Sakata K, Sakata A, Vela-Roch N, Espinosa R, Escalante A, Kong L, Nakabayashi T, Cheng J, Talal N, Dang H
The University of Texas Health Science Center at San Antonio, Department of Medicine, 78284-7874, USA.
Eur J Immunol. 1998 Sep;28(9):2648-60. doi: 10.1002/(SICI)1521-4141(199809)28:09<2648::AID-IMMU2648>3.0.CO;2-M.
Fas (CD95) is a cell surface receptor whose biological function in circulating peripheral T cells is not well understood. To address the question of abnormal T cell sensitivity to Fas stimulation in systemic lupus erythematosus (SLE), we studied Fas-transduced stimulation and apoptosis in peripheral blood T cells from patients with SLE and normal control. Immobilized anti-Fas monoclonal antibodies (mAb) (imCH-11; IgM type) significantly stimulated SLE T cell proliferation compared to T cells from normal donors and patients with rheumatoid arthritis (p < 0.003 and p < 0.005, respectively). The soluble form of CH-11 and other immobilized anti-Fas mAb (UB-2, ZB-4; IgG type) failed to stimulate lupus T cells while immobilized human Fas ligand did. Furthermore, imCH-11 induced IL-2 and IL-6 mRNA expression. However, imCH-11 activation failed to induce expression of the T cell activation surface molecules CD25 and CD69. Addition of exogenous ceramide, a second messenger for Fas-mediated apoptosis signaling, also induced T cell proliferation in SLE and normal controls. Moreover, fumonisin B1, a specific ceramide synthase inhibitor, and caspase inhibitors markedly suppressed imCH-11 induced T cell proliferation, suggesting that the ceramide pathway may be involved in Fas-transduced stimulation signals in SLE T cells. These results show that SLE T cells have an alteration in the Fas signal transduction pathway leading to cell proliferation. This defect may be important in Fas-mediated peripheral immune homeostasis.
Fas（CD95）是一种细胞表面受体，其在循环外周T细胞中的生物学功能尚未完全明确。为了探讨系统性红斑狼疮（SLE）中T细胞对Fas刺激的异常敏感性问题，我们研究了SLE患者和正常对照外周血T细胞中Fas转导的刺激和凋亡情况。与正常供体和类风湿关节炎患者的T细胞相比，固定化抗Fas单克隆抗体（mAb）（imCH-11；IgM型）显著刺激了SLE T细胞增殖（分别为p < 0.003和p < 0.005）。CH-11的可溶性形式和其他固定化抗Fas mAb（UB-2、ZB-4；IgG型）未能刺激狼疮T细胞，而固定化人Fas配体则可以。此外，imCH-11诱导了IL-2和IL-6 mRNA表达。然而，imCH-11激活未能诱导T细胞活化表面分子CD25和CD69的表达。添加外源性神经酰胺（Fas介导的凋亡信号的第二信使）也诱导了SLE和正常对照中的T细胞增殖。此外，伏马菌素B1（一种特异性神经酰胺合酶抑制剂）和半胱天冬酶抑制剂显著抑制了imCH-11诱导的T细胞增殖，表明神经酰胺途径可能参与了SLE T细胞中Fas转导的刺激信号。这些结果表明，SLE T细胞在Fas信号转导途径中存在导致细胞增殖的改变。这种缺陷可能在Fas介导的外周免疫稳态中起重要作用。
