Modulation of Inflammatory Responses by Helminth Glycans

描述(申请人提供)：寄生蠕虫(蠕虫)感染抑制各种人类炎症性疾病的炎症。据认为，蠕虫或其产物诱导调节性T(Treg)细胞，或者激活巨噬细胞，从而抑制炎性T细胞的效应功能。然而，寄生虫的免疫调节机制仍不完全清楚。炎症反应的调节主要通过先天免疫系统通过抗原提呈细胞(APC)进行，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，可通过表面受体(如Toll样受体(TLRs)和包括C型凝集素受体(CLRs)在内的糖链结合蛋白)通过特定的信号转导各种功能表型。DC中CLR和TLR介导的信号的分子串扰是形成免疫和耐受之间平衡的主要决定因素。我们的中心假设是蠕虫的特定糖链及其空间呈现诱导APC中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反应，从而提供抗炎保护。为了验证这一假设，我们提出了三个具体目标。(目的1a)我们将通过糖链微阵列分析鉴定猪毛滴虫和曼氏血吸虫的糖链配体，它们与DC和M上的特定CLR结合；(1b)我们将确定CLRs结合糖链的亲和力与APC通过这些受体内化糖链的能力之间的关系。(目标2a)我们将确定猪毛虫和曼氏血吸虫糖蛋白多糖诱导的信号通路，以及它们对TLR诱导的信号通路的影响；(2b)我们将定义蠕虫多糖的结构组成和空间分布如何与它们产生抗炎型APC的能力有关。(目的3a)我们将利用实验性自身免疫性脑脊髓炎(EAE)小鼠模型，确定经选择的蠕虫多糖冲击的DC如何抑制炎症T细胞的产生；(3b)我们将利用实验性自身免疫性脑脊髓炎(EAE)的小鼠模型，探索选定的多糖在体外诱导APC抗炎特性的能力与它们在体内诱导宿主保护的能力之间的关系。

DESCRIPTION (provided by applicant): 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).