The first step in type I hypersensitivity reactions involves an antigen binding to an antibody, IgE, on the surface of mast cells and basophils, which is known as sensitization (Fig. 19.2). This results in very little if any type of reaction upon initial exposure. It is the subsequent exposure to the same or similar antigen that results in an allergic reaction. After being sensitized to a specific antigen, the host recognizes the offending antigen and forms a cross-linking of two IgE antibodies, which results in degranulation and release of mediators from both mast cells and basophils. These mediators include histamine, arachidonic acid metabolites (leukotrienes and prostaglandins), kinins, eosinophil chemotactic factor of anaphylaxis (ECF-A), and platelet-activating factor (PAF). For unknown reasons, nonallergic individuals exposed to antigens result in IgG antibody formation and lack the cross-linking of IgE antibodies.

Histamine activates receptors directly by binding H₁, H₂, and H₃ receptors. The receptors of primary concern in type I reactions are mainly the H₁ and H₂ receptors. H₁ receptor activation results in flushing, tachycardia, and increase in mucous production, whereas H₂ receptor activation increases gastric secretion and vascular permeability. Arachidonic acid metabolites, both leukotrienes and prostaglandins, are responsible for creating physiological changes in the host resulting in unwanted side effects. Leukotrienes are involved in bronchoconstriction via smooth muscle contraction, increased vascular permeability, and myocardial depression. Prostaglandins produce vasodilatation, bronchospasm, increased vascular permeability, and pulmonary hypertension.

Kinins are small peptides that produce vasodilatation, increase vascular permeability, and bronchoconstriction. They are also involved in stimulating the release of nitric oxide and prostacyclin. ECF-A is a small-molecular-weight peptide mediator involved in chemotaxis of eosinophils at the site of the allergic reaction and inflammation. PAF is involved in stimulating both platelets and leukocytes to release inflammatory products and is responsible for local and systemic anticoagulation.

Anaphylaxis is one example of a type I allergic reaction along with allergic rhinitis, extrinsic asthma, urticaria, and angioedema (lisinopril). Anaphylaxis is an exaggerated form of type I hypersensitivity and can be caused by food (peanuts), drugs (penicillin), latex, contrast dye, and shellfish. This reaction, as stated above, requires prior exposure to the specific offending antigen or a similar structured molecule to form cross-linked IgE antibodies. If not recognized early, anaphylaxis can become life threatening.

Type II hypersensitivity is cytotoxic, involving complement activation. An antigen is introduced into the host, which is attached to an antibody, IgG or IgM. This combination of antigen–antibody activates complement, which results in the lysis of the antigen. After lysis of the antigen, phagocytosis is initiated. Examples of type II hypersensitivity reactions include hemolytic transfusion reactions, autoimmune hemolytic anemia, drug-induced hemolytic anemia (quinine, penicillin, hydralazine), and heparin-induced thrombocytopenia.

Type III hypersensitivity reactions involve the formation of antigen–antibody complexes, which are then deposited in various tissues. This deposition initiates an inflammatory response involving complement and neutrophil activation, resulting in damage to the tissue for that given organ system. The antigen may be exogenous (bacterial, viral, parasitic) or endogenous (non-organ-specific autoimmunity such as systemic lupus erythematosus (SLE)). The antigen is soluble and not attached to the organ involved. Examples of type III hypersensitivity reactions include serum sickness, skin reactions (SLE, Arthus reaction), SLE (kidneys), polyarteritis (arteries), and rheumatoid arthritis (joints).

Type IV hypersensitivity is also known as delayed type hypersensitivity due to the absence of immediate signs and symptoms. This reaction involves sensitized T-cell lymphocytes (helper T cells), which releases lymphokines. Lymphokines are involved in inflammation and activation of T lymphocytes (cytotoxic T cells). Cytotoxic T cells specifically attack and kill these antigens on subsequent exposure. This reaction results in tissue damage. Examples of type IV hypersensitivity reactions include graft-versus-host reactions, tuberculin immunity, and contact dermatitis (poison ivy, chemicals, heavy metals).