Role of Protective and Pathogenic B cells in Modulating Pediatric Severe Malaria

保护性和致病性 B 细胞在调节小儿重症疟疾中的作用

• 批准号: 8410603
• 负责人: Tom Were
• 金额: $ 4.86万
• 依托单位: KENYA MEDICAL RESEARCH INSTITUTE (KEMRI)
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-09 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8410603
• 关键词: 3 year old; Accounting; Acute; Anemia; Antibodies; Antibody Formation; Antigens; Antimalarials; Area; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; BLR1 gene; Binding; Biological; Biological Assay; CCR5 gene; CD34 gene; CXC Chemokines; CXCL12 gene; CXCL13 gene; CXCR4 Receptors; CXCR4 gene; Child; Childhood; Chronic; Clinical; Clinical Trials; Collection; Complex; Development; Disease; Disease Outcome; Enzyme-Linked Immunosorbent Assay; Erythrocytes; Erythroid; Erythrophagocytosis; Erythropoiesis; Flow Cytometry; Functional disorder; Goals; HIV; Health; Hemoglobin concentration result; Hospitals; Human; IgE; Immune response; Immunity; Immunoglobulin Class Switching; In Vitro; Infant; Infection; Inflammatory; Interferon Type II; Interferons; Interleukin-10; Intervention; Investigation; Kenya; Laboratories; Life; Ligands; Low Birth Weight Infant; Low affinity IgE receptor; Lupus; Macrophage Inflammatory Protein-1; Malaria; Malaria Vaccines; Measurement; Measures; Mediating; Mediator of activation protein; Memory; Memory B-Lymphocyte; Modeling; Molecular; Morbidity - disease rate; Mus; Parasitemia; Pathogenesis; Pathway interactions; Pattern; Phenotype; Plasma; Plasmodium falciparum; Production; Prospective Studies; RNA; Rheumatoid Arthritis; Risk; Role; Severities; Severity of illness; Signal Transduction; Small Inducible Cytokine A3; Stromal Cell-Derived Factor 1; Stromal Cells; Surface; TNF gene; Therapeutic; Time; Transcript; Visit; base; chemokine; chemokine receptor; cohort; conditioning; cytokine; density; follow-up; hemozoin; human CXCL13 protein; improved; mortality; novel; novel vaccines; public health relevance; receptor; research study; response; transmission process; treatment duration

DESCRIPTION (provided by applicant): Severe malarial anemia (SMA) is the most common clinical manifestation of severe malaria in infants and young children living in holoendemic Plasmodium falciparum transmission areas. SMA accounts for the greatest degree of global malaria-attributable morbidity and mortality. The pathophysiology of SMA is complex and multi-factorial and has been attributed to direct and indirect destruction of infected and uninfected erythrocytes, suppression of erythropoiesis, erythrophagocytosis, and dysregulation in cytokine production. However, the paucity of information on the immunological basis of SMA is a significant hindrance since a successful malaria vaccine must protect against development of life-threatening SMA. Different B cell subsets regulate protective and pathogenic immune responses associated with disease outcomes in a number of inflammatory mediated-diseases. Previous studies showed that alterations in the circulating memory B cells and regulatory B cells are associated with disease outcomes in rheumatoid arthritis (RA). Additional studies demonstrated that decreased surface expression of CXCR4 and CXCR5 and increased intracellular SDF-1α and BCA-1 expression are associated with chronic human immunodeficiency virus, systemic lupus erythromatosus, and RA. Since na¿ve, memory and effector B cell subsets predominantly produce IL-10, TNF-α, and IFN-γ, differential expression of these subsets may be important determinants of disease severity in children with SMA. Studies in human malaria indicate that B cells mediate malarial immunity through gradual accumulation of specific memory B cells and antibody titers following repeated infection. Since cytokines/chemokines, and their receptors, can modulate B cell subsets and erythropoiesis, the current proposal will explore the role of different B cell subsets (expressing CXCR4/BCA-1 and CXCR5/SDF-1α) in conditioning the development of SMA and suppression of erythroid development. Additional studies showed that increased activation of B cells through the IgE/CD23 pathway promotes increased production of erythropoietic suppressive mediators such as MIP-1α. In addition, elevated IgE and soluble (s)CD23 are associated with increased severity of pediatric malaria. Moreover, increased activation of the IgE/CD23 axis is associated with profound anemia in murine models. Since, both CD23 and MIP-1α regulate IgE synthesis, and are inversely correlated with hemoglobin levels, we will determine the effect of B cell expression of IgE/CD23 and MIP-1α on the development of SMA. This proposal will also determine the effect of Plasmodium falciparum-derived hemozoin (PfHz) on IgE class switching and cytokine/chemokine B cell expression following activation of TLR9 (CD289). Although PfHz can promote antibody class switching and activation of CD289, no studies to date have been performed in children with SMA. The overall objective of this proposal is to investigate the role of different B cell subsets and the IgE/CD23 axis in regulatin the development of SMA in children less than 3 years of age residing in a holoendemic P. falciparum transmission area of western Kenya. The overall hypothesis of this proposal is that PfHz alters the production of cytokines (IL-10, TNF-α, and IFN-γ) and chemokines (SDF-1α, BCA-1 and MIP-1α) which, in turn, promote differentiation of B cell subsets into different effector and regulatory phenotypes. To accomplish the experimental objectives, we will utilize a hospital-based prospective study with a longitudinal follow-up perio of 36 months. Since the underlying molecular basis required for development of protective immunity against SMA remains largely undefined, our investigations will focus on the ability of cytokines (IL-10, TNF-α, and IFN-γ), chemokines (i.e., CXCR4/SDF-1α, CXCR5/BCA-1 and CCR5/MIP-1α), and PfHz to modulate B cell subsets and development of SMA. Since this proposal will perform investigations in extensively phenotyped cohorts of children, we will maximize our ability to successfully identify those B cell subsets tha influence the development of SMA.

描述（由申请人提供）：严重疟疾贫血（SMA）是生活在恶性疟原虫传播地区的婴儿和幼儿中最常见的严重疟疾临床表现，SMA 是全球疟疾发病率和死亡率的最大原因。 SMA 的病理生理学是复杂且多因素的，归因于感染和未感染红细胞的直接和间接破坏、然而，关于 SMA 免疫学基础的信息匮乏是一个重大障碍，因为成功的疟疾疫苗必须防止危及生命的 SMA 的发展。不同的 B 细胞亚群调节保护性和致病性免疫。先前的研究表明，循环记忆 B 细胞和调节性 B 细胞的改变与类风湿性关节炎的疾病结果相关。 (RA). 其他研究表明，CXCR4 和 CXCR5 表面表达减少以及细胞内 SDF-1α 和 BCA-1 表达增加与慢性人类免疫缺陷病毒、系统性红斑狼疮和 RA 相关。 ve，记忆和效应 B 细胞亚群主要产生 IL-10、TNF-α 和 IFN-γ，这些亚群的差异表达可能是 SMA 儿童疾病严重程度的重要决定因素。对人类疟疾的研究表明，B 细胞介导疟疾。由于细胞因子/趋化因子及其受体可以调节 B 细胞亚群和红细胞生成，因此当前的提案将探讨不同的作用。 B 细胞亚群（表达 CXCR4/BCA-1 和 CXCR5/SDF-1α）调节 SMA 的发展和抑制红细胞发育。其他研究表明，通过 IgE/CD23 途径增加 B 细胞的激活可促进红细胞生成抑制的产生。此外，IgE 和可溶性 (s)CD23 的升高与儿童疟疾严重程度的增加有关。 IgE/CD23 轴与小鼠模型中的严重贫血相关，因为 CD23 和 MIP-1α 都调节 IgE 合成，并且与血红蛋白水平呈负相关，因此我们将确定 IgE/CD23 和 MIP-1α 的 B 细胞表达的影响。该提案还将确定恶性疟原虫衍生的疟原虫色素 (PfHz) 对 IgE 类别转换和TLR9 (CD289) 激活后细胞因子/趋化因子 B 细胞的表达虽然 PfHz 可以促进抗体类别转换和 CD289 激活，但迄今为止尚未在 SMA 儿童中进行研究。不同 B 细胞亚群和 IgE/CD23 轴在调节居住在西部恶性疟原虫恶性疟传播区的 3 岁以下儿童 SMA 的发展中肯尼亚 该提案的总体假设是 PfHz 改变细胞因子（IL-10、TNF-α 和 IFN-γ）和趋化因子（SDF-1α、BCA-1 和 MIP-1α）的产生，进而，促进 B 细胞亚群分化为不同的效应和调节表型，为了实现实验目标，我们将利用一项基于医院的前瞻性研究，进行为期 36 个月的纵向随访，以了解开发所需的分子基础。针对 SMA 的保护性免疫在很大程度上仍不明确，我们的研究将集中于细胞因子（IL-10、TNF-α 和 IFN-γ）、趋化因子（即 CXCR4/SDF-1α、CXCR5/BCA-1 和 CCR5/ MIP-1α）和 PfHz 来调节 B 细胞亚群和 SMA 的发育，由于该提案将在广泛表型的儿童群体中进行研究，因此我们将最大限度地发挥我们成功的能力。确定影响 SMA 发展的 B 细胞亚群。