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

• 成果类型: Article
• 署名作者: Taghipour-Mirakmahaleh, Reza; Morin, Francoise; Zhang, Yu; Bourhoven, Louis; Beland, Louis-Charles; Zhou, Qun; Jaworski, Julie; Park, Anna; Dominguez, Juan Manuel; Corbeil, Jacques; Flanagan, Eoin P.; Marignier, Romain; Larochelle, Catherine; Kerfoot, Steven M.; Vallieres, Luc
• 署名单位: Laval University; Sanofi-Aventis; Sanofi USA; Laval University; Mayo Clinic; Mayo Clinic; Mayo Clinic; CHU Lyon; Universite de Montreal; Western University (University of Western Ontario)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2424988122
• 发表日期: 2025-12-23
• 页码: e2424988122
• 关键词: demyelinating autoimmune disease; MOG antibody disease; experimental autoimmune disease; autoantibody; antibody-secreting cells; experimental allergic encephalomyelitis; BARR-VIRUS INFECTION; B-CELL DEPLETION; monoclonal-antibody; germinal center; t-cells; glycoprotein; induction; cns; disease

摘要

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.