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

Area of Science:

• Neuroimmunology
• Stem Cell Biology
• Neuromuscular Disorders

Background:

• Multifocal motor neuropathy (MMN) is characterized by IgM autoantibodies targeting gangliosides, particularly GM1.
• The role of complement activation in MMN pathogenesis and its correlation with clinical manifestations remain incompletely understood.

Purpose of the Study:

• To investigate the relationship between IgM seropositivity, complement activation, and clinical parameters in MMN.
• To evaluate the efficacy of IV immunoglobulin (IVIg) and complement inhibitors in an induced pluripotent stem cell (iPSC)-derived motor neuron (MN) model of MMN.

Main Methods:

• Serum samples from 137 MMN patients were used to assess IgM binding and C3 fixation on iPSC MNs.
• Correlation analysis was performed between antibody binding, complement fixation, and clinical parameters (MRC sum scores).
• Efficacy of IVIg and complement inhibitors in preventing C3 fixation was tested in the iPSC MN model.

Main Results:

• Increased IgM binding and complement activation (C3 fixation) were observed in MMN patient samples compared to controls.
• Higher antibody binding correlated with increased C3 fixation, muscle weakness, and higher IVIg doses.
• Complement activation, not IgM binding alone, correlated with sensory abnormalities, brachial plexus MRI findings, and axonal damage.

Conclusions:

• IgM antibodies in MMN induce complement activation on iPSC MNs, significantly correlating with clinical outcomes.
• Complement inhibitors demonstrated high efficacy in preventing complement activation in the iPSC MN model.
• The iPSC MN model serves as a viable platform for preclinical screening of novel MMN therapeutics.