FcR Deficient Mice Susceptibility to Pathogens

描述(申请人提供)：C型凝集素家族的碳水化合物结合蛋白参与炎症反应期间的细胞交通、免疫细胞激活过程以及通过微生物决定因素与这些微生物的结合而识别病原体的机制。病原体选择了其中的许多途径来提供手段，通过这些途径，它们可以逃避免疫反应，并在免疫监视下持续存在。一个亚家族，DC-SIGN及其小鼠同源物SIGN R1，与高甘露糖低聚糖以及含有岩藻糖的多糖结合，如Lewis X三糖。这些结合的特异性是这些分子与HIV和其他病毒的包膜糖蛋白以及细菌、原生动物和蠕虫病原体的表面糖蛋白相互作用的能力的基础。人类免疫缺陷病毒、结核分枝杆菌和曼氏葡萄球菌已经选择了这一途径，通过隔离在树突状细胞内，并通过触发抑制炎性TH1类型反应的途径来逃避免疫反应，包括调节TLR信号和阻止树突状细胞成熟。我们最近描述了一种由SIGN R1和DC SIGN介导的新的结合作用，涉及在健康成年人血清中发现的一种糖型免疫球蛋白Ig G，它能导致抗炎反应，能够保护自己免受自身抗体的致病作用。本提案中描述的研究将集中于通过以下三个目标定义这种新型的抗炎反应：目标1将通过在配体和受体中产生明确的突变并进行详细的结合研究来剖析SIGN R1、DC-SIGN和12，6sialylFc之间结合作用的特异性；目标2将通过转录组和蛋白质组分析解决这种结合作用在边缘带巨噬细胞和人DC中诱导的信号通路；目标3将通过产生和分析已定义的转基因和敲除小鼠品系来解决DC-SIGN和SIGN R1参与12，6sialylFc在体内的生物学后果。公共卫生相关性：这些研究将剖析由12，6sialylFc启动的内源性抗炎途径，这将作为开发治疗自身免疫性疾病的新型抗炎疗法的指南，并作为一种压倒病原体免疫逃避的手段。

DESCRIPTION (provided by applicant): Carbohydrate binding proteins of the C-type lectin family are involved in the mechanisms by which cell traffic during an inflammatory response, in the processes of immune cell activation and in the recognition of pathogens through the binding of microbial determinants on these microorganisms. Pathogens have co-opted many of these pathways to provide means by which they can evade the immune response and persist despite immune surveillance. One sub-family, DC-SIGN and its murine homologue, SIGN R1, bind to high mannose oligosaccharides, as well as fucose containing glycans, such as the Lewisx trisaccharides. These binding specificities underlie the ability of these molecules to interact with the envelope glycoprotein of HIV and other virus, as well as the surface glycoproteins of bacterial, protozoal and helminthic pathogens. HIV, M. tuberculosis and S. mansoni have co-opted this pathway to evade immune responses by sequestering within DCs and by triggering pathways that suppresses inflammatory, TH1 type responses, including modulating TLR signaling and preventing DC maturation. We recently described a novel binding interaction mediated by SIGN R1 and DC SIGN, involving a glycoform of IgG found in the serum of healthy adults, 12,6sialylFc, that results in an anti-inflammatory response, capable of conferring protection from the pathogenic effects of autoantibodies. The studies described in this proposal will focus on defining this novel, anti-inflammatory response through the following three aims: Aim 1 will dissect the specificity of the binding interaction between SIGN R1, DC-SIGN and 12,6sialylFc by generating defined mutations in both the ligand and receptors and performing detailed binding studies; Aim 2 will address the signaling pathways induced by this binding interaction in marginal zone macrophages and human DCs through transcriptome and proteome analysis and Aim 3 will address the biological consequences in vivo of DC-SIGN and SIGN R1 engagement of 12,6sialylFc through the generation and analysis of defined transgenic and knockout strains of mice. PUBLIC HEALTH RELEVANCE: These studies will dissect an endogenous, anti-inflammatory pathway, initiated by 12,6sialylFc, that that will serve as a guide for the development of novel anti- inflammatory therapeutics for the treatment of autoimmune disorders and as a means of overriding immune evasion by pathogens.