Modulation of Inflammatory Responses by Helminth Glycans

项目摘要 寄生虫（蠕虫）感染可抑制多种人类炎症性疾病中的炎症。 紊乱据认为，蠕虫或其产物诱导调节性T（Treg）细胞，并且替代性地， 激活的巨噬细胞，抑制炎症T细胞的效应功能。但 蠕虫的免疫调节机制仍不完全清楚。调控 炎症反应主要通过先天免疫系统通过抗原呈递介导 细胞（APC），包括树突状细胞（DC）和巨噬细胞（M）。DC和M <$具有独特的可塑性 在通过经由表面受体的特异性信号传导采用各种功能表型中，例如Toll- 类受体（TLR）和聚糖结合蛋白，包括C型凝集素受体（CLR）。分子 在DC中，EGFR和TLR介导的信号的串扰是形成平衡的主要决定因素 免疫力和耐受力之间的区别我们的中心假设是，蠕虫的特定聚糖及其 空间呈递诱导APC中的CLR介导的信号通路，这有助于 产生抗炎和调节性适应性免疫应答， 对抗炎症为了验证这一假设，我们提出了三个具体目标。(Aim 1a）我们将确定 T. suis和S. mansoni通过聚糖结合DC和M？上的特异性CLRs 微阵列分析;（1b）我们将定义CLR与聚糖结合的亲合力之间的关系 以及APC通过这些受体内化聚糖的能力。(Aim 2a）我们将定义 T. suis和S. mansoni糖蛋白及其对 TLR诱导的信号通路;（2b）我们将定义TLR诱导的信号通路的结构组成和空间分布 蠕虫聚糖的呈递与它们产生抗炎型APC的能力有关。 (Aim 3a）我们将定义用选定的蠕虫聚糖脉冲的DC如何抑制 （3b）我们将探索所选聚糖与炎症T细胞的能力之间的关系。 在体外诱导APC抗炎特性，以及它们在体内诱导宿主保护的能力， 使用实验性自身免疫性脑脊髓炎（EAE）的鼠模型。

Project Summary Infections with parasitic worms (helminths) suppress inflammation in a variety of human inflammatory disorders. It is thought that worms or their products induce regulatory T (Treg) cells and alternatively activated macrophages that dampen the effector functions of inflammatory T cells. However, the helminth immunoregulatory mechanisms are still incompletely understood. The regulation of inflammatory responses is mainly mediated via the innate immune system through antigen presenting cells (APC), including dendritic cells (DC) and macrophages (M¿). DC and M¿ have unique plasticity in adopting various functional phenotypes through specific signaling via surface receptors, such as Toll- like receptors (TLRs) and glycan-binding proteins including C-type lectin receptors (CLRs). Molecular cross-talk of CLR- and TLR-mediated signals in DC is the main determinant that shapes the balance between immunity and tolerance. Our central hypothesis is that specific glycans of helminths and their spatial presentation induce CLR-mediated signaling pathways in APC, which contribute to the generation of anti-inflammatory and regulatory adaptive immune responses that confer protection against inflammation. To test this hypothesis we propose 3 specific aims. (Aim 1a) We will identify the glycan ligands of T. suis and S. mansoni that bind to specific CLRs on DC and M¿ by glycan microarray analysis; (1b) We will define the relationship between the avidity of glycan-binding by CLRs and the capacity of the APC to internalize the glycans via these receptors. (Aim 2a) We will define the signaling pathways induced by glycans of T. suis and S. mansoni glycoproteins, and their influence on TLR-induced signaling pathways; (2b) We will define how the structural composition and spatial presentation of the helminth glycans relate to their capacity to generate anti-inflammatory-type APC. (Aim 3a) We will define how DC pulsed with selected helminth glycans suppress the generation of inflammatory T cells; (3b) We will explore the relationship between the capacity of selected glycans to induce anti-inflammatory properties in APC in vitro, and their capacity to induce host protection in vivo, using the murine model for experimental autoimmune encephalomyelitis (EAE).