Kumar Varsha, Ali Syed R, Konrad Stephanie, Zwirner Jörg, Verbeek J Sjef, Schmidt Reinhold E, Gessner J Engelbert
Department of Clinical Immunology, Medical School Hannover, Hannover, Germany.
J Clin Invest. 2006 Feb;116(2):512-20. doi: 10.1172/JCI25536.
Complement C5a, a potent anaphylatoxin, is a candidate target molecule for the treatment of inflammatory diseases, such as myocardial ischemia/reperfusion injury, RA, and the antiphospholipid syndrome. In contrast, up until now, no specific contribution of C5a and its receptor, C5aR, was recognized in diseases of antibody-dependent type II autoimmunity. Here we identify C5a as a novel key mediator of autoimmune hemolytic anemia (AIHA) and show that mice lacking C5aR are partially resistant to this IgG autoantibody-induced disease model. Upon administration of anti-erythrocyte antibodies, upregulation of activating Fcgamma receptors (FcgammaRs) on Kupffer cells, as observed in WT mice, was absent in C5aR-deficient mice, and FcgammaR-mediated in vivo erythrophagocytosis was impaired. Surprisingly, in mice deficient in FcgammaRI and FcgammaRIII, anti-erythrocyte antibody-induced C5 and C5a production was abolished, demonstrating the existence of a previously unidentified FcgammaR-mediated C5a-generating pathway. These results show that the development of a full-blown antibody-dependent autoimmune disease requires C5a--produced by and acting on FcgammaR--and may suggest therapeutic benefits of C5 and/or C5a/C5aR blockade in AIHA and other diseases closely related to type II autoimmune injury.
补体C5a是一种强效过敏毒素，是治疗炎症性疾病（如心肌缺血/再灌注损伤、类风湿性关节炎和抗磷脂综合征）的候选靶分子。相比之下，到目前为止，在抗体依赖性II型自身免疫性疾病中，尚未发现C5a及其受体C5aR有特定作用。在此，我们确定C5a是自身免疫性溶血性贫血（AIHA）的一种新型关键介质，并表明缺乏C5aR的小鼠对这种IgG自身抗体诱导的疾病模型具有部分抗性。在给予抗红细胞抗体后，野生型小鼠中观察到的库普弗细胞上激活型Fcγ受体（FcγRs）上调，在C5aR缺陷小鼠中未出现，并且FcγR介导的体内红细胞吞噬作用受损。令人惊讶的是，在缺乏FcγRI和FcγRIII的小鼠中，抗红细胞抗体诱导的C5和C5a产生被消除，这证明存在一种先前未被识别的FcγR介导产生C5a的途径。这些结果表明，全面发展的抗体依赖性自身免疫性疾病需要由FcγR产生并作用于FcγR的C5a，并且可能提示C5和/或C5a/C5aR阻断在AIHA和其他与II型自身免疫性损伤密切相关的疾病中的治疗益处。
