Muhimbili University of Health and Allied Sciences, Dar-es-Salaam, Tanzania.
Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
Br J Haematol. 2018 Sep;182(6):758-776. doi: 10.1111/bjh.15443. Epub 2018 Jul 5.
This review examines the evidence that bone marrow failure (BMF) in aplastic anaemia (AA) is due to loss of haematopoietic stem cells (HSCs), which, in turn, is caused by deranged immunity and inflammation. We also consider how the course of the disease and the response to immuno-suppressive therapy are influenced by the nature and specificity of the pathogenic process. A somatic mutation of the PIGA gene underlies the clonal disease paroxysmal nocturnal haemoglobinuria (PNH): there is direct evidence that the expansion of the PIGA mutant clone results from Darwinian selection exerted by a glycosyl-phosphatidyl-inositol -specific auto-immune attack. Thus, PNH patients are a unique subset of patients with AA, in whom haematopoiesis recovers through this escape mechanism. A similar process, although less effective, may operate when the auto-immune attack is against a human leucocyte antigen (HLA) molecule and an HLA mutation has produced a clone missing that molecule. We then discuss the significance of other mutant clones that are frequently found in AA, presumably due to a combination of genetic drift and selection. These clones are not causative of AA, but they emerge in AA and they may be pre-leukaemic: unlike a PIGA mutant clone, in general they are unable to effectively reconstitute haematopoiesis.
这篇综述探讨了骨髓衰竭（BMF）在再生障碍性贫血（AA）中的证据，其归因于造血干细胞（HSCs）的丧失，而这反过来又是由免疫和炎症失调引起的。我们还考虑了疾病的过程和对免疫抑制治疗的反应如何受到致病过程的性质和特异性的影响。PIGA 基因突变是阵发性睡眠性血红蛋白尿症（PNH）克隆性疾病的基础：有直接证据表明，PIGA 突变克隆的扩展是由糖基磷脂酰肌醇特异性自身免疫攻击施加的达尔文选择所致。因此，PNH 患者是 AA 患者中的一个独特亚群，其中造血通过这种逃逸机制恢复。当自身免疫攻击针对人类白细胞抗原（HLA）分子并且 HLA 突变产生缺失该分子的克隆时，可能会发生类似但效果较差的过程。然后，我们讨论了在 AA 中经常发现的其他突变克隆的意义，这些克隆可能是由于遗传漂移和选择的结合所致。这些克隆不是 AA 的病因，但它们出现在 AA 中，可能是白血病前的：与 PIGA 突变克隆不同，它们通常无法有效地重建造血。
