Mechanisms of Hypersensitivity

Baldo, Brian A.; Pham, Nghia H.

Allergic reactions to drugs are not always the result of the drug’s protein-binding capacity, biotransformation, or degradation. Mediator release from mast cells may occur via cross-linking of cell-bound IgE by di-(multi)valent free drug. The FcεRI high affinity receptor on mast cells has a central role in IgE-mediated allergic release of inflammatory mediators leading to the symptoms of an immediate allergic reaction. The low affinity IgE receptor FcεRII (CD23) has multiple functions including the up- and downregulation of IgE synthesis by B cells. Physiological and pharmacological effects of histamine are mediated through four receptors, H(1), H(2,) H(3), and H(4.) Cysteinyl leukotrienes and PAF are powerful mediators of anaphylaxis, asthma, and shock. Sphingosine-1-phosphate, elevated in the lungs of asthmatics, regulates pulmonary epithelium permeability and contributes to the pathogenesis of anaphylaxis. Urticaria is a heterogeneous disease with many subtypes. Both ACE inhibitors and angiotensin II receptor blockers may cause angioedema. Abacavir changes the shape of the HLA antigen-binding cleft producing an alteration in the repertoire of self-peptides that bind HLA-B*57:01 and a T cell response to self-proteins. Drug-induced delayed-type cutaneous hypersensitivity reactions are mediated by CD4+ and CD8+ CD3+ T cells in the dermis and epidermis. Type IV reactions include allergic contact dermatitis, maculopapular exanthema, fixed drug eruption, baboon syndrome, psoriasis, AGEP, DRESS, erythema multiforme, vitiligo, Sweet’s syndrome, SJS, and TEN. Granulysin appears to be a key molecule for keratinocyte killing in SJS/TEN. Drugs provide good examples of types II (immune hemolytic anemia, drug-induced thrombocytopenia) and III (serum sickness-like, vasculitis) hypersensitivities. Causes and mechanisms of pruritus are many and varied.