Pathogenesis of drug allergy – current concepts and recent insights

Drug hypersensitivity reactions (DHRs) may be caused by immunologic and non‐immunologic mechanisms. According to the World Allergy Organization, drug allergy (DA) encompasses the subgroup of immunologic DHRs which are mediated either by specific antibodies or specific T lymphocytes. Due to the immunologic memory, DA reactions bear an increased risk for dramatically enhanced reactions on re‐exposure. Some current concepts of DA were described decades ago. Drug allergies to soluble macromolecular protein drugs such as biopharmaceuticals are predominantly T cell‐dependent drug‐specific antibody responses leading to IgE‐or IgG‐mediated allergy. However, most drugs are too small to be directly recognized by specific B and T cells. Immune reactions to low‐molecular drugs have been explained by the hapten model: a hapten drug can bind covalently to soluble autologous proteins (e.g. serum albumin). Resulting compounds may then be recognized by matching B cell receptors (BCRs) and induce a specific T cell‐dependent IgE‐or IgG‐antibody production. Drug haptens may bind to extra‐ or intracellular proteins, which are processed and presented by various professional antigen‐presenting cells (APCs). Depending on the APC, they may induce not only specific antibody production, but also non‐immediate T cell‐mediated DA. More recently, a supplementary effector mechanism for non‐immediate DA to low‐molecular drugs has been described, namely the pharmacological interaction of native low‐molecular drugs with immune receptors (p‐i‐concept). Low‐molecular drugs may directly and reversibly attach to immune receptors. These non‐covalent interactions may modify the affinity between autologous major histocompatibility complex (MHC), presented peptides and specifically primed T cell receptors (TCRs) and thereby stimulate T cells. A special type of p‐i‐reaction has been recently described between the antiviral drug abacavir and the F pocket of HLA‐B*57:01. This interaction causes an alteration of the MHC‐presented self‐peptide repertoire and may consecutively lead to a kind of auto‐reactivity. Such types of reactions can explain the strong MHC‐HLA associations which have been found for some T cell‐mediated DHRs.