AFFECTED ERYTHROCYTES OF PATIENTS WITH PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA ARE DEFICIENT IN THE COMPLEMENT REGULATORY PROTEIN, DECAY ACCELERATING FACTOR
AFFECTED ERYTHROCYTES OF PATIENTS WITH PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA ARE DEFICIENT IN THE COMPLEMENT REGULATORY PROTEIN, DECAY ACCELERATING FACTOR
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DOI：
10.1073/pnas.80.16.5066
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发表时间：
1983-01-01
期刊：
影响因子：
--
通讯作者：
AUSTEN, KF
中科院分区：
文献类型：
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作者：
NICHOLSONWELLER, A;MARCH, JP;AUSTEN, KF
阵发性睡眠性血红蛋白尿症（PNH）是骨髓干细胞的获得性缺陷，其中受影响的克隆产生具有对补体介导的溶解异常敏感的膜的红细胞（还有粒细胞和血小板）。来自PNH患者的异常红细胞（E）（PNH-E）对体外人补体裂解的敏感性比来自未受影响个体的正常E和来自PNH患者中未受影响克隆的功能正常E（I型PNH-E）高3-5倍（II型PNH-E）或15-25倍（III型PNH-E）。通过经典或旁路途径激活补体后，与正常E相比，异常量的C3 b [补体成分3b]沉积在PNH-E的膜上，表明PNH-E膜不能调节负责C3 b沉积的事件。从正常人E基质中分离出两种降低经典和旁路途径C3转化酶在靶细胞上的稳定性的蛋白质：70，000 MW的基质衰变加速因子（decay accelerating factor of stroma，C3 b）和250，000 MW的C3 b受体（C3 bR）。从125 I-表面标记的正常E的溶解膜的特异性免疫沉淀证明这两种蛋白质。3例PNH-E患者的特异性免疫沉淀物显示C3 bR，但缺乏C3 bR，II型PNH-E相对缺乏C3 bR，III型PNH-E完全缺乏C3 bR。中和分离的PNH活性的抗体在被II型PNH-E弱吸附而不被III型PNH-E吸附的条件下被完整的正常E吸附。缺乏免疫沉淀和抗体吸附评估的PNH-E中的ESTA抗原的缺陷，可以解释PNH-E补体介导的溶解的异常敏感性，并表明ESTA可以保护正常E的膜损伤导致自体补体激活。
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired defect of bone marrow stem cells in which the affected clones produce erythrocytes (also granulocytes and platelets) with membranes that are abnormally sensitive to complement-mediated lysis. Abnormal erythrocytes (E) from patients with PNH (PNH-E) are 3-5 times more sensitive (type II PNH-E) or 15-25 times more sensitive (type III PNH-E) to lysis in vitro by human complement than normal E from unaffected individuals and the functionally normal E that arise from unaffected clones in PNH patients (type I PNH-E). After complement activation by either the classical or alternative pathway, abnormal amounts of C3b [complement component 3b] are deposited on the membranes of PNH-E compared with normal E, suggesting that the PNH-E membrane cannot regulate the events responsible for C3b deposition. Two proteins that decrease the stability of the classical and alternative pathway C3 convertases on target cells were isolated from normal human E stroma: the 70,000 MW decay accelerating factor of stroma (DAF) and the 250,000 MW C3b receptor (C3bR). Specific immune precipitates of solubilized membranes from 125I-surface-labeled normal E demonstrate both proteins. Specific immune precipitates of PNH-E from 3 patients show C3bR but are deficient in DAF; type II PNH-E are relatively deficient and type III PNH-E are totally deficient in DAF. Antibody that neutralizes the activity of isolated DAF is adsorbed by intact normal E under conditions in which it is weakly adsorbed by type II PNH-E and not adsorbed by type III PNH-E. The deficiency of DAF antigen in PNH-E, as assessed by lack of immunoprecipitation and antibody adsorption, could explain the abnormal sensitivity of PNH-E to complement-mediated lysis and suggests that DAF may protect the membranes of normal E from damage resulting from autologous complement activation.