期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 125, 期 3, 页码 703-710出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2009.10.030
关键词
Stevens-Johnson syndrome; toxic epidermal necrolysis; drug allergy; NK-CTLs; CD94/NKG2C; HLA-E
资金
- Ministerio de Sanidad/ISCIII, Spain [PI 06/0441]
- FIBHULP
Background: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are severe, bullous cutaneous diseases with uncertain pathogenesis, although cytotoxic T cells seem to be involved. Natural killer (NK) like activity has been found in blister infiltrates. Cytotoxic T lymphocytes (CTLs) with NK-like activity (NK-CTLs) have been shown to express T-cell receptors restricted by the HLA-Ib molecule HLA-E. Alternatively, the HLA-E specific activating receptor CD94/NKG2C can trigger T-cell receptor independent cytotoxicity in CTLs. Objective: Our aim was to test whether HLA-E expression sensitizes keratinocytes to killing by CTLs with NK-like activity and to explore the expression of activating receptors specific for HLA-E in blister cytotoxic lymphocytes. Methods: We used flow cytometry and immunohistochemistry to analyze HLA-E expression in keratinocytes from affected skin in patients with SJS, TEN, and other less severe drug-induced exanthemas. The expression of CD94/NKG2C was analyzed by means of flow cytometry in PBMCs and blister cells from patients. PBMCs and blister cells were analyzed for their ability to kill HLA-E expressing cells. Involvement of CD94/NKG2C in triggering degranulation of cytolytic cells was explored by means of CD107a mobilization assays and standard cytotoxicity chromium release assays. Results: We found that keratinocytes from affected skin expressed HLA-E and that cell-surface HLA-E sensitizes keratinocytes to killing by CD94/NKG2C(+) CTLs. Frequencies of CD94/NKG2C(+) peripheral blood T and NK cells were increased in patients with SJS and TEN during the acute phase. Moreover, activated blister T and NK lymphocytes expressed CD94/NKG2C and were able to degranulate in response to HLA-E+ cells in an NKG2C-dependent manner. Conclusion: CD94/NKG2C might be involved in triggering cytotoxic lymphocytes in patients with SJS and TEN. (J Allergy Clin Immunol 2010;125:703-10.)
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