低密度脂蛋白受体相关蛋白4（Lrp4）是肌细胞膜上的一种跨膜蛋白质，作为聚集蛋白的受体，在乙酰胆碱受体（AChR）聚集和维持在突触后膜上形成神经肌肉接头中起促进作用。大约3%-50%的AChR抗体（AChRAb）阴性的重症肌无力（MG）患者存在抗Lrp4抗体，这些抗体能否介导MG的发病还不清楚。本研究筛选AChRAb阴性的MG患者测定其Lrp4抗体，将Lrp4抗体阳性的MG血清加入培养细胞以及大鼠肌肉冰冻切片上，观察其与Lrp4的结合活性；在培养肌细胞中观察Lrp4抗体对聚集蛋白诱导的AChR聚集的影响；注射大鼠诱导MG模型，以鉴定Lrp4抗体的致病性。将Lrp4及其Lrp4单克隆抗体，注射动物诱导MG模型，以测定其致病作用。通过对人和动物、单克隆抗体和多克隆抗体、体内和体外的系统性实验研究，探讨Lrp4及其抗体的致病作用及其机制，对临床诊断和治疗AChRAb阴性的患者，具有重要指导作用。

Low density lipoprotein receptor-related protein 4 (Lrp4) is a transmemberane protein concentrated in the postsynaptic membranes of neuromuscular junction (NMJ). It acts as the receptor of agrin in inducing the formation and maintenance of acetylcholine receptor (AChR) clusters. It has been found that anti- Lrp4 antibody exists in 3%-50% of the myasthenia gravis (MG) patients with anti-AChR antibody (AChRAb) negative. So far it is still not clear that anti-Lrp4 antibody can mediate the pathogenesis of MG. In this study, the anti-Lrp4 antibody positive sera, determined from the MG patients with AChRAb negative, will be tested for the binding activity to antigen Lrp4 in the cultured cells transfected with Lrp4 gene and expressed in the cell membranes, as well as in the cryosection of rat skeletal muscles, and for the effects of inhibition on the AChR clusters induced by agrin. Furthermore, the cell-expressed extracellular domains of Lrp4 will be immunized in mice to induce active experimental autoimmune MG (EAMG) model, and the sera (or IgG) from MG patients with anti-Lrp4 antibody positive, and the monoclonal antibody (mAb) against Lrp4, isolated from EAMG mice, will be injected in rats to induce passive EAMG model for the determination of pathogenicity. This research will hold the promise for the clinical diagnosis and treatment of MG, especially the MG patients with AChRAb negative.