Hypersensitivity

Hypersensitivity is defined as "altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen.."

Classification

The four-group classification was proposed in 1963.

Type 1 - immediate (or atopic, or anaphylactic)

Type 1 hypersensitivity is an allergic reaction provoked by reexposure to a specific type of antigen referred to as an allergen. 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.

Examples

• Allergic asthma
• Allergic conjunctivitis
• Allergic rhinitis ("hay fever")
• Anaphylaxis (defined as "may include rapidly progressing urticaria, respiratory distress, vascular collapse, systemic shock")
• Angioedema
• Eosinophilia
• Urticaria (hives)

Treatment

There are minimal randomized controlled trials to guide treatment, especially for treating anaphylaxis.

One protocol that successfully treated 241 drug hypersensitivity reactions is:

• Reactions without a decrease in blood pressure. Give 40 to 60 mg of prednisolone and then 10 mg of loratadine or cetirizine for 2 days.
• Reactions with anaphylaxis. Give 0.25 µg of intramuscular epinephrine in addition to prednisolone or antihistamine. Repeat epinephrine every 15 minutes if necessary.
• Reactions with hypotension. Give plasma expanders as needed.

For treating anaphylaxis, in the absence of empiric evidence a review of six clinical practice guidelines found that:

• Epinephrine intramuscularly at doses ranging from 0.01 mg/kg up to 0.5 mg is recommended by all guidelines.
• Antihistamines (H₁) are recommended by all but one guideline. Most recommended diphenhydramine while one guideline recommended chlorphenamine. The one dissenting guideline is from Australia where the only parenteral antihistamine is promethazine. While this guideline does not recommend antihistamines, it allows oral, non-drowsiness-inducing antihistamines that do not act on other receptors for other amines (such as serotonin or catecholamines).
• Antihistamines (H₂) were not studied in this review.
• Glucocorticoids parenterally are recommended by all but two guidelines.

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 diseases

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 of hypersensitivity, it is mediated by T-cells rather than B-cells.

Type 4 reactions can be subdivided by the specific type of T-cell response that occurs when macrophages present antigen in a complex with either type 1 or 2 major histocompatibility complex.

• Type 4a: T-helper (CD4⁺) Type 1 (T_H1) T cells secrete interferon-gamma which activates macrophages to produce complement-fixing antibody isotypes. Rashes that are mediated by this type may be eczematous.
• Type 4b: T-helper (CD4⁺) Type 2 (T_H2) T cells secrete the cytokines interleukin-4 and interleukin-5, which promote B-cell production of IgE and IgG4, macrophage deactivation, and mast-cell and eosinophil responses. Rashes that are mediated by this type may include bullae.
• Type 4c: Cytolytic T-cells (CD8⁺) (CTLs or T_C cells) T cells secrete the cytokines performin and granzyme B. Rashes that are mediated by this type may include bullae and/or pustules.
• Type 4d: T-cells produce interleukin-8 which activates neutrophils. Rashes that are mediated by this type may include pustules.

Some clinical examples:

• Atopic dermatitis (eczema)
• Contact dermatitis. An example is the poison ivy rash, which is predominantly a Type 4a reaction.
• Coeliac disease
• Chronic transplant rejection
• Leprosy
• Mantoux test
• Temporal arteritis
• Tuberculosis

Type 5 - stimulatory

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

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