Young Neal S., Abkowitz Janis L., Luzzatto Lucio
Hematology Am Soc Hematol Educ Program. 2000:18-38. doi: 10.1182/asheducation-2000.1.18.
This review addresses three related bone marrow failure diseases, the study of which has generated important insights in hematopoiesis, red cell biology, and immune-mediated blood cell injury. In Section I, Dr. Young summarizes the current knowledge of acquired aplastic anemia. In most patients, an autoimmune mechanism has been inferred from positive responses to nontransplant therapies and laboratory data. Cytotoxic T cell attack, with production of type I cytokines, leads to hematopoietic stem cell destruction and ultimately pancytopenia; this underlying mechanism is similar to other human disorders of lymphocyte-mediated, tissue-specific organ destruction (diabetes, multiple sclerosis, uveitis, colitis, etc.). The antigen that incites disease is unknown in aplastic anemia as in other autoimmune diseases; post-hepatitis aplasia is an obvious target for virus discovery. Aplastic anemia can be effectively treated by either stem cell transplantation or immunosuppression. Results of recent trials with antilymphocyte globulins and high dose cyclophosphamide are reviewed. Dr. Abkowitz discusses the diagnosis and clinical approach to patients with acquired pure red cell aplasia, both secondary and idiopathic, in Section II. The pathophysiology of various PRCA syndromes including immunologic inhibition of red cell differentiation, viral infection (especially human parvovirus B19), and myelodysplasia are discussed. An animal model of PRCA (secondary to infection with feline leukemia virus [FeLV], subgroup C) is presented. Understanding the mechanisms by which erythropoiesis is impaired provides for insights into the process of normal red cell differentiation, as well as a rational strategy for patient management. Among the acquired cytopenias paroxysmal nocturnal hemoglobinuria (PNH) is relatively rare; however, it can pose formidable management problems. Since its first recognition as a disease, PNH has been correctly classified as a hemolytic anemia; however, the frequent co-existence of other cytopenias has hinted strongly at a more complex pathogenesis. In Section III, Dr. Luzzatto examines recent progress in this area, with special emphasis on the somatic mutations in the PIG-A gene and resulting phenotypes. Animal models of PNH and the association of PNH with bone marrow failure are also reviewed. Expansion of PNH clones must reflect somatic cell selection, probably as part of an autoimmune process. Outstanding issues in treatment are illustrated through clinical cases of PNH. Biologic inferences from PNH may be relevant to our understanding of more common marrow failure syndromes like myelodysplasia.
本综述探讨了三种相关的骨髓衰竭疾病，对这些疾病的研究在造血、红细胞生物学以及免疫介导的血细胞损伤方面产生了重要见解。在第一部分，杨博士总结了获得性再生障碍性贫血的现有知识。在大多数患者中，从对非移植治疗的阳性反应和实验室数据推断出存在自身免疫机制。细胞毒性T细胞攻击并产生I型细胞因子，导致造血干细胞破坏，最终引发全血细胞减少；这种潜在机制类似于其他淋巴细胞介导的组织特异性器官破坏的人类疾病（糖尿病、多发性硬化症、葡萄膜炎、结肠炎等）。与其他自身免疫性疾病一样，再生障碍性贫血中引发疾病的抗原尚不清楚；肝炎后再生障碍是病毒发现的一个明显目标。再生障碍性贫血可通过干细胞移植或免疫抑制有效治疗。本文回顾了近期抗淋巴细胞球蛋白和高剂量环磷酰胺试验的结果。在第二部分，阿布科维茨博士讨论了获得性纯红细胞再生障碍患者（包括继发性和特发性）的诊断和临床处理方法。讨论了各种纯红细胞再生障碍综合征的病理生理学，包括红细胞分化的免疫抑制、病毒感染（特别是人细小病毒B19）和骨髓增生异常。介绍了一种纯红细胞再生障碍的动物模型（继发于猫白血病病毒C亚群感染）。了解红细胞生成受损的机制有助于深入了解正常红细胞分化过程，以及为患者管理提供合理策略。在获得性血细胞减少症中，阵发性睡眠性血红蛋白尿（PNH）相对罕见；然而，它可能带来棘手的管理问题。自从首次被确认为一种疾病以来，PNH一直被正确归类为溶血性贫血；然而，其他血细胞减少症的频繁共存强烈暗示了其发病机制更为复杂。在第三部分，卢扎托博士研究了该领域的最新进展，特别强调了PIG - A基因的体细胞突变及其产生的表型。还回顾了PNH的动物模型以及PNH与骨髓衰竭的关联。PNH克隆的扩增必定反映了体细胞选择，这可能是自身免疫过程的一部分。通过PNH的临床病例说明了治疗中的突出问题。PNH的生物学推断可能与我们对骨髓增生异常等更常见的骨髓衰竭综合征的理解相关。
