The role of microglia in neuromyelitis optica

视神经肌萎缩症（NMO）是一种严重的，复发性IgG介导的自身免疫性疾病，靶向 中枢神经系统（CNS），诱导视神经的炎症和优先脱髓鞘， 脊髓大多数患者都有严重的损伤。星形胶质细胞特异性IgG自身抗体 水通道蛋白-4（AQP 4）是引起该病的主要病理生理机制。然而，在这方面， 关于IgG结合到免疫球蛋白后驱动NMO损伤进展的机制知之甚少。 星形胶质细胞膜进入中枢神经系统。我们提出的项目将调查潜在的 小胶质细胞（CNS的常驻免疫细胞）对演变中的NMO损伤的贡献。我们有 开发了一个信息丰富的NMO小鼠模型。鞘内输注NMO-IgG。我们的初步 结果显示，显著的运动功能障碍、星形胶质细胞活化和早期小胶质细胞的独特模式， 对星形胶质细胞的研究防止小胶质细胞活性抑制运动发育 功能障碍总之，这些数据清楚地表明星形胶质细胞-小胶质细胞通讯是早期事件 NMO-IgG进入CNS后。 目标1，将研究星形胶质细胞-小胶质细胞串扰的机制;目标2，将评估 小胶质细胞对NMO发病机制的贡献，目标3将利用新的遗传工具来操纵 小胶质细胞活性作为NMO管理的潜在治疗方法。 我们提出的研究代表了第一次尝试调查小胶质细胞的具体贡献 NMO的发病机制。这些结果应该阐明星形胶质细胞-小胶质细胞串扰的重要性， NMO的基本机制。这项研究不仅将提高对神经免疫的理解， 但将潜在地确定小胶质细胞是NMO治疗相关靶点。

Neuromyelitis optica (NMO) is a severe, relapsing IgG-mediated autoimmune disease targeting the central nervous system (CNS), inducing inflammation and preferential demyelination of optic nerve and spinal cord. Most patients experience severe impairments. IgG autoantibodies specific for the astrocytic aquaporin-4 (AQP4) water channel are the primary cause of the disease pathophysiology. However, little is known about the mechanisms driving NMO lesion progression following the binding of IgG to the astrocyte membrane on entering the CNS. Our proposed project will investigate the potential contribution of microglia, the resident immune cell of the CNS, to the evolving NMO lesion. We have developed an informative mouse model of NMO. NMO-IgG is infused intrathecally. Our preliminary results show significant motor dysfunction, astrocyte activation, and a unique pattern of early microglial convergence on astrocytes. Prevention of microglial activity suppressed development of motor dysfunction. In sum, these data clearly indicate astrocyte-microglia communication as an early event after NMO-IgG enters the CNS. Aim 1, will investigate the mechanisms underlying astrocyte-microglia crosstalk; Aim 2, will assess the contribution of microglia to NMO pathogenesis, and Aim 3 will utilize novel genetic tools to manipulate microglial activity as a potential therapeutic approach to NMO management. The research we propose represents the first attempt to investigate the specific contribution of microglia to NMO pathogenesis. The results should clarify the importance of astrocyte-microglia crosstalk and its underlying mechanisms in NMO. The study will not only improve understanding of neuroimmune interaction in NMO but will potentially establish that microglia are a pertinent target for NMO therapy.