CD94/NKG2C is a killer effector molecule in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis Esther Morel, PhD, Salvador Escamochero,

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Presentation transcript:

CD94/NKG2C is a killer effector molecule in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis Esther Morel, PhD, Salvador Escamochero, BS, Rosario Cabañas, MD, PhD, Rosa Díaz, MD, PhD, Ana Fiandor, MD, Teresa Bellón, PhD Journal of Allergy and Clinical Immunology Volume 125, Issue 3, Pages 703-710.e8 (March 2010) DOI: 10.1016/j.jaci.2009.10.030 Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 HLA-E expression in affected skin. A, Flow cytometric analysis of HLA-I (solid histograms) and HLA-E (open histograms) expression in keratinocytes from a representative patient with MPE and a healthy donor (HD). B, Mean fluorescence intensity (MFI) of HLA-I and HLA-E expression in keratinocytes from 5 healthy donors (HD) and 8 patients (P). Horizontal bars correspond to the mean values. C, Immunoperoxidase staining of HLA-E in skin biopsy specimens from 3 patients. Original magnification 200× (panels a-f) and 400× (panels g-h). Arrowheads in panel h show specific staining in keratinocytes within necrotic skin. D, Immunoblot analysis of soluble HLA-E (sHLA-E) in fluids and sera from acute or resolution samples in 3 representative patients with SJS/TEN, healthy donors, and patients with mechanical trauma (MT). Culture supernatants from the HLA-I− cell line 721.221 and its HLA-E transfectant, 221.AEH, were used as negative and positive controls. Journal of Allergy and Clinical Immunology 2010 125, 703-710.e8DOI: (10.1016/j.jaci.2009.10.030) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Cytotoxic lymphocytes are activated by HLA-E in peripheral blood and blister fluid from patients with SJS/TEN. A, 51Cr release assays showing lysis of PBMCs from healthy donors and patients with MPE and SJS/TEN against the 721.221 and 221.AEH cell lines. Means and SEMs of independent experiments are shown. B and C, BFCs from patients with SJS/TEN were used as effector cells in 51Cr release assays. Fig 2, B, Mean values and SEMs of percentages of lysis against 721.221 and 221.AEH cells. Fig 2, C, Lysis of primary allogenic keratinocytes (KC) pretreated or not with IFN-γ by BFCs from 2 representative patients. Journal of Allergy and Clinical Immunology 2010 125, 703-710.e8DOI: (10.1016/j.jaci.2009.10.030) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 CD94/NKG2C expression in lymphocytes or blasts from patients with SJS/TEN. A, Frequencies of CD94/NKG2C+ cells in CD3+CD8+, CD3+CD8−, and CD3− peripheral blood lymphocytes from 3 representative acute samples (SJS8, SJS2, and TEN2) and 1 resolution sample (TEN2 resolution). B, Frequencies of CD94/NKG2C+ cells in blister lymphocytes or blasts in 3 representative patients. PerCP, Peridinin-chlorophyll-protein. Journal of Allergy and Clinical Immunology 2010 125, 703-710.e8DOI: (10.1016/j.jaci.2009.10.030) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 CD94/NKG2C expression on peripheral blood lymphocytes and blasts from patients with SJS/TEN. A, Frequencies of CD94/NKG2C+ cells in peripheral blood lymphocytes or blast subpopulations in acute samples from patients with SJS/TEN. B, Frequencies of CD94/NKG2C+ cells in peripheral blood lymphocyte (L) or blast (B) subpopulations in acute and resolution samples from 3 patients with SJS/TEN. Journal of Allergy and Clinical Immunology 2010 125, 703-710.e8DOI: (10.1016/j.jaci.2009.10.030) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Peripheral blood NK and T lymphocytes from patients with SJS/TEN recognize HLA-E through the activating receptor CD94/NKG2C. A, Cytotoxicity mediated by PBMCs from patients' acute samples and samples from healthy donors against 721.221 and 221.AEH cell lines in the presence or absence of blocking anti-NKG2C mAbs. Means and SEMs of independent experiments carried out with 3 patients with SJS are shown. B, CD107a mobilization assays. Graphs show the percentage of CD107a+ cells in CD3+ or CD3− lymphocyte subpopulations expressing or not CD94/NKG2C in a representative patient with SJS on coculture with 721.221 and 221.AEH cell lines. Journal of Allergy and Clinical Immunology 2010 125, 703-710.e8DOI: (10.1016/j.jaci.2009.10.030) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 CD94/NKG2C-dependent degranulation in blister lymphocytes. A and B, BFCs from patients SJS6 and SJS4 were cultured alone or with 721.221 and 221.AEH cells in the absence or presence of anti-NKG2C mAbs. Fig 6, A, shows percentages of CD3+CD8+CD107a+ lymphocytes in a representative experiment. Fig 6, B, CD3−CD107a+ blister fluid lymphocytes in patient SJS6 after coculture in the absence or presence of 721.221 or 221.AEH cells and blocking anti-NKG2C mAbs. C, Induction of surface CD107a in total and CD3− BFCs from patient SJS4 after coculture in the absence or presence of autologous keratinocytes (KC) pretreated or not with IFN-γ and with or without specific anti-NKG2C mAbs. Mean percentages of CD107a+ lymphocytes in triplicate cultures are shown. Journal of Allergy and Clinical Immunology 2010 125, 703-710.e8DOI: (10.1016/j.jaci.2009.10.030) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Flow cytometric analysis of cell-surface receptor expression on T lymphocytes from peripheral blood and blister fluids from patients with SJS/TEN. Panels show frequencies of CD8+, CD94+, CD56+, KIR2DL2/L3/S2+, HLA-DR+, and CD25+ cells in CD3+ blister fluid and peripheral blood lymphocytes from acute and resolution samples in a representative patient with TEN. Journal of Allergy and Clinical Immunology 2010 125, 703-710.e8DOI: (10.1016/j.jaci.2009.10.030) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

FasL and IFN-γ levels in sera and blister fluids from patients with SJS/TEN. Graphs show picograms of FasL and IFN-γ per milliliter of serum or blister fluid from patients' acute samples and healthy donors (HD). Horizontal bars correspond to mean values. ∗P value, Wilcoxon matched pair test; #P value, Mann-Whitney U test. Journal of Allergy and Clinical Immunology 2010 125, 703-710.e8DOI: (10.1016/j.jaci.2009.10.030) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

HLA -E–specific CD56+CD8+ T-cell clones are cytotoxic against IFN-γ–stimulated keratinocytes expressing HLA-E. A, HLA-I and HLA-E expression in primary keratinocytes and HaCaT cells stimulated or not with IFN-γ. Staining with control IgG1 and specific mAbs is shown. B and C, Cytotoxicity mediated by CD56+CD8+ T-cell clones against HaCaT keratinocytes pretreated or not with IFN-γ. The 721.221 cell line and its HLA-E transfectant, 221.AEH, were used as negative and positive controls, respectively. Fig E3, B, Percentages of lysis from 3 representative clones of 5 tested. Fig E3, C, Lysis in the presence of anti HLA-E and anti-HLA-I mAbs. Journal of Allergy and Clinical Immunology 2010 125, 703-710.e8DOI: (10.1016/j.jaci.2009.10.030) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Flow cytometric analysis of receptor expression in PBMCs Flow cytometric analysis of receptor expression in PBMCs. A, Percentages of CD94+, CD94/NKG2A+, and CD94/NKG2C+ cells in CD3+ and CD3− peripheral blood lymphocytes from patients with SJS/TEN (acute samples) and healthy donors (HD). B, Percentages of CD94/NKG2C+ cells (means ± SEMs) in CD3+CD8+ and CD3− peripheral blood lymphocytes from acute samples in patients with SJS/TEN and MPE . ∗P value, Wilcoxon matched pair test; #P value, Mann-Whitney U test. Journal of Allergy and Clinical Immunology 2010 125, 703-710.e8DOI: (10.1016/j.jaci.2009.10.030) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

CD94/NKG2C expression on peripheral blood lymphocytes and blasts in acute and resolution samples from patients with drug-induced cutaneous reactions. A, CD3 and CD8 expression and forward scatter (FSC) analysis in total PBMCs from a representative patient. Red- and blue-colored populations correspond to lymphocytes and blasts, respectively. B, Panels show percentages of CD3+CD8+, CD94/NKG2C+, and CD3−CD94/NKG2C+ cells in peripheral blood lymphocytes (red gates) or blasts (blue gates) in 3 patients. Journal of Allergy and Clinical Immunology 2010 125, 703-710.e8DOI: (10.1016/j.jaci.2009.10.030) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Journal of Allergy and Clinical Immunology 2010 125, 703-710 Journal of Allergy and Clinical Immunology 2010 125, 703-710.e8DOI: (10.1016/j.jaci.2009.10.030) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions