Immunopathology: Hypersensitivity Flashcards
What is Hypersensitivity?
An immune response that results in tissue injury or immune-mediated tissue injury. The target could be foreign or self antigens
Classified into 4 basic varieties by Gel and Coombs: types I to IV
This classification is based on the pathogenesis of the operative immune mechanisms in each case
Type I hypersensitivity
Also known as immediate hypersensitivity, anaphylaxis, immediate allergy, and atopic reactions
Seen in
Hay fever
Bronchial asthma
Anaphylactic shock
Skin allergy (hives)
Allergic conjuctivitis
Type II hypersensitivity
Complement-mediated cytotoxicity (direct lysis): Complement products directly lyse the target cells by formation of C5b-9 (membrane attack complex), which has the ability to insert into the plasma membrane and form “holes” or ionic channels, thereby destroying the permeability barrier and inducing the lysis of the cell. Complement is activated by the Fc fragment of the antibodies coating the target cell
Seen in: Autoimmune haemolytic anaemia, drug-induced haemolytic anaemia, Rhesus iso-immunisation, blood transfusion reactions from major blood group incompatibility
Type II: Complement-dependent cell-mediated cytotoxicity (opsonisation) [CDCC]
Complement interaction on the cell surface leads to the formation of C3b.
Many phagocytes have binding sites for C3b. By binding to the C3b on the target cells the phagocyte is bridged to the target cells, which can then be phagocytosed
Type II Hypersensitivity: Antibody-dependent cell-mediated cytotoxicity (ADCC) and example
Here antibodies coat target cells and their Fc region bind to Fc receptors (CD16) on NK cells.
During their interaction, the NK cell inserts a protein, perforin, in the membrane of the target cell, which functions to induce apoptosis.
Seen in autoimmune thyroiditis. ADCC is an important mechanism employed in normal surveillance against spontaneous malignant tumours.
Type II Hypersensitivity: Antibody-mediated functional changes
Here the binding of an antibody to a cellular antigen leads to a stimulation of the cell with up-regulation of its normal physiological actions.
There might be up- or down-regulation:
a. In Graves disease the autoantibodies (long-acting thyroid stimulator - LATS) against the TSH-receptor mimics the effector TSH, they bind to TSH receptors thereby stimulating thyroid acinar cells (but LATS are not sensitive to negative feedback therefore causing excessive production of thyroid hormone - hyperthyroidism).
b. By contrast, in myasthenia gravis the autoantibody competes with acetylcholine for the acetycholine receptors in the neuromuscular end plate, thereby inhibiting synaptic transmission.
Type III hypersensitivity
Also known as immune complex disease
An immune complex is formed by the union of antigen and antibody
Immune complexes are normally phagocytosed (because they function as opsonins) or filtered off in the urine.
Type III Hypersensitivity is caused by failure of immune-complex clearance under 2 scenarios:
Examples of Type III reactions
- Circulating immune complex disease (Serum sickness model)
Based on the physicochemical characteristics of the immune complexes, such as size and charge, the Ag-Ab complexes formed in the circulation may get deposited in tissues including renal glomerulus, arteries, synovial membranes, lungs, skin venules, etc
- Localised immune complex disease (Arthus phenomenon model)
Occurs when a large dose of antigen is introduced locally into a tissue or organ e.g. infection
Immune complexes cause an inflammatory reaction by activating complement, thus leading to chemotactic recruitment of neutrophils and macrophages, which in turn release their tissue-damaging mediators — proteases and oxygen-derived radicals
Examples: PAN, vasculitis associated with hepatitis B, SLE, rheumatoid arthritis, most glomerulonephritides.
Mechanism of Type 1 hypersensitivity
- APC present allergen on cell surface which activates naive T helper cells to TH-2, which releases IL-4 to convert B lymphocyte to a plasma cell
- Plasma cell releases and IgE Fc end attaches to Fc receptors of mast cells and basophils
- On 2nd exposure, the allergen binds to Fab end of antibody
- There is Ca2+ influx, ↑cAMP which causes degranulation and release of chemical mediators causing the hypersensitivity reaction
Examples of PRE-FORMED mediators
PRE-FORMED
Histamine (vasodilatation, oedema); eosinophil chemotactic factor (ECF-A); heparin; serotonin.
Examples of SYNTHESISED DE NOVO mediators
SYNTHESISED DE NOVO
Leukotrienes C4, D4, E4 (bronchoconstriction, oedema); platelet activating factor; PGD2, TXA2
What are the 3 main mechanisms invloved in a Type II reaction?
- Complement-dependent cell-mediated cytotoxicity (opsonisation) [CDCC]
- Antibody-dependent cell-mediated cytotoxicity [ADCC]
- Antibody-mediated functional changes
Type IV hypersensitivity
Examples
This is an antigen-elicited cellular immune reaction that results in tissue damage and does not require participation of antibodies
T-cell mediated
Example: The tuberculin skin reaction typifies this process and contact dermatitis (poison ivy rxn)
Involves mononuclear cells that aggregate in response to subcutaneous injection of soluble protein antigen and reaches greatest intensity 24-48hrs after injection
Mechanism of Type 4
- Compound binds with body proteins, immune system reconizes these Complex protein as foreign (Ag)
- Ingested by macrophage and processed (Small reactive Ags may bind directly)
- Presented on the surface of APC’s in association with class II HLA molecules to a naive T-Helper cell
- Ag-specific T cells recognize Ag+class II molecules
- Under the effect of macrophage-derived monokine, T cell is stimulated and releases lymphokines: PAF, IL-2, and gamma-IFN.
