Institut Pasteur de Dakar, Unité d'Immunologie, Dakar, Sénégal.
PLoS One. 2010 Mar 25;5(3):e9871. doi: 10.1371/journal.pone.0009871.
Effective vaccines to combat malaria are urgently needed, but have proved elusive in the absence of validated correlates of natural immunity. Repeated blood stage infections induce antibodies considered to be the main arbiters of protection from pathology, but their essential functions have remained speculative.
METHODOLOGY/PRINCIPAL FINDINGS: This study evaluated antibody dependent respiratory burst (ADRB) activity in polymorphonuclear neutrophils (PMN) induced by Plasmodium falciparum merozoites and antibodies in the sera of two different African endemic populations, and investigated its association with naturally acquired clinical protection. Respiratory bursts by freshly isolated PMN were quantified by chemiluminescence readout in the presence of isoluminol, which preferentially detects extra-cellular reactive oxygen species (ROS). Using a standardized, high throughput protocol, 230 sera were analyzed from individuals of all age groups living in meso- (Ndiop) or holo-endemic (Dielmo) Senegalese villages, and enrolled in a cross-sectional prospective study with intensive follow-up. Statistical significance was determined using non-parametric tests and Poisson regression models. The most important finding was that PMN ADRB activity was correlated with acquired clinical protection from malaria in both high and low transmission areas (P = 0.006 and 0.036 respectively). Strikingly, individuals in Dielmo with dichotomized high ADRB indexes were seventeen fold less susceptible to malaria attacks (P = 0.006). Complementary results showed that ADRB activity was (i) dependent on intact merozoites and IgG opsonins, but not parasitized erythrocytes, or complement, (ii) correlated with merozoite specific cytophilic IgG1 and IgG3 antibody titers (P<0.001 for both), and (iii) stronger in antisera from a holo-endemic compared to a meso-endemic site (P = 0.002), and reduced in asymptomatic carriers (P<0.001).
CONCLUSIONS/SIGNIFICANCE: This work presents the first clearly demonstrated functional antibody immune correlate of clinical protection from Plasmodium falciparum malaria, and begs the question regarding the importance of ADRB by PMN for immune protection against malaria in vivo.
急需有效的疟疾疫苗，但由于缺乏天然免疫的有效指标，一直未能研制成功。反复的血期感染会诱导被认为是抵御病理损伤的主要保护作用的抗体，但这些抗体的基本功能仍然是推测性的。
方法/主要发现：本研究评估了裂殖体诱导的多形核粒细胞（PMN）依赖抗体的呼吸爆发（ADRB）活性，该活性在两种不同的非洲地方性人群的血清中被检测到，并研究了其与自然获得的临床保护的相关性。通过使用异鲁米诺进行化学发光读出，定量检测新鲜分离的 PMN 的呼吸爆发，异鲁米诺优先检测细胞外活性氧物种（ROS）。使用标准化的高通量方案，对来自居住在中（Ndiop）或全（Dielmo）塞内加尔村庄的各年龄段个体的 230 份血清进行分析，并纳入一项具有强化随访的前瞻性横断面研究。使用非参数检验和泊松回归模型确定统计学意义。最重要的发现是，PMN ADRB 活性与高、低传播地区疟疾的获得性临床保护相关（P=0.006 和 0.036）。引人注目的是，Dielmo 地区 ADRB 指数较高的个体患疟疾攻击的风险降低了 17 倍（P=0.006）。补充结果表明，ADRB 活性（i）依赖于完整的裂殖体和 IgG 调理素，但不依赖于感染的红细胞或补体，（ii）与裂殖体特异性细胞亲嗜性 IgG1 和 IgG3 抗体滴度相关（两者均 P<0.001），（iii）在全地方性地区比中地方性地区的抗血清中更强（P=0.002），并在无症状携带者中降低（P<0.001）。
结论/意义：本研究首次明确证明了临床保护免受恶性疟原虫疟疾的功能抗体免疫相关因素，并提出了PMN 依赖抗体的 ADRB 对体内抗疟免疫保护的重要性问题。
