The Function of HLA-B13:01 Involved in the Pathomechanism of Dapsone-Induced Severe Cutaneous Adverse Reactions

• Published in: Journal of investigative dermatology Vol. 138; no. 7; pp. 1546 - 1554
• Main Authors: Chen, Wei-Ti, Wang, Chuang-Wei, Lu, Chun-Wei, Chen, Chun-Bing, Lee, Hua-En, Hung, Shuen-Iu, Choon, Siew-Eng, Yang, Chih-Hsun, Liu, Ming-Tsan, Chen, Ting Jui, Fan, Wen-Lang, Su, Shih-Chi, Lin, Yang Yu-Wei, Chang, Ya-Ching, Chung, Wen-Hung
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2018
• Subjects: Adult; Aged, 80 and over; Alleles; Antigens, Differentiation, T-Lymphocyte - blood; Coculture Techniques; Dapsone - adverse effects; Drug Hypersensitivity Syndrome - blood; Drug Hypersensitivity Syndrome - etiology; Drug Hypersensitivity Syndrome - genetics; Drug Hypersensitivity Syndrome - immunology; Female; Genetic Predisposition to Disease; HLA-B13 Antigen - genetics; HLA-B13 Antigen - immunology; Humans; Leprostatic Agents - adverse effects; Leprosy - drug therapy; Malaysia; Male; Skin - immunology; Skin - pathology; T-Lymphocytes, Cytotoxic - drug effects; T-Lymphocytes, Cytotoxic - immunology; Taiwan; Young Adult; Malaysia; Taiwan; DRESS; MPE; Pc; CTLs; HHV; SCAR; EBV; TEN; PBMC; SJS; ELISpot; LAT
• ISSN: 0022-202X; 1523-1747; 1523-1747
• DOI: 10.1016/j.jid.2018.02.004

Dapsone-induced hypersensitivity reactions may cause severe cutaneous adverse reactions, such as drug reaction with eosinophilia and systemic symptoms (DRESS). It has been reported that HLA-B*13:01 is strongly associated with dapsone-induced hypersensitivity reactions among leprosy patients. However, the phenotype specificity and detailed immune mechanism of HLA-B*13:01 remain unclear. We investigated the genetic predisposition, HLA-B*13:01 function, and cytotoxic T cells involved in the pathogenesis of dapsone-induced severe cutaneous adverse reactions. We enrolled patients from Taiwan and Malaysia with DRESS and maculopapular eruption with chronic inflammatory dermatoses. Our results showed that the HLA-B*13:01 allele was present in 85.7% (6/7) of patients with dapsone DRESS (odds ratio = 49.64, 95% confidence interval = 5.89–418.13; corrected P = 2.92 × 10–4) but in only 10.8% (73/677) of general population control individuals in Taiwan. The level of granulysin, the severe cutaneous adverse reaction-specific cytotoxic protein released from cytotoxic T cells, was increased in both the plasma of DRESS patients (36.14 ± 9.02 ng/ml, P < 0.05) and in vitro lymphocyte activation test (71.4%, 5/7 patients) compared with healthy control individuals. Furthermore, dapsone-specific cytotoxic T cells were significantly activated when co-cultured with HLA-B*13:01–expressing antigen presenting cells in the presence of dapsone (3.9-fold increase, compared with cells with no HLA-B*13:01 expression; P < 0.01). This study indicates that HLA-B*13:01 is strongly associated with dapsone DRESS and describes a functional role for the HLA-restricted immune mechanism induced by dapsone.