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Recent advances in the genetics and immunology of Stevens-Johnson syndrome and toxic epidermal necrosis

  • Wen-Hung Chung
    Correspondence
    Corresponding author at: Department of Dermatology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, 199 Tung-Hwa North Road, Taipei 105, Taiwan. Tel.: +886 2 27135211; fax: +886 2 27191623.
    Affiliations
    Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Keelung and Linkou Branches, College of Medicine, Chang Gung University, Taiwan
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  • Shuen-Iu Hung
    Affiliations
    Institute of Pharmacology, College of Medicine, National Yang-Ming University, Taipei, Taiwan
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      Abstract

      Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) are rare but life-threatening severe cutaneous adverse reactions (SCARs), which are majorly (65–75%) induced by a variety of drugs. SJS/TEN could be recognized as SCARs or drug immune reactions, if the reactions are elicited by drugs. The recent studies suggested that SJS/TEN is a specific immune reaction initiated by the cytotoxic T lymphocytes (CTLs) via human leukocyte antigens (HLAs)-restricted pathway. The patho-mechanism involving HLA-restricted presentation of a drug or its metabolites for T-cell activation is supported by the findings of strong genetic associations with HLA alleles (e.g. HLA-B*15:02 and carbamazepine-SJS/TEN, and HLA-B*58:01 and allopurinol-SJS/TEN). However, the genetic associations of SJS/TEN or drug induced cutaneous immune reactions are complex, which are drug specific and ethnicity specific. The genetic polymorphisms and diversity of HLA alleles may provide different binding affinities for drug antigens to launch the activation of specific CTLs responses, further leading to the unique clinical manifestations in SJS/TEN. Fas–FasL and perforin/granzyme B have been advocated mediating the epidermal necrosis in SJS/TEN. Our recent study showed that granulysin, a cytotoxic protein produced by CTLs or natural killer (NK) cells, is the key mediator for disseminated keratinocyte death in SJS/TEN. From the point of view of a physician, the profounder understanding of the genetic predisposition and patho-mechanism we discover, the better strategies for prevention, clinical management, and therapeutic methods of SJS/TEN we can develop in the near future.

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      Biography

      Dr. Wen-Hung Chung has served as a dermatologist at Chang Gung Memorial Hospital, Taiwan since 1999. In 2008, he obtained the Ph.D. degree from the Taiwan International Graduate Program of Academia Sinica and National Yang Ming University, Taiwan. Dr. Chung has devoted himself into the investigation of severe adverse drug reactions (SCARs) for over a decade and his devotion and findings have great impact in clinic. Dr. Chung and his team has identified genetic and bio-markers for SCARs. He identified strong genetic association of HLA-B*1502 with carbamazepine-induced Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) in Han Chinese and HLA-B*5801 with allopurinol-SCARs. In addition, he also discovered granulysin as the major mediator for the extensive keratinocyte death in SJS or TEN. These important breakthroughs had been published on Nature and Nature Medicine in 2004 and 2008, respectively. Currently, these markers have been used in clinic before prescription of carbamazepine and allopurinol to prevent patients from the development of SCARs. Since these contributions, Dr. Chung had received awards of the 2006 Top 10 Rising Stars in Taiwan, 2009 the 47th Ten Outstanding Young Persons in Taiwan, and 2011 the International League of Dermatological Societies (ILDS) Young Dermatologist International Achievement Award. Dr. Chung continues his research as well as clinical works for patients with SCARs. In 2012, he establishes the first drug hypersensitivity clinical and research center in Taiwan which receives referral cases of SCARs from all over Taiwan.