B cells Regulation by Interferon-gamma in a Neuromyelitis Optica Spectrum Disorder animal model

Abstract Neuromyelitis Optica Spectrum Disorder (NMOSD) is an autoimmune disease of the central nervous system (CNS) mediated by Th17 and auto-antibody response against the water channel protein Aquaporin-4 (AQP4). In NMOSD, B cells plays a central role regulating autoreactive T and antibody secreting cells, and the use of anti-B cells therapy is a common practice for patients. Despite this, the mechanisms of B cells response against AQP4 are poorly understood. We have demonstrated that the immune tolerance against the immunodominant AQP4 201–220peptide in mice is maintained by IFN-g, controlling disease incidence, severity, and chronicity. Actively immunization of C57BL/6 (WT) treated with neutralizing anti-IFN-g antibodies, IFN-g knockout (IFNGKO) and IFN-g receptor KO (IFNRKO) mice was induced using the AQP4 201–220peptide, showing an ascendant paralysis starting from the tail to complete hind limb paralysis. CNS histological analysis showed an increased presence of T and B cells, and the complement system in lesion sites, associated with CNS damage. CNS Th17 profile was also observed in the anti-IFN-g treated group. Conversely, IFN-g treatment in IFNGKO mice decrease disease severity with a reduction of CNS CD4 +and B cells. Remarkably, IFN-g regulates the IL-6 expression by B cells in an antigen specific fashion. B-cell depletion significantly reduced the disease incidence, T cells CNS infiltration and anti-AQP4 201–220serum antibodies. Finally, using anti-IL-6R treatment, we showed that IL-6 signaling is necessary for the B cell activation and their induction of Th17 cells. In conclusion, AQP4 201–220tolerance is strictly regulated by IFN-g and its signaling, restraining B cells pathogenicity through IL-6 signaling modulation. This work was supported by National Institutes of Health grants R21AI151438 and R01 NS099334