Microbe-driven Development of GALT

微生物驱动的 GALT 开发

• 批准号: 9924442
• 负责人: Katherine L. Knight
• 金额: $ 45.98万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-25 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9924442
• 关键词: Affinity; Amino Acids; Antibody Affinity; Antibody Repertoire; Antigens; B-Cell Activation; B-Lymphocytes; Bacteria; Binding; Bone Marrow; Cell Line; Cell surface; Clustered Regularly Interspaced Short Palindromic Repeats; Development; Fishes; Fluorescent in Situ Hybridization; Framework Regions; Gene Rearrangement; Genes; Gut associated lymphoid tissue; Human; Immune Sera; Immune system; Immunofluorescence Immunologic; Immunoglobulin M; J segment gene; Knowledge; Life; Lymphoid Tissue; Mediating; Microbe; Mus; Mutate; Oryctolagus cuniculus; Polysaccharides; Proliferating; Receptors, Antigen, B-Cell; Recombinant DNA; Research; Ribosomal RNA; Secondary to; Signal Transduction; Stains; Structure; Structure of germinal center of lymph node; Surface; Testing; Tissues; bacterial lysate; combinatorial; commensal bacteria; gut microbiota; in vivo; microbiota; next generation sequencing; postnatal; response

Abstract Microbiota are required for the development of secondary lymphoid tissues, including gut- associated lymphoid tissues (GALT). Interactions between GALT and the microbiota are especially important in rabbits, as B cells proliferate and mutate their V(D)J genes in response to select commensal bacteria. Further, VHa B cells, identified because they utilize VH1, are selectively expanded in GALT as a result of specific commensal bacteria. In contrast, other B cells, designated VHn, do not expand in GALT. VHa and VHn B cells differ primarily in the external surface of framework regions (FR) 1 and 3, and we propose that VHa-specific amino acids on the external surfaces of FR1 and FR3 form a binding motif that together with TLR signaling through MyD88, mediates selective expansion of VHa B cells by binding bacterial cell surface molecules. We hypothesize that this innate-like, non-antigen-specific stimulation through the B cell receptor (BCR) facilitates selective expansion of VHa B cells and diversification of the primary Ab repertoire. In Aim 1, we will test this hypothesis by identifying bacteria in GALT that selectively bind to and activate VHa but not VHn B cells. Aim 2 will test if the identified bacteria specifically drive expansion of VHa B cells in vivo; and in Aim 3, we will explore the mechanism by which the bacteria stimulate VHa B cells. The results will elucidate a new mechanism by which bacteria interact with B cells to promote development of the immune system.

抽象的 微生物群是次级淋巴组织（包括肠道组织）发育所必需的 相关淋巴组织（GALT）。 GALT 与微生物群之间的相互作用是 对兔子尤其重要，因为 B 细胞会增殖并突变其 V(D)J 基因作为响应 选择共生细菌。此外，VHa B 细胞因利用 VH1 而被鉴定为 由于特定的共生细菌，GALT 中选择性扩增。相比之下，其他B 指定为 VHn 的细胞不会在 GALT 中扩增。 VHa 和 VHn B 细胞的主要区别在于 框架区 (FR) 1 和 3 的外表面，我们提出 VHa 特异性氨基 FR1 和 FR3 外表面上的酸形成结合基序，与 TLR 一起 通过 MyD88 发出信号，通过结合细菌细胞介导 VHa B 细胞的选择性扩增 表面分子。我们假设这种先天性的、非抗原特异性的刺激 通过 B 细胞受体 (BCR) 促进 VHa B 细胞的选择性扩增， 主要抗体库的多样化。在目标 1 中，我们将通过确定 GALT 中的细菌选择性结合并激活 VHa 但不激活 VHn B 细胞。目标 2 将测试是否 已鉴定的细菌在体内特异性驱动 VHa B 细胞的扩增；在目标 3 中，我们将 探索细菌刺激 VHa B 细胞的机制。结果将阐明 细菌与 B 细胞相互作用促进免疫发展的新机制 系统。