Turncoat antibodies unmasked in a model of autoimmune demyelination: From biology to therapy
- Reza Taghipour-Mirakmahaleh
- Françoise Morin
- Yu Zhang
- Louis Bourhoven
- Louis-Charles Béland
- Qun Zhou
- Julie Jaworski
- Anna Park
- Juan Manuel Dominguez
- Jacques Corbeil
- Eoin P. Flanagan
- Romain Marignier
- Catherine Larochelle
- Steven M. Kerfoot
- Luc Vallières
2025-12-17
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.