Project 5

总结： 炎症性疾病可由针对免疫缺陷病毒的过度活跃的免疫反应引发。 宿主/自身组织。事实上，神经炎症相关的疾病，如多发性硬化症， 并且中风可以由针对以下疾病的过度活跃的免疫应答触发和/或加重： 神经组织现在很明显，不仅是认知障碍， 例如精神分裂症和抑郁症，都与神经炎症有关。因此， 寄生蠕虫（蠕虫）感染抑制了多种免疫系统中的炎症， 紊乱正在进行的使用虫卵治疗多发性硬化症患者的临床试验显示， 有希望的结果。因此，了解蠕虫的免疫调节机制是可能的， 对对抗炎症性疾病的新策略产生巨大影响。在这种情况下， 炎症反应的调节主要通过先天免疫系统介导， 抗原呈递细胞（APC），如巨噬细胞（M？）和小胶质细胞（MG）。功能 MG和M <$的表型在对这些细胞通过一种免疫应答系统接受的外部刺激的反应中变化。 多种表面受体。据认为，蠕虫或其产品诱导交替 激活的巨噬细胞（AAM）可抑制炎症并促进组织修复。我们和 其他人最近记录了交替激活的M <$（AA-M <$）和MG（AA-MG） 具有抑制宿主炎症反应和促进伤口愈合的能力， 在某些慢性神经炎症相关疾病中的组织修复。的小鼠模型中 神经囊虫病（NCC），我们证明，AAM是必不可少的， 神经病理学和疾病严重程度。此外，与人NCC一致，高度抗原性 皮层半乳糖/半乳糖胺和葡糖胺的聚糖分子 寄生虫在CNS环境中被宿主细胞释放和吸收。作为凝集素受体 (LRs)是识别聚糖抗原的主要受体，一项关于它们在AA-M？ 和AA-MG在NCC期间CNS中的功能对于理解NCC和 神经病理状况可以在临床上得到控制。我们假设聚糖抗原 寄生虫释放的LRs会导致特异性宿主LRs的差异表达， 在AAM向CNS的发展和运输中起关键作用， 分子以及中枢神经系统免疫病理学的调节。为了验证这一假设，我们提出3 具体目标。(Aim 1）确定在细胞生长过程中LR的表达、动力学和细胞分布。 NCC通过关注Galectin-7、Galectin-9和SIGNR 1。(Aim（2）明确目标作用 AA-M和AA-MG的发展、迁移和功能中的LRs。(Aim 3）阐明 靶向LRs在调节AA-M？和AA-MG介导的CNS控制中的意义 小鼠NCC免疫发病机制。我们在计划研究中的发现预计将 提供了新的方向和方法来操纵AA-M？和AA-MG功能，以抑制 在多种炎性疾病中的炎症，包括但不限于CNS 炎症性疾病。

SUMMARY: Inflammatory disorders can be triggered by overactive immune responses directed against host/self tissues. Indeed, neuroinflammation-associated disorders such as multiple sclerosis and stroke can be triggered and/or exacerbated by overactive immune responses against nervous tissues. It is now evident that not only cognitive disorders, but classic mental diseases such as schizophrenia and depression, are related to neuroinflammation. It is thus remarkable that infection with parasitic helminths (worms) suppresses inflammation in a variety of immune disorders. Ongoing clinical trials using worm egg in patients with multiple sclerosis are showing promising results. Hence, an understanding of helminth immunoregulatory mechanisms is likely to have enormous impact on novel strategies against inflammatory disorders. In this light, the regulation of inflammatory responses is mainly mediated via the innate immune system through antigen-presenting cells (APC) such as macrophages (M¿) and microglia (MG). The functional phenotypes of MG and M¿ vary in response to external stimuli these cells receive through a wide variety of surface receptors. It is thought that worms or their products induce alternatively activated macrophages (AAM) that dampen inflammation and promotes tissue repair. We and others have recently documented that alternatively activated M¿ (AA-M¿) and MG (AA-MG) have the capacity to dampen host inflammatory responses and promote wound healing and tissue repair in certain chronic neuroinflammation-related diseases. In a mouse model of neurocysticercosis (NCC) we demonstrated that AAMs are essential in containing neuropathology and disease severity. Additionally, consistent with human NCC, highly antigenic tegument galactose/ galactosamine and glucosamine containing glycan molecules of the parasite are released and taken up by host cells in the CNS environment. As lectin receptors (LRs) are the major receptors for recognition of glycan antigens, a study of their role in AA-M¿ and AA-MG functions in the CNS during NCC are important for understanding how NCC and neuropathological conditions can be clinically controlled. We hypothesize that glycan antigens released by parasites will lead to differential expression of specific host LRs which will play a critical role in the development and trafficking of AAM into the CNS, expression of effector molecules, and regulation of CNS immunopathology. To test this hypothesis we propose 3 specific aims. (Aim 1) Determine the expression, kinetics, and cellular distribution of LRs during NCC by focusing on Galectin-7, Galectin-9, and SIGNR1. (Aim 2) Identify the role of targeted LRs in AA-M¿ and AA-MG development, migration and functions. (Aim 3) Elucidate the significance of targeted LRs in regulating AA-M¿ and AA-MG mediated control of CNS immunopathogenesis in murine NCC. Our findings in the planned studies are expected to provide new directions and approaches to manipulate AA-M¿ and AA-MG function to suppress inflammation in a variety of inflammatory disorders, including but not limited to CNS inflammatory diseases.