m. s. tvorko hypersensitivity. transplantation and tumor immunity
TRANSCRIPT
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M. S. Tvorko
Hypersensitivity. Transplantation and tumor immunity.
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Immunopathology
Hypersensitivity Autoimmunity Immunodeficiency
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ALLERGYALLERGY
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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 B-lymphocytes and antibodies circulating in the blood, allergic reactions of delayed action with T-lymphocytes.
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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 reactionMast cell mediators include histamine, heparin and other factorsThese cause, mucus secretion, vasodilation and oedema
TYPE I: IMMEDIATE (ANAPHYLACTIC) HYPERSENSITIVITY
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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
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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
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Stages of Stages of reaction and reaction and
mechanism mechanism
Prevention Prevention therapytherapy
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 degra-nulation
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
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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.
Chronic desensitization 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.
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Type II Mechanism
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
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
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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
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Type III Hypersensitivity
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RF is capable of self-
associating 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 macrophage-
surface receptors
RF is capable of self-
associating 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 macrophage-
surface receptors
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Type IV Hypersensitivity
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
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Type IV Mechanism
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Type IV Reaction – Contact Dermatitis
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Autoimmunity
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
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CLASSIFICATION OF AUTOIMMUNE DISEASES
Organ Specific• Insulin dependent diabetes mellitus (IDDM) / Type I)• Grave’s disease• Goodpasture’s syndrome• Myasthenia gravis
Systemic• Systemic lupus erythematosus• Rheumatoid arthritis• Multiple sclerosis• Sjogren’s syndrome
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ANA (antinuclear antibodies): SLE Anti-ds DNA: SLE Anti-histone: drug-induced SLE Anti-IgM (rheumatoid factor): part of RA Anti-neutrophil: vasculitis Anti-centromere: CREST - scleroderma Anti-mitochondrial: primary biliary cirrhosis Anti-basement membrane: Goodpasture’s (renal, lung) Anti-epithelial cell: pemphigus vulgaris Anti-gliadin (not an autoantibody): celiac disease,
dermatitis herpetiformis
Autoantibodies
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Systemic Lupus Erythematosus Chronic, systemic inflammatory disease caused by
immune complex formation.
The word "systemic" means the disease can affect many parts of the body.
Pathophysiology associated with clinical features secondary to immune complexes depositing in tissues resulting in inflammation.
Parts of the body affected include: the joints, skin, kidneys, heart, lungs, blood vessels, and brain.
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SLE Butterfly Rash The source of the name
"lupus" is unclear. All explanations originate with the characteristic butterfly-shaped malar rash that the disease classically exhibits across the nose and cheeks.
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
Laboratory diagnosis Anti-nuclear antibody (ANA)
HEp-2 cells Homogeneous pattern and titer > 1:160
Anti ds-DNA Crithidia lucilliae
C3 level
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RHEUMATOID ARTHRITIS (RA)
Characterized by inflammation of synovial membrane of joints and articular surfaces of cartilage and bone
Vasculitis is a systemic complication
Affects 3% to 5% of U.S. population
Female to male ratio of 3:1
HLA DR4 is genetic risk factor
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Effector mechanism• CD4 T cells, activated B cells, macrophages and plasma
cells• 85% of patients have rheumatoid factor
Rheumatoid factor• IgM, IgG and IgA specific for IgG• Immune complex formation exacerbates inflammation
Laboratory diagnosis• Rheumatoid factor• Anti-cyclic citrulinated peptide• C-reactive protein (CRP)
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Rheumatoid arthtritisRheumatoid arthtritis
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Grave’s diseaseGrave’s disease
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Myasthenia gravis
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Multiple sclerosisMultiple sclerosis
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Types of Transplants Autograft
Self tissue transferred from one site to another
Isograft Genetically identical
individuals
Allograft Different members of
the same species
Xenograft Different species
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Hyperacute Rejection
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Summary 3 major types of graft rejection
Immune response to MHC antigen is the strongest force in rejection
Graft rejection occurs in two stages
Immunosuppressive therapies used to suppress graft rejection
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