Association of Early Interferon-γ Production with Immunity to Clinical Malaria: A Longitudinal Study among Papua New Guinean Children
Association of Early Interferon-γ Production with Immunity to Clinical Malaria: A Longitudinal Study among Papua New Guinean Children
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DOI：
10.1086/592971
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发表时间：
2008-12-01
影响因子：
11.8
通讯作者：
Schofield, Louis
中科院分区：
文献类型：
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作者：
D'Ombrain, Marthe C.;Robinson, Leanne J.;Schofield, Louis
背景资料。阐明对恶性疟原虫感染的自然获得性免疫的细胞和分子基础将有助于开发合理的疟疾疫苗。先天免疫、中间免疫和获得性免疫机制都可能促进免疫。干扰素-γ(干扰素-γ)在人类疟疾的预防和发病机制中都有一定的作用。此外，在初治疟疾的捐献者中，对恶性疟原虫的快速干扰素-γ反应存在相当大的异质性。问题仍然是，在接触疟疾的个体中是否观察到类似的异质性，以及高、中或低的干扰素-γ应答与保护性免疫或发病率是否存在不同的关联。对206名巴布亚新几内亚学龄儿童进行了为期6个月的纵向队列研究。将基线采集的外周血单核细胞暴露于感染恶性疟原虫的活红细胞中。检测早期干扰素-γ反应，并用流式细胞仪鉴定表达干扰素-γ的细胞。然后测试干扰素-γ的反应性与寄生虫学和临床结果变量的相关性。在儿童中观察到早期干扰素-γ应答的疟疾特异性异质性。早期高水平的干扰素-γ应答与对高密度和临床恶性疟原虫感染的保护有关。寄生虫诱导的早期干扰素-γ主要来源于γ-βT细胞(其中68%表达自然杀伤分子CD56)和α-βT细胞，而自然杀伤细胞和其他细胞仅起很小的作用。CD56在对疟疾有反应性、表达干扰素-γ的γ-Delta T细胞中的表达与干扰素-γ的应答有关。在巴布亚新几内亚儿童中，活体寄生虫刺激的外周血单核细胞早期产生高水平的干扰素-γ与儿童对有症状的疟疾的免疫力有关，而类自然杀手的伽马-三角洲T细胞可能有助于保护。
Background. Elucidating the cellular and molecular basis of naturally acquired immunity to Plasmodium falciparum infection would assist in developing a rationally based malaria vaccine. Innate, intermediate, and adaptive immune mechanisms are all likely to contribute to immunity. Interferon-gamma (IFN-gamma) has been implicated in both protection against and the pathogenesis of malaria in humans. In addition, considerable heterogeneity exists among rapid IFN-gamma responses to P. falciparum in malaria-naive donors. The question remains whether similar heterogeneity is observed in malaria-exposed individuals and whether high, medium, or low IFN-gamma responsiveness is differentially associated with protective immunity or morbidity.Methods. A 6-month longitudinal cohort study involving 206 school-aged Papua New Guinean children was performed. Peripheral blood mononuclear cells collected at baseline were exposed to live P. falciparum-infected erythrocytes. Early IFN-gamma responses were measured, and IFN-gamma-expressing cells were characterized by flow cytometry. IFN-gamma responsiveness was then tested for associations with parasitological and clinical outcome variables.Results. Malaria-specific heterogeneity in early IFN-gamma responsiveness was observed among children. High-level early IFN-gamma responses were associated with protection from high-density and clinical P. falciparum infections. Parasite-induced early IFN-gamma was predominantly derived from gamma delta T cells (68% of which expressed the natural killer marker CD56) and alpha beta T cells, whereas natural killer cells and other cells made only minor contributions. The expression of CD56 in malaria-responsive, IFN-gamma-expressing gamma delta T cells correlated with IFN-gamma responsiveness.Conclusions. High, early IFN-gamma production by live parasite-stimulated peripheral blood mononuclear cells is a correlate of immunity to symptomatic malaria in Papua New Guinean children, and natural killer-like gamma delta T cells may contribute to protection.