Wickramasinghe S N
Division of Pathology Sciences, St Mary's Hospital Medical School, Imperial College of Science, Technology and Medicine, London, UK.
Baillieres Clin Haematol. 1995 Sep;8(3):441-59. doi: 10.1016/s0950-3536(05)80215-x.
B12- or folate-deficient haemopoietic cells display abnormalities in their morphology under both the light and electron microscope, their cell kinetics and their capacity to synthesize protein. These abnormalities are maximal in the last dividing cell class and in non-dividing cells, presumably because B12 and folate uptake is largely confined to the most immature erythroid and granulocyte precursors. In patients with moderate or severe anaemia due to B12 or folate deficiency, erythropoiesis is markedly ineffective; intramedullary cell death occurs mainly in the early and late polychromatic megaloblasts. The damaged erythroblasts appear to display neoantigens or normally-hidden antigens at their cell surface and these react with naturally occurring antibodies. The opsonised erythroblasts are then recognised by macrophages via their IgG-Fc receptors and phagocytosed. Marrow cells from B12- or folate-deficient patients show a subnormal suppression of 3H-thymidine incorporation after pre-incubation with nonradioactive deoxyuridine, suggesting that such cells suffer from an impairment of the 5,10-methylene-THF-dependent methylation of deoxyuridylate to thymidylate. However, the exact mechanism by which B12 deficiency causes a reduced supply of this folate coenzyme is uncertain. Methylcobalamin is required for the 5-methyl-THF-dependent methylation of homocysteine to methionine and an impairment of this reaction will result in both reduced conversion of 5-methyl-THF to THF and in reduced methionine synthesis. There is controversy as to whether the reduced supply of THF or methionine is responsible for the reduced availability of 5,10-methylene-THF. Currently, the balance of evidence favours the hypothesis that the reduced supply of methionine leads to reduced synthesis of formyl-THF and, eventually, of 5,10-methylene-THF. Despite the evidence for impaired thymidylate synthesis, the duration of the S phase of megaloblasts appears to be normal or only modestly increased. Data on rates of DNA strand elongation are inconsistent, with subnormal rates reported in PHA-stimulated B12- or folate-deficient lymphocytes and normal rates in B12- or folate-deficient bone marrow cells.(ABSTRACT TRUNCATED AT 400 WORDS)
维生素B12或叶酸缺乏的造血细胞在光学显微镜和电子显微镜下均表现出形态异常、细胞动力学异常以及蛋白质合成能力异常。这些异常在最后一类分裂细胞和非分裂细胞中最为明显，推测是因为维生素B12和叶酸的摄取主要局限于最不成熟的红系和粒系前体细胞。在因维生素B12或叶酸缺乏导致中度或重度贫血的患者中，红细胞生成明显无效；骨髓内细胞死亡主要发生在早幼和晚幼多染性巨幼红细胞。受损的成红细胞似乎在其细胞表面显示出新抗原或正常隐藏的抗原，这些抗原与天然存在的抗体发生反应。然后，被调理素化的成红细胞通过巨噬细胞的IgG-Fc受体被识别并被吞噬。来自维生素B12或叶酸缺乏患者的骨髓细胞在与非放射性脱氧尿苷预孵育后，对3H-胸腺嘧啶核苷掺入的抑制作用低于正常水平，这表明此类细胞存在依赖5,10-亚甲基四氢叶酸的脱氧尿苷酸甲基化生成胸苷酸的功能受损。然而，维生素B12缺乏导致这种叶酸辅酶供应减少的确切机制尚不清楚。甲钴胺是同型半胱氨酸依赖5-甲基四氢叶酸甲基化生成甲硫氨酸所必需的，该反应受损将导致5-甲基四氢叶酸向四氢叶酸的转化减少以及甲硫氨酸合成减少。关于四氢叶酸或甲硫氨酸供应减少是否导致5,10-亚甲基四氢叶酸可用性降低存在争议。目前，证据的平衡支持这样一种假说，即甲硫氨酸供应减少导致甲酰四氢叶酸合成减少，最终导致5,10-亚甲基四氢叶酸合成减少。尽管有证据表明胸苷酸合成受损，但巨幼红细胞S期的持续时间似乎正常或仅略有增加。关于DNA链延伸速率的数据并不一致，在PHA刺激的维生素B12或叶酸缺乏的淋巴细胞中报告的速率低于正常水平，而在维生素B12或叶酸缺乏的骨髓细胞中速率正常。（摘要截短至400字）
