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

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 MG patient with anti-LRP4/agrin antibodies and transferred to mice. Mice were characterized for body weight, muscle strength, twitch and tetanic force, NMJ functions including CMAP (compound muscle action potential) and endplate potentials, and NMJ structure. Effects of the antibodies on agrin-elicited MuSK activation and AChR clustering were studied and the epitopes of these antibodies were identified.Results:Patient Ig-injected mice suffered MG symptoms, including weight lost 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.Conclusions:Anti-LRP4/agrin antibodies in the MG patient is pathogenic. It impairs the NMJ by interrupting agrin-dependent LRP4-MuSK interaction.