Induction of Anti-agrin Antibodies Causes Myasthenia Gravis in Mice. (1st March 2018)

• Record Type: Journal Article
• Authors: Yan, Min; Liu, Ziyang; Fei, Erkang; Chen, Wenbing; Lai, Xinsheng; Luo, Bin; Chen, Peng; Jing, Hongyang; Pan, Jin-xiu; Rivner, Michael H.; Xiong, Wen-Cheng; Mei, Lin
• Is Part Of: Neuroscience. Volume 373(2018)
• Page Start: 113
• Page End: 121
• Publication Date: 2018-03-01
• Subjects: AChR acetylcholine receptor -- BTX bungarotoxin -- CFA complete Freund's adjuvant -- DMEM Dulbecco's Modified Eagle Medium -- EAMG experimental autoimmune MG -- ELISA enzyme-linked immunosorbent assay -- FBS fetal bovine serum -- IFA incomplete Freund's adjuvant -- LRP4 low-density lipoprotein receptor-related protein 4 -- M-agrin muscle agrin -- MG myasthenia gravis -- MuSK muscle-specific kinase -- N-agrin neural agrin -- NF neurofilament -- NMJ neuromuscular junction -- PBS phosphate-buffered saline -- SDS-PAGE sodium dodecyl sulfate–polyacrylamide gel electrophoresis -- SYN synapsin -- TMB tetramethyl benzidine; myasthenia gravis -- agrin -- antibodies -- neuromuscular junction; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2018.01.015
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: Immunization with recombinant agrin reduces muscle strength. The morphology and function of the neuromuscular junction are compromised in immunized mice. Anti-agrin serum blocks agrin-induced AChR clustering. Abstract: Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction (NMJ). Most cases of MG are caused by autoantibodies against the acetylcholine receptor (AChR), muscle-specific kinase (MuSK) and low-density lipoprotein receptor-related protein 4 (LRP4). Recent studies have identified anti-agrin antibodies in MG patients lacking these three antibodies (i.e., triple negative MG). Agrin is a basal lamina protein that has two isoforms. Neural agrin (N-agrin) binds to LRP4 to activate MuSK to induce AChR clusters and is thus critical for NMJ formation. We demonstrate that mice immunized with N-agrin showed MG-associated symptoms including muscle weakness, fragmented and distorted NMJs. These effects were not observed in mice injected with muscle agrin (M-agrin), an isoform that is inactive in inducing AChR clusters. Treatment with anti-N-agrin, but not anti-M-agrin, antibodies reduced agrin-induced AChR clusters in muscle cells. Together, these observations suggest that agrin antibodies may be play a role in MG pathogenesis.