B Cell Superantigen Immune Complex Tissue Inflammation

描述(由申请人提供)：B细胞超抗原(B细胞SAG)与传统抗原不同，它与免疫球蛋白(Ig)分子的Fab区域结合在其互补决定区域之外。这些非常规抗原可以与宿主的大量外周B细胞和血清免疫球蛋白反应，因为它们能够与整个可变区重(VH)或可变区轻(VL)基因家族的许多成员相互作用。例如，由厌氧菌株大型消化链球菌分泌的L蛋白，与大多数人VK1、VK3和VK4免疫球蛋白以及同源小鼠VK免疫球蛋白的纤维蛋白反应。B细胞与大量血清免疫球蛋白结合的能力突显了它们引起免疫复合体介导的组织损伤的可能性。本申请中提出的研究的总体目标是阐明B细胞SAG诱导的免疫复合体介导的肺部炎症的细胞和分子发病机制。其具体目标是确定B细胞SAG、L蛋白是否诱导肺炎症，1)证实免疫复合体组织损伤的组织病理学相关性，2)需要与选择性VK免疫球蛋白相互作用，3)由参与传统抗原/抗体复合体介导的组织损伤的细胞/促炎介质调控。这些目标将通过使用基因操纵的小鼠品系来检验，以分离感兴趣的因素。由于到目前为止所描述的大多数B细胞下垂来自无处不在的微生物，这些研究的信息可能有助于深入了解感染性病原体在免疫复合体介导的风湿性和自身免疫性疾病的发病机制中所起的作用。

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.