Kinoshita Taroh
Research Institute for Microbial Diseases, Osaka University.
Rinsho Ketsueki. 2017;58(4):353-362. doi: 10.11406/rinketsu.58.353.
Paroxysmal nocturnal hemoglobinuria (PNH) manifests by clonal expansion of mutant hematopoietic stem cells (HSCs) bearing a somatic mutation in the X-linked PIGA gene. PIGA mutations cause defective biosynthesis of GPI and cell surface deficiency of GPI-anchored proteins such as DAF and CD59, leading to intravascular hemolysis and thrombosis. These two major symptoms of PNH can be controlled by eculizumab, an anti-C5 monoclonal antibody. Bone marrow failure, the third major symptom of PNH, is autoimmune-mediated and contributes to the clonal expansion of GPI-defective HSCs by selectively attacking GPI-positive wild-type HSCs. GPI-defective erythrocytes, being protected from intravascular hemolysis by eculizumab, accumulate C3-derived fragments, C3b, iC3b, and C3dg, because of DAF deficiency and in turn become susceptible to CR3-mediated phagocytosis by spleen macrophages. Approximately 3% of Japanese patients with PNH are refractory to eculizumab therapy. Approximately 3% of Japanese people are heterozygous for a single nucleotide polymorphism that changes an amino acid near the eculizumab binding site. New therapeutic measures are needed to solve these issues.
阵发性睡眠性血红蛋白尿症（PNH）表现为携带X连锁PIGA基因突变的突变造血干细胞（HSC）的克隆性扩增。PIGA突变导致糖基磷脂酰肌醇（GPI）生物合成缺陷以及DAF和CD59等GPI锚定蛋白的细胞表面缺乏，从而导致血管内溶血和血栓形成。PNH的这两种主要症状可以通过抗C5单克隆抗体依库珠单抗来控制。骨髓衰竭是PNH的第三种主要症状，是自身免疫介导的，通过选择性攻击GPI阳性野生型HSC促进GPI缺陷型HSC的克隆性扩增。由于DAF缺乏，依库珠单抗保护GPI缺陷型红细胞免受血管内溶血，这些红细胞会积累C3衍生片段C3b、iC3b和C3dg，进而变得易被脾脏巨噬细胞通过CR3介导的吞噬作用吞噬。约3%的日本PNH患者对依库珠单抗治疗无效。约3%的日本人存在一种单核苷酸多态性的杂合子，该多态性改变了依库珠单抗结合位点附近的一个氨基酸。需要新的治疗措施来解决这些问题。
