Regulation of Toll-like Receptor signaling by RP105

描述（由申请人提供）：先天免疫的研究经历了一次复兴，受到先天免疫系统识别病原体所涉及的关键模式识别受体和信号通路的分子鉴定的推动。先天免疫反应受到严格的调节。反应延迟或活力不足可能导致无法控制感染。另一方面，对感染病原体的反应过于强烈本身也是有害的--这在先天免疫反应的过度激活中可以看到，这标志着微生物败血症和感染性休克。先天免疫的失调被认为是由许多微生物病原体引起的疾病的发病机理的中心，所述微生物病原体是目前关注的A类和B类生物威胁剂。相反，良好调节的先天免疫应答被认为是对这些病原体的成功免疫应答以及对这些和其他感染因子的成功疫苗接种的关键。 Toll样受体（TLR）是对多种病原体的先天性免疫识别至关重要的信号传导受体。正如预期的那样，通过TLR的信号传导在各种水平上受到严格调控。我们最近发现了一种新的TLR调节机制："B细胞特异性" TLR同源物RP 105。值得注意的是：（a）RP 105不是B细胞特异性的; RP 105表达反映了抗原呈递细胞中TLR 4的表达（B）RP 105在细胞系中充当TLR 4信号传导的特异性抑制剂;（c）来自RP 105-/-小鼠的树突细胞和巨噬细胞响应于TLR 4特异性配体产生增加量的促炎和免疫调节细胞因子，与野生型对照相比;和（d）TLR4驱动的细胞因子产生在RP 105-/-小鼠体内类似地升高。因此，这些研究的核心假设是RP105是TLR4信号传导和TLR4驱动的免疫应答的生理调节剂。这项工作的长期目标是确定对生物威胁因子和其他病原体的成功免疫反应的产生和调节的分子机制。本提案中的研究旨在体外和体内机制定义RP 105在调节TLR4信号传导和TLR4驱动的免疫应答中的作用。

DESCRIPTION (provided by applicant): The study of innate immunity has undergone a renaissance, fueled by molecular identification of critical pattern recognition receptors and signaling pathways involved in pathogen recognition by the innate immune system. Innate immune responses are tightly regulated. Responses that are delayed or of insufficient vigor can lead to a failure to control infection. On the other hand, too vigorous a response to an infecting pathogen can itself be harmful - something seen in the hyperactivation of innate immune responses that marks microbial sepsis and septic shock. Dysregulation of innate immunity is thought to be central to the pathogenesis of the diseases caused by many microbial pathogens that are of current concern as Category A and B biological threat agents. Conversely, well regulated innate immune responses are thought to be key to successful immune responses to these pathogens, as well as to successful vaccination against these and other infectious agents. Toll-like receptors (TLR) are signaling receptors that are central to innate immune recognition of a variety of pathogens. As might be expected, signaling through TLRs is tightly regulated at a variety of levels. We have recently discovered a novel mechanism of TLR regulation: the "B cell-specific" TLR homologue, RP105. Notably: (a) RP105 is not B cell-specific; RP105 expression mirrors that of TLR4 expression in antigen presenting cells (monocytes, macrophages, dendritic cells); (b) RP 105 acts as a specific inhibitor of TLR4 signaling in cell lines; (c) dendritic cells and macrophages from RP105-/- mice produce increased amounts of proinflammatory and immunoregulatory cytokines in response to TLR4-specific ligands, compared with wild-type controls; and (d) TLR4-driven cytokine production is similarly elevated in vivo in RP105-/- mice. The central hypothesis underlying these studies is thus that RP105 is a physiological regulator of TLR4 signaling and TLR4-driven immune responses. The long-term goal of this work is definition of the molecular mechanisms that underlie the generation and regulation of successful immune responses to biological threat agents and other pathogens. The studies in this proposal aim at mechanistic definition, both in vitro and in vivo, of the role of RP105 in modulating TLR4 signaling and TLR4-driven immune responses.