The Function of HLA-B*13:01 Involved in the Pathomechanism of Dapsone-Induced Severe Cutaneous Adverse Reactions

J Invest Dermatol. 2018 Jul;138(7):1546-1554. doi: 10.1016/j.jid.2018.02.004. Epub 2018 Feb 17.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Antigens, Differentiation, T-Lymphocyte
  • GNLY protein, human
  • HLA-B13 Antigen
  • Leprostatic Agents
  • Dapsone