Clinical pictures and neuromuscular junction pathomechanism in novel LDL- recepotr related protein 4 antibody-positive myasthenia gravis

重症肌无力（Myasthenia gravis，MG）是由抗乙酰胆碱受体（acetylcholine receptor，AChR）和肌肉特异性受体酪氨酸激酶（muscle-specific receptor tyrosine kinase，MuSK）的致病性自身抗体（pathogenic autoantibodies，Abs）介导的神经肌肉传递障碍引起的。日本MG患者常规AChR结合抗体和MuSK抗体的血清阳性率分别为80-85%和5-10%。2011年，在日本MG患者中发现了针对低密度脂蛋白受体相关蛋白4（Lrp 4）的自身抗体。我们开发了一种称为Gaussia荧光素酶免疫沉淀的简单技术，用于检测Lrp 4抗体。 结果，从300例缺乏AChR Ab的泛发性MG患者中，有9例Lrp 4抗体阳性。这些抗体抑制Lrp 4与其配体的结合，并且主要是IgG 1亚类。Lrp 4 ab阳性MG的病理机制有待进一步研究，包括神经肌肉接头活检。这些结果表明Lrp 4是MG患者的第三种致病性自身抗原。

Myasthenia gravis (MG) is caused by the failure of neuromuscular transmission mediated by pathogenic autoantibodies (Abs) against acetylcholine receptor (AChR) and muscle-specific receptor tyrosine kinase (MuSK). The seropositivity rates for routine AChR binding Ab and MuSK Ab in MG are 80-85% and 5-10% for MG patients in Japan, respectively. In 2011, autoantibodies against low-density lipoprotein receptor-related protein 4 (Lrp4) were identified in Japanese MG patients. We developed a simple technique termed Gaussia luciferase immunoprecipitation for detecting antibodies to Lrp4. As a result, nine generalized MG patients from 300 lacking AChR Ab are positive for Lrp4 antibodies. These antibodies inhibit binding of Lrp4 to its ligand and are predominantly of the IgG1 subclass. Further studies including neuromuscular junction biopsy are needed to clarify the pathomechanism of Lrp4 ab positive MG. These results indicate that Lrp4 is a third pathogenic autoantigen in patients with MG.