重症筋無力症の進歩：Lrp4抗体陽性MGの発見

Abstract

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. The autoimmune target in the remaining patients is unknown. In 2011, autoantibodies against low-density lipoprotein receptor-related protein 4 (Lrp4) were identified in Japanese MG patients and thereafter have been reported in Germany and the USA. 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. Thymoma was not observed in any of these patients. These antibodies inhibit binding of Lrp4 to its ligand and are predominantly of the IgG1 subclass. In other reports of Lrp4 ab, Lrp4 ab positive sera inhibited agrin-induced aggregation of AChRs in cultured myotubes, suggesting a pathogenic role regarding the dysfunction of the neuromuscular endplate. These results indicate that Lrp4 is a third autoantigen in patients with MG, and anti-Lrp4 autoantibodies may be pathogenic. Further studies including neuromuscular junction biopsy are needed to clarify the pathomechanism of Lrp4 ab positive MG.