Journal
SCIENCE ADVANCES
Volume 7, Issue 41, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abg9118
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Funding
- NIH [U01CA168930]
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Deficiency in Cosmc leads to disruption of B cell tolerance, resulting in the development of autoimmune pathologies characterized by elevated levels of self-reactive antibodies, enhanced basal activation, and increased frequency of spontaneous germinal center B cells.
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 10-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 10-glycans, is a previously unidentified immune checkpoint gene in maintaining B cell tolerance.
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