Toxic epidermal necrolysis: effector cells are drug-specific cytotoxic T cells

J Allergy Clin Immunol. 2004 Nov;114(5):1209-15. doi: 10.1016/j.jaci.2004.07.047.


Background: Toxic epidermal necrolysis (TEN) is a very rare but extremely severe drug reaction characterized by widespread apoptosis of epidermis with extensive blisters. We previously found drug-specific cytotoxic CD8 T lymphocytes in the blisters of a single patient.

Objective: To confirm the role of drug specific cytotoxic lymphocytes in a larger series, to test the cytotoxicity on keratinocytes, and to look for cross-reactivity between chemically related drugs.

Methods: The phenotype of lymphocytes present in the blister fluids of 6 patients with TEN was analyzed by flow cytometry. Cytotoxic functions were tested by chromium release assay on a variety of target cells (autologous or MHC class I-matched EBV-transformed lymphocytes, autologous keratinocytes) after nonspecific (CD3 monoclonal antibody) or specific (suspected and potentially cross-reactive drugs) activation.

Results: Blister lymphocytes were CD8 + HLA-DR + CLA + CD56 + . In all 6 cases, they were cytotoxic after nonspecific activation. A drug-specific cytotoxicity was observed in 4 cases (3 related to cotrimoxazole and 1 to carbamazepine) toward lymphocytes. Blister cells also killed IFN-gamma-activated autologous keratinocytes in the presence of drug in the 2 patients tested. Blister cells showed a strong immunoreactivity for granzyme B, and cytotoxicity was abolished by EGTA, but not by anti-Fas/CD95, suggesting perforin/granzyme-mediated killing. By using several sulfonamides for testing the specificity of the drug T-cell receptor interaction, we observed cross-reactivity only between 4 structurally closely related medications.

Conclusion: These results strongly suggest that drug-specific, MHC class I-restricted, perforin/granzyme-mediated cytotoxicity probably has a primary role in TEN.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes / immunology
  • Blister / immunology
  • Cell Line
  • Cross Reactions
  • Granzymes
  • Humans
  • Immunophenotyping
  • Keratinocytes / immunology
  • Membrane Glycoproteins / physiology
  • Perforin
  • Pore Forming Cytotoxic Proteins
  • Serine Endopeptidases / physiology
  • Stevens-Johnson Syndrome / immunology*
  • T-Lymphocytes, Cytotoxic / drug effects
  • T-Lymphocytes, Cytotoxic / immunology*
  • Trimethoprim, Sulfamethoxazole Drug Combination / pharmacology


  • Membrane Glycoproteins
  • Pore Forming Cytotoxic Proteins
  • Perforin
  • Trimethoprim, Sulfamethoxazole Drug Combination
  • GZMB protein, human
  • Granzymes
  • Serine Endopeptidases