Cosmc deficiency causes spontaneous autoimmunity by breaking B cell tolerance.

Junwei Zeng,Renyan Liu,Jiaxuan Chen,Yasuyuki Matsumoto,Jianmei Wang,Xiaohui Wang,Richard D Cummings,Hao Li,Tongzhong Ju,Kathrin Stavenhagen,Yingchun Wang,Rajindra P Aryal,Chi Luo

doi:10.1126/sciadv.abg9118

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.

Highlights

B cells play pivotal roles in mediating the pathogenesis of autoimmune diseases (AIDs), which affect ~7 to 9% of the world population [1,2,3]
Cosmc deficiency prolongs the retention of the B cell receptor (BCR) on cell surface and promotes stronger BCR signaling, which likely led to B cells’ hyperresponsiveness to stimuli. These results demonstrate that the presence of Cosmc, required for normal O-glycans on B cell glycoproteins, controls B cell tolerance by maintaining BCR signaling through regulating surface BCR internalization
By developing a mouse line in which Cosmc was deleted in B cells, we found that the absence of core 1 O-glycans on B cells can spontaneously initiate the development of AID

Summary

Introduction

B cells play pivotal roles in mediating the pathogenesis of autoimmune diseases (AIDs), which affect ~7 to 9% of the world population [1,2,3]. A hallmark of autoimmunity is the breach of B cell tolerance, where B cells are unable to distinguish self-antigens from non–self-antigens and eventually lead to the emergence of pathogenic autoantibodies. The molecular factors underneath the initial development and expansion of pathogenic autoreactive B cells remain incompletely understood. The B cell receptor (BCR) is the master regulator in controlling B cell development, differentiation, survival, and tolerance [1, 4, 5]. It is essential for B cells to receive, process, and integrate both the antigenic signals delivered via BCR and environmental cues relayed via other receptors as they give rise to opposing outcomes. In the periphery, a notable percentage of B cells in healthy host exhibit autoreactivities [7, 10], suggesting the existence of undefined mechanisms underlying the fine-tuned regulation of B cell activities

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Results

Conclusion