狼患者中罕见的SH2B3编码变异会降低B细胞耐受性,并导致自身免疫
Yaoyuan Zhang1,2, Rhiannon Morris3,4, Grant J Brown1,2
1Division of Immunology and Infectious Diseases, John Curtin School of Medical Research, The Australian National University, Acton, Australia.
细胞信号的调节者SH2B3基因的罕见变异与系统性红斑狼 (SLE) 有关. 这些变体损害了免疫系统消除自我反应性B细胞的能力,增加了狼风险.
科学领域:
- 免疫学 免疫学 免疫学
- 遗传学 是一个遗传学.
- 自免疫性疾病 自免疫性疾病
背景情况:
- 系统性红斑狼 (SLE) 是一种具有已知的遗传基础的自身免疫性疾病.
- 狼风险基因中的罕见基因变异有助于疾病发病,但它们的具体作用往往不清楚.
- 细胞因子和生长因子信号的负调节者SH2B3在超过5%的SLE患者中具有罕见的编码变异.
研究的目的:
- 为了研究在SLE患者中发现的罕见SH2B3变异的功能影响.
- 确定SH2B3在B细胞调节和自身免疫中的作用.
- 为了阐明SH2B3变异对狼病原体的贡献.
主要方法:
- 产生了携带患者衍生SH2B3变异的小鼠模型.
- 通过JAK2-STAT1.1.评估SH2B3变体对IFNGR信号传输的影响.
- 分析的B细胞种群,包括不成熟和过渡性B细胞.
- 评估了对自我反应性B细胞的负选择和自身免疫加速的影响.
主要成果:
- 在SLE患者中,SH2B3变异主要是低形态的,无法抑制IFNGR信号.
- SH2B3对于限制不成熟和过渡性B细胞数量至关重要.
- 低形态SH2B3损害了自我反应性B细胞的负选择,加速了自身免疫.
- 增加IL-4R信号和BAFF-R表达有助于观察到的自身免疫.
结论:
- 在维护B细胞耐受性方面,SH2B3起着至关重要的作用.
- 罕见的低形状SH2B3变体通过损害B细胞耐受性来促进SLE的发病.
- SH2B3变种代表了系统性红斑狼的显著遗传风险因素.
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