IgG-mediated modulation of antibody production and B cell memory to malaria: Rol

对恶性疟原虫高密度寄生虫病和临床疾病的自然获得性免疫(NAI) 间日疟原虫(PV)感染在儿童时期发展缓慢，在没有周期性加强的情况下逐渐减弱。 血液期感染。血清中的免疫球蛋白抗体对这种获得性免疫的发展至关重要。慢的 获得NAI的部分原因是产生持久疟疾特异性记忆的能力受损8 细胞(MBC)和由此产生的长寿抗体分泌浆细胞(LLPC)成为疟疾AGS的广泛谱系。 血液期PF和PV可能通过抑制疟疾MBC和LLPC的发生和维持而发挥作用 它们的高Ag负荷会引发全身性促炎反应，例如升高的肿瘤坏死因子-a、干扰素-γ 最终被下调(可能部分解释了为什么许多疟疾流行地区的儿童感染了疟疾 是无症状的)。在当前的提案中，我们检验了炎症环境引起的假设 在很少或没有NAI的个人中反复感染疟疾，例如幼儿和幼稚疟疾患者 成体，上调强大的抑制反馈环，损害MBC的生成和维持 LLPC。这里研究的一个中心目标是建立疟疾感染的易感性和 不复杂的发病率以及产生和维持疟疾抗原特异性微核细胞的能力。我们将评估 将这些关系与Pf和Pv进行比较，因为NAI到Pv的发展速度比Pf快 在巴布亚新几内亚(PNG)类似的传播条件下。研究将在以下情况下进行 来自西非和美国国立卫生研究院的合作者，以确定NAI的这些特征是否被概括 在遗传和流行病学上存在差异的人群中。虽然免疫调节机制将 广泛考虑使用基因微阵列分析已知或可疑的反馈环，抑制性 通过结合疟疾抗原免疫调节B细胞受体(BCR)激活阈值的FcyRIIB 将对复合体(IC)进行具体评估。我们将使用生物样本和临床/寄生虫数据 儿童和成人在PNG暴露于PV和PF中，由西南地区经批准的IRB方案主持 太平洋ICEMR。该项目的具体目标是：一)将非传染性疾病的程度与疟疾的特定群体联系起来 MBC频率、广度和持久性；ii)确定由以下因素引起的免疫调节网络 急性疟疾及其与MBC世代的关系；(Iii)评估FCGR2B是否发挥作用 多态影响NAI和疟疾抗原特异性MBC的发育。

Naturally acquired immunity (NAI) to high-density parasitemia and clinical illness from P. falciparum (Pf) and P. vivax (Pv) infection develops slowly during childhood and wanes in the absence of periodic boosting from blood stage infection. Serum IgG antibodies are critical for development of this acquired immunity. The slow acquisition of NAI arises, in part, from an impaired ability to generate persisting malaria-specific memory 8 cells (MBC) and resulting long-lived Ab secreting plasma cells (LLPC) to a broad repertoire malaria Ags. Blood stage Pf and Pv may suppress generation and maintenance of malaria MBC and LLPC by virtue of their high Ag loads that elicit systemic pro-inflammatory responses, e.g. increased TNF-a, IFN-y which are eventually down-regulated (possibly explaining, in part, why many malaria infected children in endemic areas are asymptomatic). In the current proposal we examine the hypothesis that the inflammatory milieu elicited by repeated malaria infections among individuals with little or no NAI, e.g. young children and malaria naive adults, upregulates potent inhibitory feedback loops that impair generation and maintenance of MBC and LLPC. A central goal of research here is to establish a link between susceptibility to malaria infection and uncomplicated morbidity and the ability to generate and sustain malaria Ag-specific MBC. We will evaluate and compare these relationships with respect Pf and Pv since NAI to Pv develops more rapidly than to Pf under conditions of similar transmission in Papua New Guinea (PNG). The studies will be performed with collaborators from West Africa and NIH in order to determine whether these features of NAI are generalized across populations that diverge genetically and epidemiologically. While immune regulatory mechanisms will be considered broadly using gene microarray analysis of known or suspected feedback loops, inhibitory FcyRIIB that regulates the B cell receptor (BCR) activation threshold by binding malaria Ag immune complexes (IC) will be evaluated specifically. We will use biological samples and clinical/parasite data from children and adults exposed to Pv and Pf in PNG under the auspices of approved IRB protocols of the SW Pacific ICEMR. The specific objective of the project are: i) Correlate the degree of NAI with malaria Agspecific MBC frequency, breadth and durability; ii) Determine the immunoregulatory networks elicited by acute malaria and their relation to generation Pf MBC; (iii) Assess whether FCGR2B functional polymorphisms impact NAI and malaria Ag-specific MBC development.