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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.
Glossary
- α-BTX=
- α-bungarotoxin;
- ACh=
- acetylcholine;
- AChR=
- acetylcholine receptor;
- AP=
- alkaline phosphatase;
- CMAP=
- compound muscle action potential;
- DNMG=
- double seronegative (anti-AChR and anti-MUSK negative) myasthenia gravis;
- EAMG=
- experimental autoimmune myasthenia gravis;
- ECD=
- extracellular domain;
- EPP=
- end plate potential;
- HA=
- hemagglutinin;
- Ig=
- immunoglobulin;
- IRB=
- institutional review board;
- LG3=
- laminin G-like 3 domain;
- LRP4=
- low-density lipoprotein receptor-related protein 4;
- MEPP=
- miniature end plate potential;
- MG=
- myasthenia gravis;
- MuSK=
- muscle-specific tyrosine kinase;
- NMJ=
- neuromuscular junction;
- PBS=
- phosphate-buffered saline;
- PFA=
- paraformaldehyde;
- PPR=
- paired-pulse ratio;
- RT=
- room temperature;
- SAS=
- saturated ammonium sulfate
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
↵* These authors contributed equally to this work as co–first authors.
Editorial, page 463
- Received December 16, 2020.
- Accepted in final form June 22, 2021.
- © 2021 American Academy of Neurology
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