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

IgG 介导的抗体产生和 B 细胞对疟疾记忆的调节：Rol

• 批准号: 8477355
• 负责人: Christopher L King
• 金额: $ 23.58万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8477355
• 关键词: 12 year old; Acute; Adult; Africa; Age; Alleles; Amino Acids; Antibodies; Antibody Formation; Antigen Presentation; Antigen-Antibody Complex; Antigens; Antimalarials; Area; Asia; B-Cell Development; B-Lymphocytes; Binding; Biological; Biological Assay; Blood; Cells; Cerebral Malaria; Chemoprophylaxis; Child; Childhood; Clinical; Data; Development; Erythrocytes; FCGR2B gene; Feedback; Flow Cytometry; Frequencies; Generations; Genes; Genetic Polymorphism; Goals; Homologous Gene; Immune; Immunity; Immunoglobulin G; Individual; Infection; Inflammatory; Inflammatory Response; Institutional Review Boards; Interferons; Interleukin-10; Knowledge; Life; Link; Maintenance; Malaria; Malaria Vaccines; Measures; Mediating; Memory; Memory B-Lymphocyte; Microarray Analysis; Molecular; Mononuclear; Morbidity - disease rate; Mus; Mutation; Papua New Guinea; Parasitemia; Parasites; Peripheral Blood Mononuclear Cell; Phagocytes; Phenotype; Plasma Cells; Plasmodium falciparum; Population; Predisposition; Preschool Child; Protocols documentation; Public Health; Receptor Activation; Receptors, Antigen, B-Cell; Research; SNP genotyping; Sampling; Serum; Signal Transduction; Staging; Symptoms; T-Lymphocyte; TNF gene; Testing; Tetanus Toxoid; United States National Institutes of Health; Vaccines; acquired immunity; base; cytokine; density; design; experience; mutant; novel; response; transmission process; vector control

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.

自然获得性免疫（NAI）对高密度寄生虫病和恶性疟原虫（Pf）的临床疾病