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. 2025 Jan;12(1):e200339.
doi: 10.1212/NXI.0000000000200339. Epub 2024 Nov 21.

The Role of Complement Activation in IgM M-Protein-Associated Neuropathies

Johannes P M van de Mortel  1 , Kevin Budding  1 , Kim Dijkxhoorn  1 , Monique C Minnema  1 , Alexander F J E Vrancken  1 , Nicolette C Notermans  1 , W Ludo van der Pol  1 ; IMAGiNe Consortium  1
Collaborators, Affiliations

The Role of Complement Activation in IgM M-Protein-Associated Neuropathies

Johannes P M van de Mortel et al. Neurol Neuroimmunol Neuroinflamm. 2025 Jan.

Abstract

Background and objectives: Polyneuropathy associated with an immunoglobulin M (IgM) monoclonal gammopathy is characterized by slowly progressive, predominantly distal sensorimotor deficits, sensory ataxia, and electrophysiologic features of demyelination. IgM antibodies against myelin-associated glycoprotein (MAG) are present in serum from most patients. Nerve damage most likely results from the concerted action of binding of anti-MAG antibodies to nerves, followed by complement activation. The interaction of anti-MAG antibodies with complement activation and their relation to clinical characteristics have not been studied in detail. We studied the correlation among anti-MAG antibody titers, complement activation, and IgM-associated polyneuropathy disease severity.

Methods: We used serum samples from 101 patients with IgM-associated polyneuropathy to assess IgM anti-MAG titers by ELISA and antibody-mediated complement deposition using both an ELISA-based system and a cell-based system of primate peripheral nerve slides. We studied correlations of complement activation with anti-MAG ELISA titers and clinical characteristics.

Results: IgM anti-MAG titers varied from negative to strongly positive. Complement deposition in the ELISA-based system correlated significantly with anti-MAG antibody titer (Spearman rho 0.80; p < 0.0001) despite large variability between serum samples with comparable anti-MAG titers. This variability was even larger in the cell-based assay, which also showed complement deposition in IgM anti-MAG negative patients, indicating the presence of autoantibodies directed against epitopes other than MAG in a subset of patients with IgM-associated polyneuropathy. Clinical characteristics did not correlate with anti-MAG titers or complement activation.

Discussion: Anti-MAG antibody titers correlate with the level of complement activation in both ELISA and cell-based systems. However, clinical characteristics of IgM-associated polyneuropathy do not or only weakly correlate with titers or the level of complement deposition. The lack of clear correlations between complement activation and clinical characteristics does, at this stage, not support the use of complement inhibitors in the treatment of IgM-associated polyneuropathy.

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Conflict of interest statement

J. van de Mortel reports no disclosures relevant to the manuscript; K. Budding and K. Dijkxhoorn are employees of the UMC Utrecht on a research collaboration agreement with argenx BVBA. M. Minnema, A. Vrancken, and N. Notermans report no disclosures relevant to the manuscript; W. van der Pol serves on the scientific advisory board for SMA Europe, provides ad hoc consultancy for argenx, Biogen, Roche, and Novartis, is the local PI of the ARDA and ARDA + trials for MMN, and receives research support from the Prinses Beatrix Spierfonds, Vriendenloterij, and Stichting Spieren voor Spieren. Go to Neurology.org/NN for full disclosures.

Figures

Figure 1
Figure 1. Cell-Based Assay to Study IgM Anti-MAG-Mediated Complement Activation
Figure 2
Figure 2. ELISA-Based Essay to Study IgM Anti-MAG-Mediated Complement Activation
See this image and copyright information in PMC

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