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Role of blister fluid soluble HLA-E In SJS/TEN

机译：起泡的可溶性HLA-E在SJS / TEN中的作用

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BackgroundStevens-Johnson syndrome (SJS) and toxic epidermalnecrolysis (TEN) are life-threatening hypersensitivityreactions to medications characterized by keratinocyteapoptosis, the formation of subepidermal blisters, andskin detachment. Cytotoxic lymphocytes including CTLsand NK cells seem to be the main effectors of keratinocytekilling. Natural killer cytotoxic activity is regulatedthrough the balance of activating and inhibitory signalsdelivered by innate receptors, some of which recognizeHLA class I antigens. Among them, inhibitory CD94/NKG2A and activating CD94/NKG2C receptors are specificfor the non-classical HLA class Ib molecule HLA-E,and are expressed not only in NK cells but also in subsetsof T lymphocytes. We have previously reported that theactivating receptor CD94/NKG2C is overexpressed inlymphocytes from SJS/TEN patients resulting in net activationand lysis of HLA-E+ targets. Moreover, HLA-Ewas found to be overexpressed in affected skin, and inagreement with previous reports showing soluble HLA-E(sHLA-E) released in response to cell activation, wefound sHLA-E in blister fluids from SJS/TEN patients.ObjectiveTo explore the impact of sHLA-E in the functionalcapacities of cytotoxic lymphocytes.MethodsConditioned media enriched in sHLA-E or sHLA-B27(used as a negative control) were prepared and assayedin 51Cr release assays using purified CD94/NKG2A+ orCD94/NKG2C+ primary human NK cells as effectorcells. Production of IFN- was also investigated. Westernblot was performed to study the phosphorylation statusof the signal transducing molecule DAP12.ResultsThe cytotoxic activity and the production of IFN- byNKG2C+ NK cells were significantly increased in the presenceof sHLA-E. Moreover, increased phosphorylation ofDAP12 was detected. In addition, blister fluids from SJS/TEN patients, were also able to specifically increase thecytotoxic activity of NKG2C+ NK cells, and this effect wasreverted in the presence of blocking antibodies againstHLA-E.ConclusionsHLA-E acts as an agonist of the activating receptorCD94/NKG2C. The results suggest that sHLA-E moleculesin blister fluids may contribute to the massive killingof keratinocytes in SJS/TEN patients by enhancing theactivity of NKG2C+ cytotoxic lymphocytes.
机译：背景史蒂文斯-约翰逊综合症（SJS）和中毒性表皮坏死溶解（TEN）是对以角质形成细胞凋亡，表皮下水疱的形成和皮肤脱离为特征的药物的威胁生命的超敏反应。细胞毒性淋巴细胞包括CTL和NK细胞似乎是角质形成细胞杀伤的主要效应器。天然杀伤剂的细胞毒性活性是通过先天性受体传递的激活信号和抑制信号的平衡来调节的，其中一些先天性受体识别HLA I类抗原。其中，抑制性CD94 / NKG2A和激活性CD94 / NKG2C受体对非经典HLA Ib类分子HLA-E具有特异性，不仅在NK细胞中表达，而且在T淋巴细胞亚群中表达。我们以前曾报道过，活化受体CD94 / NKG2C是SJS / TEN患者的淋巴细胞过度表达，导致HLA-E +靶标的净活化和裂解。此外，还发现HLA-E在受影响的皮肤中过表达，并且与先前的报告显示可溶性HLA-E（sHLA-E）是由于细胞活化而释放的报道不同，我们发现sHLA-E存在于SJS / TEN患者的起泡液中。方法制备富含sHLA-E或sHLA-B27（用作阴性对照）的条件培养基，并使用纯化的CD94 / NKG2A +或CD94 / NKG2C +原代人NK细胞在51Cr释放试验中进行测定作为效应细胞。还研究了IFN-的产生。结果：在存在sHLA-E的情况下，NKG2C + NK细胞的细胞毒活性和IFN-γ的产生显着增加。Westernblot用于研究信号转导分子DAP12的磷酸化状态。此外，检测到DAP12的磷酸化增加。此外，来自SJS / TEN患者的水泡液也能够特异性增强NKG2C + NK细胞的细胞毒活性，并且在存在针对HLA-E的封闭抗体的情况下这种作用得以恢复。结论HLA-E充当激活受体CD94 /的激动剂。 NKG2C。结果表明，水泡液中的sHLA-E分子可能通过增强NKG2C +细胞毒性淋巴细胞的活性而导致SJS / TEN患者的角质形成细胞的大量杀伤。

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