Drug allergies: mechanism and genetic factors

Drug allergies do not depend on the pharmacologic profile of the drug, but on the susceptibility of the treated individual. Drug allergies involve the immune system, particularly drug reacting T cells or drug specific antibodies. Although the adaptive immune system is supposed to recognize rather macromolecules and proteins than drugs, small molecules and notably drugs are also able to induce immune responses. This phenomenon can be explained by several concepts. According to the hapten theory, a drug or its metabolites must first make covalent bindings with endogenous macromolecules in order to become antigenic. Then, the induced modification of the macromolecule can be recognized as non-self by the adaptive immune system and an immune response can arise. Many studies on contact allergies and antibodies mediated drug allergies corroborate the hapten theory. Nevertheless, this mechanism cannot explain allergies to chemically inert drugs. In such cases, pharmacological interactions (non covalent) between drugs and immune receptors (so called p-i-concept) can lead to immune stimulation without modification of macromolecules. This mechanism seems to be particularly relevant for delayed type reactions, mediated by T cells directly. In the last decade, genetic factors associated with drug allergies have been identified for several drug allergies. The identified HLA-alleles associated with severe drug allergies underscore the important role of drug reacting T cells in the pathogenesis of drug allergy.