Telegina Ekaterina, Reshetnyak Tatiana, Moshnikova Anna, Proussakova Olga, Zhukova Alexandra, Kuznetsova Alla, Ivanov Alexei, Paltsev Michail, Beletsky Igor
Institute of Molecular Medicine at Sechenov's Moscow Medical Academy, Moscow, Russia.
Immunol Lett. 2009 Jan 29;122(1):12-7. doi: 10.1016/j.imlet.2008.10.003. Epub 2008 Nov 14.
Fas/FasL system is involved in pathogenesis of a variety of autoimmune diseases. In overwhelming majority of situations alterations in Fas and FasL expression are viewed in frames of Fas-mediated apoptosis. In the present work we tested a possible involvement of Fas-ligand-mediated "reverse signaling" in pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We show that high level of sFas in RA patient blood correlates with a high activity of disease; in SLE patients with elevated sFas level there was a correlation between sFas concentration and leucopenia, and tissue and organ damage. We showed for the first time that at high concentrations in serum sFas is present in oligomeric form. Oligomeric sFas demonstrated cytotoxicity in lymphocyte primary culture and in transformed cells, while non-toxic recombinant Fas-ligand partially blocked this effect. Besides, immunohistochemical analysis of PBLs and injured synovia of RA patients revealed the high expression of Fas-ligand. All this together allow assuming the involvement of cytotoxic "reversed signaling" in the pathogenesis of autoimmune diseases.
Fas/FasL系统参与多种自身免疫性疾病的发病机制。在绝大多数情况下，Fas和FasL表达的改变是在Fas介导的细胞凋亡框架内进行观察的。在本研究中，我们测试了Fas配体介导的“反向信号传导”在类风湿性关节炎（RA）和系统性红斑狼疮（SLE）等自身免疫性疾病发病机制中的可能作用。我们发现，RA患者血液中高水平的可溶性Fas（sFas）与疾病的高活性相关；在sFas水平升高的SLE患者中，sFas浓度与白细胞减少以及组织和器官损伤之间存在相关性。我们首次表明，血清中高浓度的sFas以寡聚体形式存在。寡聚体sFas在淋巴细胞原代培养和转化细胞中表现出细胞毒性，而无毒的重组Fas配体部分阻断了这种作用。此外，对RA患者外周血淋巴细胞（PBLs）和受损滑膜的免疫组织化学分析显示Fas配体的高表达。所有这些共同表明细胞毒性“反向信号传导”参与了自身免疫性疾病的发病机制。
