Plasmodium Falciparum Infection and Interference with Effective B Cell Memory

描述(由申请人提供)：在恶性疟疾流行地区，自然获得性免疫对于调节恶性疟疾的发病率和死亡率至关重要，在那里，一些人每年被感染数百次。对恶性疟原虫(Pf)的体液反应是这种免疫的重要组成部分，而Pf特异的记忆B细胞(MBCs)在有效反应的形成和维持中可能是重要的。不幸的是，对临床疾病的保护需要多年的时间才能形成，在此期间，住在流行区的儿童经历了多次出现症状的疟疾，每年导致100多万人死亡。为什么抗疟疾免疫发展得如此缓慢？一种可能的解释是，PF感染干扰了有效B细胞记忆的发展。最近在HIV感染者的血液中发现了一种非典型的MBC表型，显示出亲和力较低的成熟和分化为抗体分泌细胞的能力较弱的证据。最近的研究表明，生活在疟疾流行区的人具有类似非典型微核细胞的频率升高，但PF暴露与非典型微核细胞频率之间的关系尚未得到详细调查。此外，目前还不清楚这些细胞在疟疾感染者身上会产生什么后果。我们假设，频繁暴露于PF会导致PF特异的B细胞选择性地转变为非典型的MBC表型，从而延迟获得对PF的保护性免疫。我们处于一个独特的位置来检验这一假设，因为我们可以接触到生活在疟疾传播强度高但不同的地区的一组具有良好特征的受试者，并建立了实验室基础设施。我们在乌干达托罗罗的PF传播强度是世界上最高的之一，来自该站点的初步数据表明，在这种情况下，PF特异性抗体反应的亲和力可能会受到影响。我们将通过以下具体目标来验证我们的假设：1)测量生活在乌干达高传播区的儿童中PF暴露与非典型记忆B细胞丰富之间的关联；以及2)测量非典型记忆B细胞丰富与疟疾保护性体液免疫的血清学和寄生虫学证据之间的关联。我们预计，这项研究将表明，暴露于PF的增加与B细胞记忆缺陷的增加有关，其特征是PF特异性多核细胞比例较高，表现为非典型表型，并有证据表明PF特异性抗体亲和力和控制血液期寄生虫的能力降低。如果是这样的话，与流行的疟疾控制努力将推迟获得免疫力的观念背道而驰，这些战略旨在 减少暴露可能会对免疫力产生积极影响。此外，本研究建立的PF特异性B细胞的鉴定方法将在研究PF的体液免疫方面具有广泛的应用前景。

DESCRIPTION (provided by applicant): Naturally acquired immunity is critical in modulating morbidity and mortality from falciparum malaria in endemic areas, where some individuals are infected hundreds of times per year. Humoral responses to Plasmodium falciparum (Pf) are a critical component of this immunity, and Pf-specific memory B cells (MBCs) are likely important in the development and maintenance of an effective response. Unfortunately, protection from clinical disease takes many years to develop, during which time children living in endemic areas experience multiple episodes of symptomatic malaria, resulting in over 1 million deaths annually. Why does antimalarial immunity develop so slowly? One potential explanation is that Pf infection interferes with the development of effective B cell memory. An atypical phenotype of MBC, exhibiting evidence for lower affinity maturation and less capacity for differentiation into antibody secreting cells, has recently been described in the blood of HIV infected subjects. Recent studies have demonstrated that people living in malaria endemic areas have elevated frequencies of similar atypical MBCs, but the relationship between Pf exposure and frequencies of atypical MBCs has not been investigated in detail. Moreover, it is unclear what the consequences of these cells are in malaria infected individuals. We hypothesize that frequent exposure to Pf results in the selective diversion of Pf-specific B cells into an atypical MBC phenotype, delaying the acquisition of protective immunity to Pf. We are in a unique position to test this hypothesis, with access to a well characterized cohort of subjects living in an area of high but heterogeneous malaria transmission intensity and established laboratory infrastructure. Pf transmission intensity at our site in Tororo, Uganda ranks among the highest in the world, and preliminary data from this site suggest that affinity of Pf-specific antibody responses may be compromised in this setting. We will test our hypothesis with the following Specific Aims: 1) To measure the association between Pf exposure and enrichment of atypical memory B cells in children living in a high transmission region of Uganda.; and 2) To measure the association between enrichment of atypical memory B cells and serological and parasitological evidence of protective humoral immunity to malaria. We anticipate this study will show that increased exposure to Pf is associated with increased defects in B cell memory, characterized by higher proportions of Pf-specific MBCs showing an atypical phenotype and evidence of reduced Pf-specific antibody affinity and ability to control blood stage parasites. If so, counter to prevailig notions that malaria control efforts will delay the acquisition of immunity, strategies designed to reduce exposure may have a positive impact on immunity. In addition, methods to characterize Pf-specific B cells developed in this study will have broad application for investigating humoral immunity to Pf.