Hypersensitivity

Hypersensitivity refers to undesirable (damaging, discomfort-producing and sometimes fatal) reactions produced by the normal immune system. Hypersensitivity reactions require a pre-sensitized (immune) state of the host. The four-group classification was expounded by P. H. G. Gell and Robin Coombs in 1963.^[1]

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Type 1 - immediate (or atopic, or anaphylactic)

Main article: Allergy

Type 1 hypersensitivity is an allergic reaction provoked by reexposure to a specific type of antigen referred to as an allergen.^[2] Exposure may be by ingestion, inhalation, injection, or direct contact. The difference between a normal immune response and a type I hypersensitive response is that plasma cells secrete IgE. This class of antibodies binds to Fc receptors on the surface of tissue mast cells and blood basophils. Mast cells and basophils coated by IgE are "sensitized." Later exposure to the same allergen, cross-links the bound IgE on sensitized cells resulting in degranulation and the secretion of pharmacologically active mediators such as histamine, leukotriene, and prostaglandin that act on the surrounding tissues. The principal effects of these products are vasodilation and smooth-muscle contraction.

The reaction may be either local or systemic. Symptoms vary from mild irritation to sudden death from anaphylactic shock. Treatment usually involves epinephrine, antihistamines, and corticosteroids. If the entire body gets involved, then anaphylaxis can take place; an acute, systemic reaction that can prove fatal.

Some examples:

• Allergic asthma
• Allergic conjunctivitis
• Allergic rhinitis ("hay fever")
• Anaphylaxis
• Angioedema
• Urticaria (hives)
• Eosinophilia
• Penicillin
• Cephalosporin

Type 2 - antibody-dependent

In type 2 hypersensitivity, the antibodies produced by the immune response bind to antigens on the patient's own cell surfaces. The antigens recognized in this way may either be intrinsic ("self" antigen, innately part of the patient's cells) or extrinsic (absorbed onto the cells during exposure to some foreign antigen, possibly as part of infection with a pathogen). These cells are recognised by macrophages or dendritic cells which act as antigen presenting cells, this causes a B cell response where antibodies are produced against the foreign antigen.

An example here is the reaction to penicillin where the drug can bind to red blood cells causing them to be recognised as different, B cell proliferation will take place and antibodies to the drug are produced. IgG and IgM antibodies bind to these antigens to form complexes that activate the classical pathway of complement activation for eliminating cells presenting foreign antigens (which are usually, but not in this case, pathogens). That is, mediators of acute inflammation are generated at the site and membrane attack complexes cause cell lysis and death. The reaction takes hours to a day.

Another form of type 2 hypersensitivity is called antibody-dependent cell-mediated cytotoxicity (ADCC). Here, cells exhibiting the foreign antigen are tagged with antibodies (IgG or IgM). These tagged cells are then recognised by natural killer (NK) cells and macrophages (recognised via IgG bound (via the Fc region) to the effector cell surface receptor, CD16 (FcγRIII)), which in turn kill these tagged cells.

Some examples:

• Autoimmune hemolytic anemia
• Goodpasture's syndrome
• Pemphigus
• Pernicious anemia (if autoimmune)
• Immune thrombocytopenia
• Transfusion reactions
• Hashimoto's thyroiditis
• Graves disease (see type V below)
• Myasthenia gravis (see type V below)
• Rheumatic fever
• Hemolytic disease of the newborn (erythroblastosis fetalis)
• Acute transplant rejection

Type 3 - immune complex

Type 3 hypersensitivity occurs when antigens and antibodies are present in roughly equal amounts, causing extensive cross-linking. Large immune complexes that cannot be cleared are deposited in vessel walls and induce an inflammatory response. The reaction can take hours, days, or even weeks to develop.

Some clinical examples:

• Rheumatoid arthritis
• Immune complex glomerulonephritis
• Serum sickness
• Subacute bacterial endocarditis
• Symptoms of malaria
• Systemic lupus erythematosus
• Arthus reaction
• Farmer's lung (Arthus-type reaction)

Type 4 - cell-mediated (delayed-type hypersensitivity, DTH)

See also: Cell mediated immunity

Type 4 hypersensitivity is often called delayed type as the reaction takes two to three days to develop. Unlike the other types, it is not antibody mediated but rather is a type of cell-mediated response.

CD8+ cytotoxic T cells and CD4+ helper T cells recognise antigen in a complex with either type 1 or 2 major histocompatibility complex. The antigen-presenting cells in this case are macrophages which secrete IL-12, which stimulates the proliferation of further CD4+ T cells. CD4+ T cells secrete IL-2 and interferon gamma, further inducing the release of other Type 1 cytokines, thus mediating the immune response. Activated CD8+ T cells destroy target cells on contact while activated macrophages produce hydrolytic enzymes and, on presentation with certain intracellular pathogens, transform into multinucleated giant cells.

Some clinical examples:

• Contact dermatitis (poison ivy rash, for example)
• Atopic dermatitis (eczema)
• Temporal arteritis
• Symptoms of leprosy
• Symptoms of tuberculosis
• Mantoux test
• Coeliac disease
• Chronic transplant rejection

Type 5 - stimulatory

This is an additional type that is sometimes (often in Britain) used as a distinction from Type 2.^[3]

Instead of binding to cell surface components, the antibodies recognize and bind to the cell surface receptors, which either prevents the intended ligand binding with the receptor or mimics the effects of the ligand, thus impairing cell signalling.

Some clinical examples:

• Graves disease
• Myasthenia gravis

(There is also a type 6 hypersensitivity reaction in which natural killer cells lyse cells that have been coated in antibody and this reaction is thought to be implicated with certain autoimmune diseases, tumour rejection & parasite rejection).

See also

• Allergy

References

1. ^ Gell PGH, Coombs RRA, eds. Clinical Aspects of Immunology. 1st ed. Oxford, England: Blackwell; 1963.
2. ^ med/1101 at eMedicine
3. ^ Rajan TV. The Gell-Coombs classification of hypersensitivity reactions: a re-interpretation. Trends Immunol. 2003 Jul;24(7):376-9. PMID 12860528