Factors regulating the induction and development of B cell–mediated autoimmunity are not well understood. Here, we report that targeted deletion in murine B cells of X-linked Cosmc, encoding the chaperone required for expression of core 1 O-glycans, causes the spontaneous development of autoimmune pathologies due to a breakdown of B cell tolerance. BC-CosmcKO mice display multiple phenotypic abnormalities, including severe weight loss, ocular manifestations, lymphadenopathy, and increased female-associated mortality. Disruption of B cell tolerance in BC-CosmcKO mice is manifested as elevated self-reactive IgM and IgG autoantibodies. Cosmc-deficient B cells exhibit enhanced basal activation and responsiveness to stimuli. There is also an elevated frequency of spontaneous germinal center B cells in BC-CosmcKO mice. Mechanistically, loss of Cosmc confers enhanced B cell receptor (BCR) signaling through diminished BCR internalization. The results demonstrate that Cosmc, through control of core 1 O-glycans, is a previously unidentified immune checkpoint gene in maintaining B cell tolerance.
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Zeng, Junwei; Aryal, Rajindra P.; Stavenhagen, Kathrin; Luo, Chi; Liu, Renyan; Wang, Xiaohui; Chen, Jiaxuan; Li, Hao; Matsumoto, Yasuyuki; Wang, Yingchun; Wang, Jianmei; Ju, Tongzhong; and Cummings, Richard D.. 2021. Cosmc Deficiency Causes Spontaneous Autoimmunity by Breaking B Cell Tolerance. Science Advances. Vol.7(41). https://doi.org/10.1126/sciadv.abg9118 PMID: 34613773