Cosmc deficiency causes spontaneous autoimmunity by breaking B cell tolerance

• Type of Material: Article
• Authors: Richard Cummings, Emory University; Tongzhong Ju, Emory University; Junwei Zeng, Harvard Medical School; Rajindra P Aryal, Harvard Medical School; Kathrin Stavenhagen, Harvard Medical School; Chi Luo, Dana-Farber Cancer Institute; Renyan Liu, Dana-Farber Cancer Institute; Xiaohui Wang, Harvard School of Dental Medicine; Jiaxuan Chen, Harvard Medical School; Hao Li, Harvard Medical School; Yasuyuki Matsumoto, Harvard Medical School; Yingchun Wang, Emory University; Jianmei Wang, Emory University; Richard D Cummings, Harvard Medical School
• Language: English
• Date: 2021-10-01
• Publisher: AMER ASSOC ADVANCEMENT SCIENCE
• Publication Version: Final Published Version
• Copyright Statement: © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1126/sciadv.abg9118
• Title of Journal or Parent Work: SCIENCE ADVANCES
• Volume: 7
• Issue: 41
• Start Page: eabg9118
• End Page: eabg9118
• Grant/Funding Information: This work was supported by NIH grant U01CA168930 to T.J. and R.D.C.
• Keywords: Multidisciplinary Sciences; Science & Technology; Science & Technology - Other Topics; GERMINAL-CENTER; TYROSINE; MECHANISMS; IMMUNE-COMPLEXES; IGA NEPHROPATHY; NEGATIVE REGULATOR; CHAPERONE; CD22; PEANUT LECTIN; ACTIVATION
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Oncology; Chemistry, Biochemistry

Abstract

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.