Anti-myelin autoreactive B cells have a reduced response to BCR stimulation 2922

Abstract Description Peripheral B-cell tolerance typically requires regular exposure to autoantigens to induce B-cell anergy. However, B cells in the periphery do not regularly encounter tissue-restricted autoantigens, like those sequestered within the CNS. We demonstrated that B cells reactive to myelin oligodendrocyte glycoprotein (MOG) have a weaker response to BCR stimulation, yet do not exhibit a phenotype consistent with tolerance from regular autoantigens exposure. How B cell tolerance to tissue-restricted autoantigens is induced or maintained remains unclear. To understand the mechanism(s) limiting the anti-MOG B cell response, we analyzed in vitro B cell responses in IgHMOG mice, where 30% of B cells are MOG-specific (MOG-sp). Compared to MOG-nonsp B cells, MOG-sp B cells showed defective proliferation and failed to downregulate IgD upon activation. Further, BCR-proximal signalling (p-Syk, p-Tyr, Ca2+ flux) in MOG-sp B cells was not reduced, as is typical with B cell anergy. We also found that downstream BCR-signalling pathways (p-ERK, p-AKT, p-p38, NF-κB) were intact in MOG-sp B cells. Finally, we observed that MOG-sp B cells preferentially underwent apoptosis after BCR stimulation. We will further characterize their metabolic phenotype, transcriptome, and epigenetic regulation to understand the underlying mechanisms. This work may identify a novel mechanism that limits B cells specific for tissue-restricted autoantigens, independent of regular autoantigens exposure. Topic Categories Basic Autoimmunity (BA)