Turncoat antibodies unmasked in a model of autoimmune demyelination: From biology to therapy
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (15)
Reza Taghipour-Mirakmahaleh
Neuroscience Unit, University Hospital Center of Quebec–Laval University
Françoise Morin
Neuroscience Unit, University Hospital Center of Quebec–Laval University
Yu Zhang
Xiangya Hospital, Central South University Changsha China
Louis Bourhoven
Neuroscience Unit, University Hospital Center of Quebec–Laval University
Louis-Charles Béland
Neuroscience Unit, University Hospital Center of Quebec–Laval University
Qun Zhou
Large Molecule Research
Julie Jaworski
Large Molecule Research
Anna Park
Juan Manuel Dominguez
Infection and Immunity Unit, Big Data Research Center, University Hospital Center of Quebec–Laval University
Jacques Corbeil
Infection and Immunity Unit, Big Data Research Center, University Hospital Center of Quebec–Laval University
Eoin P. Flanagan
Department of Neurology, Mayo Clinic
Romain Marignier
Service de Sclérose en Plaques, Pathologies de la Myéline et Neuro-Inflammation, Hôpital Neurologique Pierre Wertheimer
Catherine Larochelle
Neuroimmunology Research Laboratory, Multiple Sclerosis Clinic, University of Montreal Hospital Research Center
Steven M. Kerfoot
Department of Microbiology and Immunology, Western University
Luc Vallières
Neuroscience Unit, University Hospital Center of Quebec–Laval University