Abstract
Abstract
Cutaneous eruptions caused by drug hypersensitivity reactions have been the subject of great interest to dermatologists for more than half a century. The precise molecular pathways involved in their pathogenesis are becoming clearer but there remain many areas that are poorly understood. Close delineation of the mechanistic pathways has been possible for some reactions including those where a close association with a specific human leukocyte antigen (HLA) type has been demonstrated. This work was led by the discovery that abacavir directly binds the HLA‐B*5701 major histocompatibility complex (MHC) peptide groove thereby altering the repertoire of self‐peptides that can be expressed in the MHC. Such novel self‐peptides are targeted T cells, which results in cytokine inflammation and induces clinical features typical of a drug hypersensitivity syndrome. HLA associations with severe cutaneous adverse reactions have now been shown for many different drugs. Despite the initial enthusiasm of this approach, it has become apparent that some drug–HLA associations have a lower odds ratio than others. This underscores the interpretation that other individual factors are at play as well as HLA sequence. Indeed, drug/HLA/clinical phenotype do not always correlate. For example, carbamazepine hypersensitivity is associated with both HLA‐B*1502 and HLA‐A*3101, yet genetic studies show that the former only predisposes to Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) although the latter associates with exanthems, systemic hypersensitivity and SJS/TEN. In TEN, multiple molecular mechanisms of keratinocyte death have been postulated but two predominate including: (i) FasL upregulation and induction of Fas‐mediated keratinocyte cell death; and (ii) cytotoxic granulysin production by T, natural killer (NK) and NKT cells. Whether these act independently or synergistically remains to be established.