New Insights into Molecular Pathogenesis of Bone Marrow Failure in Paroxysmal Nocturnal Hemoglobinuria
New Insights into Molecular Pathogenesis of Bone Marrow Failure in Paroxysmal Nocturnal Hemoglobinuria
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DOI：
10.1532/ijh97.07029
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发表时间：
2007-07
影响因子：
2.1
通讯作者：
T. Kawaguchi;H. Nakakuma
中科院分区：
文献类型：
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作者：
T. Kawaguchi;H. Nakakuma
阵发性睡眠性血红蛋白尿 (PNH) 是由带有磷脂酰肌醇聚糖 A 类基因 (PIGA) 突变的造血干细胞的克隆扩增引起的。 PNH 克隆无法产生糖基磷脂酰肌醇 (GPI) 或表达一系列 GPI 连接的膜蛋白，包括补体调节蛋白，导致补体介导的血管内溶血和血栓形成。骨髓衰竭是 PNH 的另一个特征。目前认为，免疫介导的造血细胞损伤与 PNH 骨髓衰竭以及再生障碍性贫血（一种众所周知的 PNH 相关疾病）有关。越来越多的证据表明，自身免疫攻击使得 PNH 克隆选择性地在受损的骨髓中存活，从而导致 PNH 特征性的临床表现。作为触发骨髓细胞免疫攻击的候选分子，应激诱导膜蛋白和维尔姆斯肿瘤蛋白 WT1 被提出。在应激诱导蛋白中，GPI 连接蛋白（例如巨细胞病毒糖蛋白 UL16 结合蛋白）是独特的候选蛋白，不仅能诱导免疫攻击，还能使 PNH 克隆在攻击中幸存下来。在这里，我们概述了目前对 PNH 骨髓衰竭分子发病机制的认识。
Paroxysmal nocturnal hemoglobinuria (PNH) is caused by the clonal expansion of hematopoietic stem cells with mutations of the phosphatidylinositol glycan-class A gene (PIGA). PNH clones then fail to generate glycosylphosphatidylinositol (GPI) or to express a series of GPI-linked membrane proteins including complement-regulatory proteins, resulting in complement-mediated intravascular hemolysis and thrombosis. Bone marrow failure is another characteristic feature of PNH. It is currently considered that immune-mediated injury of hematopoietic cells is implicated in PNH marrow failure as well as in aplastic anemia, a well-known PNH-related disorder. There is increasing evidence that the autoimmune attack allows PNH clones to selectively survive in the injured marrow, leading to clinical manifestations characteristic of PNH. As candidate molecules that trigger the immune attack on marrow cells, stress-inducible membrane proteins and Wilms’ tumor protein WT1 have been proposed. Among the stress-inducible proteins, GPI-linked proteins, such as cytomegalovirus glycoprotein UL16-binding protein, are distinct candidates that not only induce immune attack, but also allow PNH clones to survive the attack. Here, we overview the current understanding of the molecular pathogenesis of bone marrow failure in PNH.