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Characterized by inflammation of synovial
membrane of joints and articular surfaces of
cartilage and bone
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Vasculitis is a systemic complication
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Affects 3% to 5% of U.S. population
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Female to male ratio of 3:1
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HLA DR4 is genetic risk factor
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Effector mechanism
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CD4 T cells, activated B cells, macrophages and plasma cells
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85% of patients have rheumatoid factor
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Rheumatoid factor
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IgM, IgG and IgA specific for IgG
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Immune complex formation exacerbates inflammation
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Laboratory diagnosis
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Rheumatoid factor
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Anti-cyclic citrulinated peptide
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C-reactive protein (CRP)
Rheumatoid arthtritis
Grave’s disease
Myasthenia gravis
Multiple sclerosis
Types of Transplants
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Autograft
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Isograft
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Genetically identical
individuals
Allograft
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Self tissue
transferred from one
site to another
Different members of
the same species
Xenograft
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Different species
Hyperacute Rejection
Summary
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3 major types of graft rejection
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Immune response to MHC antigen is the
strongest force in rejection
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Graft rejection occurs in two stages
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Immunosuppressive therapies used to
suppress graft rejection