Evans Ceri, Orf Katharine, Horvath Erzsebet, Levin Michael, De La Fuente Josu, Chakravorty Subarna, Cunnington Aubrey J
Section of Paediatrics, Imperial College, London, UK.
Section of Paediatrics, Imperial College, London, UK Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, UK.
Haematologica. 2015 Dec;100(12):1508-16. doi: 10.3324/haematol.2015.128777. Epub 2015 Aug 27.
Sickle cell disease is a risk factor for invasive bacterial infections, and splenic dysfunction is believed to be the main underlying cause. We have previously shown that the liberation of heme in acute hemolysis can induce heme oxygenase-1 during granulopoiesis, impairing the ability of developing neutrophils to mount a bactericidal oxidative burst, and increasing susceptibility to bacterial infection. We hypothesized that this may also occur with the chronic hemolysis of sickle cell disease, potentially contributing to susceptibility to infections. We found that neutrophil oxidative burst activity was significantly lower in treatment-naïve children with sickle cell disease compared to age-, gender- and ethnicity-matched controls, whilst degranulation was similar. The defect in neutrophil oxidative burst was quantitatively related to both systemic heme oxygenase-1 activity (assessed by carboxyhemoglobin concentration) and neutrophil mobilization. A distinct population of heme oxygenase-1-expressing cells was present in the bone marrow of children with sickle cell disease, but not in healthy children, with a surface marker profile consistent with neutrophil progenitors (CD49d(Hi) CD24(Lo) CD15(Int) CD16(Int) CD11b(+/-)). Incubation of promyelocytic HL-60 cells with the heme oxygenase-1 substrate and inducer, hemin, demonstrated that heme oxygenase-1 induction during neutrophilic differentiation could reduce oxidative burst capacity. These findings indicate that impairment of neutrophil oxidative burst activity in sickle cell disease is associated with hemolysis and heme oxygenase-1 expression. Neutrophil dysfunction might contribute to risk of infection in sickle cell disease, and measurement of neutrophil oxidative burst might be used to identify patients at greatest risk of infection, who might benefit from enhanced prophylaxis.
镰状细胞病是侵袭性细菌感染的一个危险因素，脾功能障碍被认为是主要的潜在病因。我们之前已经表明，急性溶血过程中血红素的释放可在粒细胞生成过程中诱导血红素加氧酶-1，损害发育中的中性粒细胞产生杀菌性氧化爆发的能力，并增加对细菌感染的易感性。我们推测，这在镰状细胞病的慢性溶血过程中也可能发生，可能导致对感染的易感性增加。我们发现，与年龄、性别和种族匹配的对照组相比，未经治疗的镰状细胞病患儿的中性粒细胞氧化爆发活性显著降低，而脱颗粒情况相似。中性粒细胞氧化爆发的缺陷在数量上与全身血红素加氧酶-1活性（通过羧基血红蛋白浓度评估）和中性粒细胞动员均相关。在镰状细胞病患儿的骨髓中存在一群表达血红素加氧酶-1的细胞，而健康儿童中则没有，其表面标志物谱与中性粒细胞祖细胞一致（CD49d(高) CD24(低) CD15(中) CD16(中) CD11b(±)）。用血红素加氧酶-1底物和诱导剂血红素孵育早幼粒细胞HL-60细胞表明，中性粒细胞分化过程中血红素加氧酶-1的诱导可降低氧化爆发能力。这些发现表明，镰状细胞病中中性粒细胞氧化爆发活性的损害与溶血和血红素加氧酶-1表达有关。中性粒细胞功能障碍可能导致镰状细胞病患者发生感染的风险增加，测量中性粒细胞氧化爆发可能用于识别感染风险最高的患者，这些患者可能从强化预防中获益。
