B Cell Superantigen Immune Complex Tissue Inflammation

B 细胞超抗原免疫复合物组织炎症

• 批准号: 7179280
• 负责人: ARNOLD I LEVINSON
• 金额: $ 34.36万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-15 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7179280
• 关键词: Antigen Receptors; Antigen-Antibody Complex; Antigens; Arthus Reaction; Autoimmune Diseases; B-Lymphocytes; Binding; Cells; Complement; Complementarity Determining Regions; Complex; Cutaneous; Deposition; Event; Family; Framework Regions; Frequencies; Gene Family; Goals; Human; Immunoglobulin G; Immunoglobulin M; Immunoglobulin Variable Region; Immunoglobulins; In Vitro; Inbred BALB C Mice; Infectious Agent; Inflammation; Inflammatory; Injury; Light; Lung; Lung Inflammation; Mediating; Mediator of activation protein; Microbe; Modeling; Molecular; Mouse Strains; Mus; Numbers; Oryctolagus cuniculus; Outcome; Pathogenesis; Pathology; Peptostreptococcus; Peripheral; Peritonitis; Process; Property; Proteins; Reaction; Reporting; Research Personnel; Serum; Superantigens; TNF gene; Tissues; Trees; antigen binding; base; chemokine; clinically relevant; human disease; insight; interest; macrophage; mast cell; member; microbial; mouse model; programs; respiratory

DESCRIPTION (provided by applicant): B cell superantigens (B cell SAgs), unlike conventional antigens, bind to the Fab regions of immunoglobulin (Ig) molecules outside their complementarity determining regions. These unconventional antigens can react with a substantial amount of a host's peripheral B cells and serum immunoglobulins by virtue of their ability to interact with many members of an entire variable region heavy (VH) or variable region light (VL) gene family. For example, protein L, secreted by the anaerobic strain Peptostreptococcus magnus, reacts with the Fabs of most human Vk1+, Vk3+, and Vk4+ Igs and homologous murine Vk+ Igs. The ability of B cell SAgs to bind to a large amount of serum IgG underscores their potential to cause imune complex-mediated tissue injury. The overall objective of the studies proposed in this application is to elucidate the cellular and molecular pathogenesis of B cell SAg-induced immune complex-mediated inflammation in the lung. The specific goals are to determine whether lung inflammation induced by the B cell SAg, protein L, 1) demonstrates histopathological correlates of immune complex tissue injury, 2) requires the interaction with selective Vk Igs and 3) is orchestrated by cells/proinflammatory mediators involved in conventional antigen/antibody complex-mediated tissue injury. These objectives will be examined by using mouse strains manipulated genetically to isolate the factors of interest. Since most of the B cell SAgs described to date are derived from ubiquitous microbes, information from these studies will likely provide insight into mechanisms by which infectious agents contribute to the pathogenesis of immune complex-mediated rheumatic and autoimmune disorders.

描述（由申请人提供）：与常规抗原不同，B细胞超抗原（B细胞SAgs）与免疫球蛋白（Ig）分子的互补决定区之外的Fab区结合。这些非常规抗原能够与大量的宿主外周B细胞和血清免疫球蛋白发生反应，因为它们能够与整个可变区重链（VH）或可变区轻链（VL）基因家族的许多成员相互作用。例如，厌氧菌株大消化链球菌分泌的蛋白 L 与大多数人类 Vk1+、Vk3+ 和 Vk4+ Igs 以及同源鼠 Vk+ Igs 的 Fab 发生反应。 B 细胞 SAgs 与大量血清 IgG 结合的能力强调了它们引起免疫复合物介导的组织损伤的潜力。本申请提出的研究的总体目标是阐明 B 细胞 SAg 诱导的免疫复合物介导的肺部炎症的细胞和分子发病机制。具体目标是确定 B 细胞 SAg、蛋白 L 诱导的肺部炎症是否 1) 证明了免疫复合物组织损伤的组织病理学相关性，2) 需要与选择性 Vk Igs 相互作用，3) 由参与传统抗原/抗体复合物介导的组织损伤的细胞/促炎介质精心策划。这些目标将通过使用经过基因操作的小鼠品系来分离感兴趣的因子来检验。由于迄今为止描述的大多数 B 细胞 SAgs 都源自普遍存在的微生物，因此这些研究的信息可能会深入了解感染因子导致免疫复合物介导的风湿病和自身免疫性疾病发病机制的机制。