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Impact of coding risk variant IFNGR2 on the B cell-intrinsic IFN-γ signaling pathway in multiple sclerosis

Publication year 2024
Published in Journal of autoimmunity
Authors Laurens Bogers, Jasper Rip, Liza Rijvers, Jamie van Langelaar, Steven C Koetzier, Kirsten L Kuiper, Veronique Meerdink, Annet F Wierenga-Wolf, Marie-José Melief, Ana M Marques, Joost Smolders, Marvin M van Luijn

B cells of people with multiple sclerosis (MS) are more responsive to IFN-γ, corresponding to their brain-homing potential. We studied how a coding single nucleotide polymorphism (SNP) in IFNGR2 (rs9808753) co-operates with Epstein-Barr virus (EBV) infection as MS risk factors to affect the IFN-γ signaling pathway in human B cells. In both cell lines and primary cells, EBV infection positively associated with IFN-γ receptor expression and STAT1 phosphorylation. The IFNGR2 risk SNP selectively promoted downstream signaling via STAT1, particularly in transitional B cells. Altogether, EBV and the IFNGR2 risk SNP independently amplify IFN-γ signaling, potentially driving B cells to enter the MS brain.

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