FcR Deficient Mice Susceptibility to Pathogens

描述（由申请人提供）：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细胞运输的机制，参与免疫细胞激活过程，并通过与这些微生物上的微生物决定因子结合来识别病原体。病原体已经选择了许多这些途径来提供手段，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。其中一个亚家族DC-SIGN及其小鼠同源物SIGN R1与高甘露糖低聚糖结合，并与含有糖聚糖（如Lewisx三糖）结合。这些结合特异性是这些分子能够与HIV和其他病毒的包膜糖蛋白以及细菌、原虫和蠕虫病原体的表面糖蛋白相互作用的基础。HIV、M. tuberculosis和S. mansoni通过在DC内隔离和触发抑制炎症、TH1型反应的途径（包括调节TLR信号传导和阻止DC成熟）来利用这一途径逃避免疫应答。我们最近描述了一种由SIGN R1和DC SIGN介导的新型结合相互作用，涉及健康成人血清中发现的IgG糖型12,6sialylfc，可导致抗炎反应，能够保护免受自身抗体的致病作用。本提案中描述的研究将侧重于通过以下三个目标来定义这种新的抗炎反应：目的1将通过在配体和受体中产生定义的突变并进行详细的结合研究，剖析SIGN R1， DC-SIGN和12,6sialylfc之间结合相互作用的特异性；Aim 2将通过转录组和蛋白质组分析研究巨噬细胞与人类dc结合相互作用诱导的信号通路，Aim 3将通过生成和分析小鼠转基因和敲除菌株来研究DC-SIGN和SIGN R1与126sialylfc结合在体内的生物学后果。公共卫生相关性：这些研究将剖析由126sialylfc启动的内源性抗炎途径，这将作为开发用于治疗自身免疫性疾病的新型抗炎疗法的指南，并作为克服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.