Hebbel R P, Miller W J
Blood. 1984 Sep;64(3):733-41.
Hemolytic anemia in sickle disease involves both intravascular and extravascular destruction of erythrocytes. Since the latter presumably involves the reticuloendothelial system, we have examined interactions between sickle erythrocytes and macrophages. In erythrophagocytosis assays, 18.9 +/- 7.2% of human marrow macrophages ingest sickle RBCs, while only 3.1 +/- 2.1% ingest normal RBCs. This abnormality is not explained by reticulocytosis, and it is strongly dependent upon RBC density. The interaction between sickle RBCs and macrophages appears to be partly immunologic, since it is partially blocked by Fc receptor blockade. Also, admixture of sickle RBCs (pretreated with rabbit anti-human-Ig) and Fc-receptor-bearing K562 cells results in 15.6 +/- 10.6% K562-RBC rosette formation compared with only 0.5 +/- 1.2% for normal RBCs. Regarding other factors that might promote erythrophagocytosis, sickle RBCs are found to spontaneously generate twice-normal amounts of dialdehyde byproducts of lipid peroxidation ("malondialdehyde" or MDA). Peroxide or reagent-MDA treatment of normal RBCs significantly enhances their phagocytosis, and MDA is at least 50 times more potent than other aldehydes studied here. Oxidative and immunologic effects may be related, since exposure of MDA-treated RBCs to immunoglobulin-containing human sera results in a further significant enhancement of erythrophagocytosis. For comparison of different sickle patients, an adherence assay demonstrates that sickle RBCs are 1.03 to 6.85 times more adherent to macrophages than are normal RBCs, and degree of adherence correlates significantly with irreversibly sickled cell (ISC) counts and hematologic variables reflecting hemolytic rate. We conclude that propensity for RBC interaction with macrophages is likely to be a determinant of hemolytic rate in sickle disease. Pertinent mechanisms appear to involve modification of RBC membranes by dialdehyde byproducts of excessive autoxidation and the abnormal acquisition of surface immunoglobulin on sickle RBCs, although participation of other membrane defects has not been excluded. Interestingly, the data further suggest the possibility that appearance of the "senescence antigen" in old normal RBCs represents modification of the membrane by "MDA."
镰状细胞病中的溶血性贫血涉及红细胞的血管内和血管外破坏。由于后者可能涉及网状内皮系统，我们研究了镰状红细胞与巨噬细胞之间的相互作用。在红细胞吞噬试验中，18.9±7.2%的人类骨髓巨噬细胞摄取镰状红细胞，而只有3.1±2.1%摄取正常红细胞。这种异常不能用网织红细胞增多来解释，并且它强烈依赖于红细胞密度。镰状红细胞与巨噬细胞之间的相互作用似乎部分是免疫性的，因为它被Fc受体阻断部分阻断。此外，镰状红细胞（用兔抗人Ig预处理）与带有Fc受体的K562细胞混合后，K562-红细胞玫瑰花结形成率为15.6±10.6%，而正常红细胞仅为0.5±1.2%。关于可能促进红细胞吞噬作用的其他因素，发现镰状红细胞自发产生的脂质过氧化二醛副产物（“丙二醛”或MDA）量是正常量的两倍。用过氧化物或试剂MDA处理正常红细胞可显著增强其吞噬作用，并且MDA的效力至少比这里研究的其他醛高50倍。氧化作用和免疫作用可能相关，因为将经MDA处理的红细胞暴露于含免疫球蛋白的人血清中会导致红细胞吞噬作用进一步显著增强。为了比较不同的镰状细胞病患者，一项黏附试验表明，镰状红细胞与巨噬细胞的黏附力比正常红细胞高1.03至6.85倍，黏附程度与不可逆镰状细胞（ISC）计数以及反映溶血率的血液学变量显著相关。我们得出结论，红细胞与巨噬细胞相互作用的倾向可能是镰状细胞病溶血率的一个决定因素。相关机制似乎涉及过度自氧化产生的二醛副产物对红细胞膜的修饰以及镰状红细胞表面免疫球蛋白的异常获得，尽管尚未排除其他膜缺陷的参与。有趣的是，数据进一步表明，衰老正常红细胞中“衰老抗原”的出现可能代表膜被“MDA”修饰。
