IgM Anti-Ganglioside Binding and Complement Activation in an iPSC-Derived Motor Neuron Model for Multifocal Motor Neuropathy

Abstract

BACKGROUND AND OBJECTIVES: Multifocal motor neuropathy (MMN) is an asymmetric motor neuropathy driven by IgM autoantibodies targeting gangliosides, particularly GM1. In this study, we investigated the relationship between IgM seropositivity, complement activation, and clinical parameters using an induced pluripotent stem cell (iPSC)-derived motor neuron (MN) model of MMN. METHODS: We used serum samples from 137 patients with MMN to assess IgM binding and subsequent C3 fixation to iPSC MNs and their correlation with clinical parameters, including muscle strength expressed as MRC sum scores, obtained from patient records. In addition, we tested the efficacy of IV immunoglobulin (IVIg) and specific complement inhibitors to prevent C3 fixation to MNs. RESULTS: We observed increased IgM binding to iPSC MNs using serum samples from patients with MMN compared with those from healthy controls, which correlated with IgM anti-ganglioside antibody titers. Higher antibody binding correlated with levels of C3 fixation, more severe weakness, and the need for higher IVIg doses. Complement activation, but not IgM binding, also correlated with vibration sense abnormalities, brachial plexus MRI abnormalities, and the degree of axonal damage. At therapeutic concentrations, IVIg moderately inhibited complement activation (34%-54%) while specific complement inhibitors were highly effective (89.1%-98.7%) in the iPSC MN model. DISCUSSION: This study demonstrates that IgM antibodies in serum samples from patients with MMN induce complement activation on iPSC MNs, which correlates significantly with clinical outcomes. In addition, our findings indicate that complement inhibitors offer a potentially targeted novel therapeutic strategy for MMN and that our iPSC MN model is a viable preclinical screening platform.