C5a及受体CD88在小鼠视神经脊髓炎疾病模型发病过程中的作用及其机制的研究

Neuromyelitis optica spectrum disorders (NMOSD) are severe autoimmune demyelinating diseases involving central nervous system. The anti-aquaporin 4 (AQP4) antibody induced complement-dependent cytotoxity (CDC) and antibody-dependent complement-mediated cytotoxity (ADCC) play important role in the pathogenesis. As the cardinal elements in CDC and ADCC, many complement proteins have been studied well in NMOSD, which lead to discover a series of promising targets for the therapy. C5a is produced in CDC and plays a crucial part in ADCC, which means that C5a bridges between CDC and ADCC. However, the role of C5a and its receptor CD88 in NMOSD remains largely unknown. In our preexperiment, we found that the CD88 blocker could inhibit neutrophil and macrophage/microglia infiltration, and reduce the loss of AQP4, astrocytes and myelin, which suggested the important role of C5a and its receptor CD88 in NMOSD. We will interfere the binding of C5a and CD88 to investigate the their role in the pathogenesis of NMOSD in animals, and to study the possible mechanism in vitro, and we attempt to provide a new target for the therapy.

视神经脊髓炎谱系疾病（NMOSD）是一类自身免疫异常导致的中枢神经系统脱髓鞘性疾病。其中抗水通道蛋白4抗体所引发的补体依赖的细胞毒性作用(CDC)和抗体依赖的细胞介导的细胞毒性作用(ADCC)在其致病机制中发挥重要作用。补体是CDC和ADCC的核心角色，各补体成份在CDC和ADCC的作用机制被研究的越来越清楚，并由此产生了一系列新的治疗靶点。C5a是一种在CDC中产生的蛋白产物，同时能够在ADCC中发挥重要作用。但是C5a及其主要受体CD88在NMOSD中的作用却研究甚少。我们前期的实验数据发现C5a-CD88的阻断剂能够抑制NMOSD小鼠模型的病灶形成。因此，C5a及其受体CD88在NMOSD中可能扮演重要作用。本项目首先将通过干预C5a与CD88的结合，在动物水平来研究C5a在NMOSD发病机制中的作用，然后在细胞水平来探究这种作用可能的机制，并试图为该病的治疗研究提供一个新的靶点。

视神经脊髓炎谱系疾病是一类自身免疫系统异常导致中枢神经系统脱髓鞘性疾病。其中抗水通道蛋白4抗体所引发的补体依赖的细胞毒性作用和抗体依赖的细胞介导的细胞毒性作用在该病的致病机制中发挥着重要作用。补体是两种细胞毒性作用中的核心角色，各补体成份在两种细胞毒性作用的致病机制被研究的越来越清楚，并由此产生了一系列新的治疗靶点。C5a是一种在补体依赖的细胞毒性作用中产生的蛋白产物，同时能够在抗体依赖的细胞介导的细胞毒性作用中发挥重要，也就是说C5a在两种细胞毒性中起着重要的桥接作用。.本研究通过基因删除、中和性抗体及小分子抑制剂干预C5a与CD88的结合，发现能够抑制小鼠视神经脊髓炎谱系病灶的形成，并且这种作用可能是通过抑制中性粒细胞的趋化作用、中性粒细胞和巨噬细胞的吞噬功能和产生活性氧能力来实现的。这为将来通过干扰C5a-CD88治疗NMOSD提供了概念证据。