Anti-epileptic drugs and severe cutaneous drug reactions in certain ethnic populations & HLA association

Abstract

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe adverse reactions, which could be induced by a variety of drugs. It was proposed that human leukocyte antigen (HLA)-restricted presentation of antigens (drugs or their metabolites) to T lymphocytes initiates the immune reactions of SJS-TEN. The genetic susceptibility and the exact immunological pathogenesis were not clear until the recent studies. It was first identified that HLA-B*1502 is strongly associated with carbamazepine (CBZ)-induced SJS-TEN and HLA-B*5801 with allopurinol-SJS- TEN in Han Chinese. The same associations had been validated across different human populations. For the downstream danger signals, Fas-Fas ligand (FasL) and perforin -granzyme B had been advocated as cytotoxic mediators for keratinocyte death in SJS-TEN. However, expression levels of these cytotoxic proteins from the skin lesions were too low to explain the distinct and extensive epidermal necrosis. In recent study it was identified that the granulysin, a cytotoxic protein released from cytotoxic T cells or natural killer (NK) cells, is a key mediator for disseminated keratinocyte death in SJS-TEN. The article aims to provide an outlay of both of the genomic and immunologic perspectives of SJS-TEN. These studies give us a better understanding of the immune mechanisms, biomarkers for disease prevention and early diagnosis, as well as providing the therapeutic targets for the treatments of SJS-TEN.