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: 8660360
• 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/8660360
• 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; 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（由适用提供）：严重的疟疾贫血（SMA）是居住在恶性疟原虫传播区域中的婴儿和幼儿中严重疟疾的最常见临床表现。 SMA占全球疟疾 - 可归因的发病率和死亡率最大的程度。 SMA的病理生理学是复杂的，多因素，并且归因于感染和未感染的红细胞的直接和间接破坏，抑制红细胞生成，红细胞增多症，以及细胞因子产生的失调。但是，由于成功的疟疾疫苗必须预防危及生命的SMA的发展，因此缺乏有关SMA免疫学基础的信息是一个重大的障碍。不同的B细胞子集调节了许多与疾病结局相关的受保护和致病性免疫复杂。先前的研究表明，循环记忆B细胞和调节B细胞的改变与类风湿关节炎（RA）的疾病结局有关。其他研究表明，CXCR4和CXCR5的表面表达降低以及细胞内SDF-1α和BCA-1表达的增加与慢性人类免疫缺陷病毒，全身性红斑狼疮和RA有关。由于NA ve，记忆和效应B细胞子集主要产生IL-10，TNF-α和IFN-γ，因此这些子集的差异表达可能是SMA儿童疾病严重程度的重要决定剂。对人疟疾的研究表明，B细胞反复感染后，通过特定记忆B细胞和抗体滴度的成绩积累，疟疾免疫学中值。由于细胞因子/趋化因子及其受体可以调节B细胞子集和红细胞生成，因此当前的建议将探索不同B细胞子集（表达CXCR4/BCA4/BCA-1和CXCR5/SDF-1α）在调节SMA发展和抑制红细胞发育中的作用。其他研究表明，通过IGE/CD23途径增加B细胞的激活会促进红细胞生成抑制介质（如MIP-1α）的产生增加。另外，升高的IgE和固体CD23与小儿疟疾的严重程度增加有关。此外，在鼠模型中，IgE/CD23轴的激活增加与深度贫血有关。由于CD23和MIP-1α都调节IgE合成，并且与血红蛋白水平成反比，因此我们将确定IgE/CD23和MIP-1α的B细胞表达对SMA发展的影响。该建议还将确定恶性疟原虫衍生的血元（PFHZ）对TLR9激活后IgE类转换和细胞因子/趋化因子B细胞表达的影响（CD289）。尽管PFHZ可以促进CD289的抗体类切换和激活，但迄今为止，在SMA儿童中尚未进行研究。该提案的总体目的是研究不同B细胞子集的作用和IgE/CD23轴在调节肯尼亚西部全体疟原虫传播区域不到3岁的儿童中SMA的发展。该提案的总体假设是PFHZ改变了细胞因子（IL-10，TNF-α和IFN-γ）和趋化因子（SDF-1α，BCA-1和MIP-1α）的产生，从而促进B细胞亚群体分化为不同的效应和调节型现象。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，其纵向随访期为36个月。 Since the underlying molecular basis required for development of protected immunology against SMA remains largely undefined, our investments 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.由于该提案将在广泛表型的儿童中进行投资，因此我们将最大程度地提高我们成功识别这些B细胞子集的能力，这会影响SMA的发展。