粘蛋白
自身免疫
生物
免疫学
自身抗体
B细胞
T细胞
突变体
分子生物学
抗体
细胞生物学
免疫系统
遗传学
基因
生物化学
作者
Sheng Xiao,Craig R. Brooks,Chen Zhu,Chuan Wu,Johanna M. Sweere,Sonia Petecka,Ada Yeste,Francisco J. Quintana,Takaharu Ichimura,Raymond A. Sobel,Joseph V. Bonventre,Vijay K. Kuchroo
标识
DOI:10.1073/pnas.1120914109
摘要
Tim-1, a type I transmembrane glycoprotein, consists of an IgV domain and a mucin domain. The IgV domain is essential for binding Tim-1 to its ligands, but little is known about the role of the mucin domain, even though genetic association of TIM-1 with atopy/asthma has been linked to the length of mucin domain. We generated a Tim-1-mutant mouse (Tim-1(Δmucin)) in which the mucin domain was deleted genetically. The mutant mice showed a profound defect in IL-10 production from regulatory B cells (Bregs). Associated with the loss of IL-10 production in B cells, older Tim-1(Δmucin) mice developed spontaneous autoimmunity associated with hyperactive T cells, with increased production of IFN-γ and elevated serum levels of Ig and autoantibodies. However, Tim-1(Δmucin) mice did not develop frank systemic autoimmune disease unless they were crossed onto the Fas-mutant lpr mice on a C57BL/6 background. Tim-1(Δmucin)lpr mice developed accelerated and fulminant systemic autoimmunity with accumulation of abnormal double-negative T cells and autoantibodies to a number of lupus-associated autoantigens. Thus, Tim-1 plays a critical role in maintaining suppressive Breg function, and our data also demonstrate an unexpected role of the Tim-1 mucin domain in regulating Breg function and maintaining self-tolerance.
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