Cosmc deficiency causes spontaneous autoimmunity by breaking B cell tolerance.
Cosmc deficiency causes spontaneous autoimmunity by breaking B cell tolerance.
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Cosmc 缺陷会破坏 B 细胞耐受性，从而导致自发性自身免疫。
DOI：
10.1126/sciadv.abg9118
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发表时间：
2021-10-08
期刊：
影响因子：
13.6
通讯作者：
Cummings RD
中科院分区：
文献类型：
--
作者：
Zeng J;Aryal RP;Stavenhagen K;Luo C;Liu R;Wang X;Chen J;Li H;Matsumoto Y;Wang Y;Wang J;Ju T;Cummings RD
由 X 连锁 Cosmc 控制的 B 细胞糖蛋白上的 O 聚糖是 B 细胞耐受和预防自身免疫所必需的。调节 B 细胞介导的自身免疫的诱导和发展的因素尚不清楚。在这里，我们报告说，小鼠 B 细胞中 X 连锁 Cosmc（编码核心 1 O-聚糖表达所需的分子伴侣）的靶向缺失，会因 B 细胞耐受性破坏而导致自身免疫病理的自发发展。 BC-CosmcKO 小鼠表现出多种表型异常，包括严重体重减轻、眼部表现、淋巴结肿大和雌性相关死亡率增加。 BC-CosmcKO 小鼠 B 细胞耐受性的破坏表现为自身反应性 IgM 和 IgG 自身抗体升高。 Cosmc 缺陷的 B 细胞表现出增强的基础激活和对刺激的反应能力。 BC-CosmcKO 小鼠中自发生发中心 B 细胞的频率也升高。从机制上讲，Cosmc 的缺失会通过减少 BCR 内化而增强 B 细胞受体 (BCR) 信号传导。结果表明，Cosmc通过控制核心1 O-聚糖，是一种先前未鉴定的维持B细胞耐受性的免疫检查点基因。
O-glycans on B cell glycoproteins controlled by X-linked Cosmc are required for B cell tolerance and preventing autoimmunity. 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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DOI：
10.1084/jem.20060221
发表时间：
2006-07-10
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Gazumyan A;Reichlin A;Nussenzweig MC
通讯作者：
Nussenzweig MC
DOI：
10.1002/trc2.12040
发表时间：
2020-01-01
影响因子：
4.8
作者：
Gollamudi, Seema;Lekhraj, Rukmani;Lalezari, Parviz
通讯作者：
Lalezari, Parviz
影响因子：
8.8
作者：
Rose, M L;Habeshaw, J A;Kennedy, R;Sloane, J;Wiltshaw, E;Davies, A J
通讯作者：
Davies, A J
DOI：
10.1038/s41575-020-0331-7
发表时间：
2020-10
期刊：
Nature reviews. Gastroenterology & hepatology
影响因子：
--
作者：
Kudelka MR;Stowell SR;Cummings RD;Neish AS
通讯作者：
Neish AS
影响因子：
32.4
作者：
CYSTER, JG;GOODNOW, CC
通讯作者：
GOODNOW, CC