Fadlon E, Vordermeier S, Pearson T C, Mire-Sluis A R, Dumonde D C, Phillips J, Fishlock K, Brown K A
Department of Immunology, St Thomas' Hospital, London, UK.
Blood. 1998 Jan 1;91(1):266-74.
There is increasing interest in the role of blood polymorphonuclear leukocytes (PMNs) in the pathogenesis of sickle cell crisis. We studied the adherence of PMNs from 18 sickle cell patients in crisis, 25 out of crisis, and 43 healthy subjects (controls) to monolayers of human umbilical cord endothelium that were either untreated or pretreated with tumor necrosis factor alpha (TNFalpha). Overall, the PMNs from patients in crisis were more adherent than control PMNs to untreated endothelial monolayers (mean 53% increase; P < .001) and TNFalpha-treated monolayers (mean 41% increase; P < .002). Increased adhesiveness was not associated with an abnormal expression of CD11a, CD11b, CD11c, CD18, CD62L, or CD15. There was an increase in the number of PMNs expressing CD64 in patients in crisis (median value, 44%) compared with patients out of crisis (median, 21%; P = .025) and controls (median, 6.5%; P < .001). Sera from patients in crisis had normal levels of granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interferon-gamma, TNFalpha, interleukin-1 (IL-1), IL-6, or IL-8 and did not modify the adherence of PMNs or their expression of CD64. Only IFN-gamma induced CD64 expression on PMNs, but this effect was not associated with enhanced binding to endothelium. Because PMNs bound to endothelial monolayers were CD64(+) and CD64-enriched PMNs were 7 times more adherent to endothelial monolayers than CD64-depleted PMNs, it is likely that CD64 is a marker of adherent PMNs. Two of the three anti-CD64 antibodies used in our antibody blocking studies (clones 32.2 and 197) partially inhibited the binding of sickle cell PMNs to untreated endothelium (mean inhibitions of 33% [P = .01] and 21% [P = .03], respectively), whereas only one (clone 197) inhibited binding to TNFalpha-treated endothelium (mean inhibition, 29%; P = . 004). In some patients with sickle cell disease, an enhanced PMN adhesion to vascular endothelium could contribute to the vascular occlusion that characterizes the acute crisis of the disease.
血液多形核白细胞（PMN）在镰状细胞危象发病机制中的作用日益受到关注。我们研究了18例处于危象期的镰状细胞病患者、25例非危象期患者以及43名健康受试者（对照组）的PMN与人脐静脉内皮细胞单层的黏附情况，这些内皮细胞单层要么未经处理，要么用肿瘤坏死因子α（TNFα）进行预处理。总体而言，处于危象期患者的PMN与未经处理的内皮细胞单层相比，黏附性更强（平均增加53%；P <.001），与经TNFα处理的单层相比也是如此（平均增加41%；P <.002）。黏附性增加与CD11a、CD11b、CD11c、CD18、CD62L或CD15的异常表达无关。与非危象期患者（中位数为21%；P = 0.025）和对照组（中位数为6.5%；P <.001）相比，处于危象期患者中表达CD64的PMN数量增加（中位数为44%）。处于危象期患者的血清中粒细胞集落刺激因子、粒细胞 - 巨噬细胞集落刺激因子、干扰素 - γ、TNFα、白细胞介素 - 1（IL - 1）、IL - 6或IL - 8水平正常，且不会改变PMN的黏附性或其CD64的表达。只有干扰素 - γ能诱导PMN上CD64的表达，但这种作用与增强的与内皮细胞的结合无关。由于与内皮细胞单层结合的PMN是CD64(+)，且富含CD64的PMN与内皮细胞单层的黏附性比缺乏CD64的PMN高7倍，因此CD64很可能是黏附性PMN的标志物。在我们的抗体阻断研究中使用的三种抗CD64抗体中的两种（克隆32.2和197）部分抑制了镰状细胞病患者的PMN与未经处理的内皮细胞的结合（平均抑制率分别为33% [P = 0.01]和21% [P = 0.03]），而只有一种（克隆197）抑制了与经TNFα处理的内皮细胞的结合（平均抑制率为29%；P = 0.004）。在一些镰状细胞病患者中，PMN对血管内皮的黏附增强可能导致血管闭塞，这是该疾病急性危象的特征。
