B Cell Superantigen Immune Complex Tissue Inflammation

描述（由申请人提供）：与常规抗原不同，B细胞超抗原（B细胞SAg）与免疫球蛋白（IG）分子的互补决定区外的Fab B区结合。这些非常规抗原可与大量宿主外周B细胞和血清免疫球蛋白反应，这是由于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，由厌氧菌株大消化链霉菌分泌的蛋白L与大多数人Vk 1+、Vk 3+和Vk 4 + Ig以及同源鼠Vk+ Ig的Fab反应。B细胞SAg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。本申请中提出的研究的总体目标是阐明肺中B细胞SAg诱导的免疫复合物介导的炎症的细胞和分子发病机制。具体目标是确定由B细胞SAg（蛋白L）诱导的肺部炎症是否1）显示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 Ig的相互作用和3）由参与常规抗原/抗体复合物介导的组织损伤的细胞/促炎介质协调。这些目标将通过使用基因操作的小鼠品系来检查，以分离感兴趣的因子。由于迄今为止所描述的大多数B细胞SAg来自普遍存在的微生物，因此来自这些研究的信息将可能提供对感染因子促成免疫复合物介导的风湿性和自身免疫性疾病的发病机制的深入了解。

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.