Journal
FRONTIERS IN IMMUNOLOGY
Volume 13, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2022.755900
Keywords
B cell; repertoire; autoimmunity; experimental autoimmune encephalomyelitis (EAE); multiple sclerosis; myelin oligodendrocyte glycoprotein (MOG); TCR1640 transgene mouse model; demyelinating antibodies
Categories
Funding
- Institut Roche
- Univ of Lille, Department of Pharmacy
- Univ of Lille, Department of Medicine
- ARSEP
- Emmy Noether Program of the German Research Foundation DFG [PE 2681/1-1]
- Institut National de la Sante' et de la Recherche me'dicale (INSERM), the University of Lille
- Agence Nationale de la Recherche sugars-in-MS [ANR-17-CE15-0028]
- French MS society (ARSEP, Fondation pour L'aide a la recherche sur la Scle'rose en plaques)
- Haut-de-France region
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The key role of B cells in multiple sclerosis is supported by various factors, such as the presence of oligoclonal bands in the cerebrospinal fluid and the efficacy of B lymphocyte depletion. Using an EAE model, this study explores the clonality of B cell response targeting myelin oligodendrocyte glycoprotein (MOG) and demonstrates the pre-clinical mobilization of the MOG-specific B cell response within brain-draining cervical lymph nodes. The study also suggests that MOG antibodies are not a reliable biomarker for disease onset and progression.
The key role of B cells in the pathophysiology of multiple sclerosis (MS) is supported by the presence of oligoclonal bands in the cerebrospinal fluid, by the association of meningeal ectopic B cell follicles with demyelination, axonal loss and reduction of astrocytes, as well as by the high efficacy of B lymphocyte depletion in controlling inflammatory parameters of MS. Here, we use a spontaneous model of experimental autoimmune encephalomyelitis (EAE) to study the clonality of the B cell response targeting myelin oligodendrocyte glycoprotein (MOG). In particular, 94% of SJL/j mice expressing an I-A(s): MOG(92-106) specific transgenic T cell receptor (TCR1640) spontaneously develop a chronic paralytic EAE between the age of 60-500 days. The immune response is triggered by the microbiota in the gut-associated lymphoid tissue, while there is evidence that the maturation of the autoimmune demyelinating response might occur in the cervical lymph nodes owing to local brain drainage. Using MOG-protein-tetramers we tracked the autoantigen-specific B cells and localized their enrichment to the cervical lymph nodes and among the brain immune infiltrate. MOG-specific IgG1 antibodies were detected in the serum of diseased TCR1640 mice and proved pathogenic upon adoptive transfer into disease-prone recipients. The ontogeny of the MOG-specific humoral response preceded disease onset coherent with their contribution to EAE initiation. This humoral response was, however, not sufficient for disease induction as MOG-antibodies could be detected at the age of 69 days in a model with an average age of onset of 197 days. To assess the MOG-specific B cell repertoire we FACS-sorted MOG-tetramer binding cells and clonally expand them in vitro to sequence the paratopes of the IgG heavy chain and kappa light chains. Despite the fragility of clonally expanding MOG-tetramer binding effector B cells, our results indicate the selection of a common CDR-3 clonotype among the Igk light chains derived from both disease-free and diseased TCR1640 mice. Our study demonstrates the pre-clinical mobilization of the MOG-specific B cell response within the brain-draining cervical lymph nodes, and reiterates that MOG antibodies are a poor biomarker of disease onset and progression.
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