Genetic markers and danger signals in stevens-johnson syndrome and toxic epidermal necrolysis.
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening 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. However, the genetic susceptibility and the exact pathogenesis were not clear until the recent studies. We 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. Our recent study 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. This article aims to provide an overview 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.
Chung
Wen-Hung
WH
Department of Dermatology, Chang Gung Memorial Hospital, Chang Gung University, Taipei, Taiwan. chung1@cgmh.org.tw
Hung
Shuen-Iu
SI
D000493:Allopurinol / Q000009:adverse effects; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D015415:Biomarkers / Q000378:metabolism*; D002220:Carbamazepine / Q000009:adverse effects; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D020022:Genetic Predisposition to Disease; D053804:Granzymes / Q000276:immunology / Q000378:metabolism; D015235:HLA-B Antigens / Q000235:genetics / Q000378:metabolism; D059910:HLA-B15 Antigen; D006801:Humans; D015603:Keratinocytes / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D011110:Polymorphism, Genetic; D013262:Stevens-Johnson Syndrome / Q000139:chemically induced / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D015415:Biomarkers; D015235:HLA-B Antigens; C483536:HLA-B*15:02 antigen; D059910:HLA-B15 Antigen; D002220:Carbamazepine; D000493:Allopurinol; D053804:Granzymes