Characterization of LRP4/Agrin Antibodies From a Patient With Myasthenia Gravis

Zheng Yu, Meiying Zhang, Hongyang Jing, Peng Chen, Rangjuan Cao, Jinxiu Pan, Bin Luo, Yue Yu, Brandy M. Quarles, Wencheng Xiong, Michael H. Rivner, Lin Mei

Research output: Contribution to journalComment/debatepeer-review

Abstract

BACKGROUND AND OBJECTIVE: To determine whether human anti-LRP4/agrin antibodies are pathogenic in mice and to investigate underpinning pathogenic mechanisms. METHODS: Immunoglobulin (Ig) was purified from a patient with myasthenia gravis (MG) with anti-LRP4/agrin antibodies and transferred to mice. Mice were characterized for body weight, muscle strength, twitch and tetanic force, neuromuscular junction (NMJ) functions including compound muscle action potential (CMAP) and endplate potentials, and NMJ structure. Effects of the antibodies on agrin-elicited muscle-specific tyrosine kinase (MuSK) activation and AChR clustering were studied and the epitopes of these antibodies were identified. RESULTS: Patient Ig-injected mice had MG symptoms, including weight loss and muscle weakness. Decreased CMAPs, reduced twitch and tetanus force, compromised neuromuscular transmission, and NMJ fragmentation and distortion were detected in patient Ig-injected mice. Patient Ig inhibited agrin-elicited MuSK activation and AChR clustering. The patient Ig recognized the β3 domain of LRP4 and the C-terminus of agrin and reduced agrin-enhanced LRP4-MuSK interaction. DISCUSSION: Anti-LRP4/agrin antibodies in the patient with MG is pathogenic. It impairs the NMJ by interrupting agrin-dependent LRP4-MuSK interaction.

Original languageEnglish (US)
Pages (from-to)e975-e987
JournalNeurology
Volume97
Issue number10
DOIs
StatePublished - Sep 7 2021

ASJC Scopus subject areas

  • Clinical Neurology

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