Harboe M, Ulvund G, Vien L, Fung M, Mollnes T E
Institute of Immunology, Rikshospitalet University Hospital, NO-0027 Oslo, Norway.
Clin Exp Immunol. 2004 Dec;138(3):439-46. doi: 10.1111/j.1365-2249.2004.02627.x.
Complement activation with formation of biologically potent mediators like C5a and the terminal C5b-9 complex (TCC) contributes essentially to development of inflammation and tissue damage in a number of autoimmune and inflammatory conditions. A particular role for complement in the ischaemia/reperfusion injury of the heart, skeletal muscle, central nervous system, intestine and kidney has been suggested from animal studies. Previous experiments in C3 and C4 knockout mice suggested an important role of the classical or lectin pathway in initiation of complement activation during intestinal ischaemia/reperfusion injury while later use of factor D knockout mice showed the alternative pathway to be critically involved. We hypothesized that alternative pathway amplification might play a more critical role in classical pathway-induced C5 activation than previously recognized and used pathway-selective inhibitory mAbs to further elucidate the role of the alternative pathway. Here we demonstrate that selective blockade of the alternative pathway by neutralizing factor D in human serum diluted 1 : 2 with mAb 166-32 inhibited more than 80% of C5a and TCC formation induced by solid phase IgM and solid- and fluid-phase human aggregated IgG via the classical pathway. The findings emphasize the influence of alternative pathway amplification on the effect of initial classical pathway activation and the therapeutic potential of inhibiting the alternative pathway in clinical conditions with excessive and uncontrolled complement activation.
补体激活并形成如C5a和末端C5b-9复合物（TCC）等具有生物活性的介质，在许多自身免疫性和炎症性疾病中，对炎症的发展和组织损伤起着至关重要的作用。动物研究表明，补体在心脏、骨骼肌、中枢神经系统、肠道和肾脏的缺血/再灌注损伤中具有特殊作用。先前在C3和C4基因敲除小鼠中的实验表明，经典途径或凝集素途径在肠道缺血/再灌注损伤期间补体激活的起始中起重要作用，而后来使用因子D基因敲除小鼠的实验表明替代途径也至关重要。我们假设替代途径的放大在经典途径诱导的C5激活中可能比以前认识到的发挥更关键的作用，并使用途径选择性抑制性单克隆抗体来进一步阐明替代途径的作用。在此，我们证明，用单克隆抗体166-32将人血清按1:2稀释后，通过中和因子D选择性阻断替代途径，可抑制固相IgM以及固相和液相人聚集IgG通过经典途径诱导的80%以上的C5a和TCC形成。这些发现强调了替代途径放大对初始经典途径激活效果的影响，以及在补体激活过度且不受控制的临床情况下抑制替代途径的治疗潜力。
