Turncoat antibodies unmasked in a model of autoimmune demyelination: From biology to therapy

Autoantibodies contribute to many autoimmune diseases, yet there is no approved therapy to neutralize them selectively. A popular mouse model, experimental autoimmune encephalomyelitis (EAE), could serve to develop such a therapy, provided we can better understand the nature and importance of the autoantibodies involved. Here, we report the finding of autoantibody-secreting extrafollicular plasmablasts in EAE induced with specific myelin oligodendrocyte glycoprotein (MOG) antigens. Single-cell RNA sequencing reveals that these cells produce nonaffinity-matured IgG antibodies. These include pathogenic antibodies competing for shared binding space on MOG's extracellular domain. Interestingly, the synthetic anti-MOG antibody 8-18C5 can prevent the binding of pathogenic antibodies from either EAE mice or people with MOG antibody disease. Moreover, an 8-18C5 variant carrying the NNAS mutation, which inactivates its effector functions, can reduce EAE severity and promote functional recovery. In brief, this study provides not only a comprehensive characterization of the humoral response in EAE models but also a proof of concept for a therapy to antagonize pathogenic anti-MOG antibodies.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-12-17
DOI
https://doi.org/10.1073/pnas.2424988122
Primary Topic
Multiple Sclerosis Research Studies
Type
article
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article

Turncoat antibodies unmasked in a model of autoimmune demyelination: From biology to therapy

Françoise Morin, Jacques Corbeil, Eoin P. Flanagan, Luc Vallières et al.
Proceedings of the National Academy of Sciences
Multiple Sclerosis Research Studies
article

Turncoat antibodies unmasked in a model of autoimmune demyelination: From biology to therapy

Françoise Morin, Jacques Corbeil, Eoin P. Flanagan, Luc Vallières, Louis‐Charles Béland, Julie Jaworski, Juan Manuel Domínguez, Steven M. Kerfoot, Romain Marignier, Qun Zhou, Yu Zhang, Anna Park, Catherine Larochelle, Reza Taghipour-Mirakmahaleh, Louis Bourhoven
article en

Abstract

Autoantibodies contribute to many autoimmune diseases, yet there is no approved therapy to neutralize them selectively. A popular mouse model, experimental autoimmune encephalomyelitis (EAE), could serve to develop such a therapy, provided we can better understand the nature and importance of the autoantibodies involved. Here, we report the finding of autoantibody-secreting extrafollicular plasmablasts in EAE induced with specific myelin oligodendrocyte glycoprotein (MOG) antigens. Single-cell RNA sequencing reveals that these cells produce nonaffinity-matured IgG antibodies. These include pathogenic antibodies competing for shared binding space on MOG's extracellular domain. Interestingly, the synthetic anti-MOG antibody 8-18C5 can prevent the binding of pathogenic antibodies from either EAE mice or people with MOG antibody disease. Moreover, an 8-18C5 variant carrying the NNAS mutation, which inactivates its effector functions, can reduce EAE severity and promote functional recovery. In brief, this study provides not only a comprehensive characterization of the humoral response in EAE models but also a proof of concept for a therapy to antagonize pathogenic anti-MOG antibodies.

Proceedings of the National Academy of SciencesVol. 122(51)
Western University (CA), Mayo Clinic (US), WinnMed (US), Sanofi (France) (FR), Observatoire Français de la Sclérose en Plaques (FR), Hôpital Pierre Wertheimer (FR), Mayo Clinic in Arizona (US), Institute of Neuroimmunology of the Slovak Academy of Sciences (SK), Institute of Infection and Immunity (CA), Université Laval (CA)
Openalex Percentile: Top 44%
Multiple Sclerosis Research Studies
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