来自美国费恩斯坦医学研究所的Peter Gregersen及其同事发现与Lyp蛋白(PTPN22)互作的C-src酪氨酸激酶(Csk)的编码基因CSK中的调节性变异,与系统性红斑狼疮(SLE)相关。这项研究表明Lyp-Csk 复合物可通过调节B细胞的信号通路、成熟和激活,来影响机体对SLE的敏感性。相关的研究论文于10月7日在线发表在《Nature Genetics》期刊上。

-2012年11月《自然-遗传》

中文翻译


【题目】CSK调控的多态性与系统性红斑狼疮相关,且影响B细胞的信号通路和激活作用

【译文】C-src酪氨酸激酶(Csk)会与胞内的磷酸酶Lyp(PTPN22基因编码)互作,Csk还能在淋巴细胞内修饰下游Src激酶,如Lyn的激活状态。我们发现CSK基因与系统性红斑狼疮(SLE)相关,且将这个基因精确定位到内含子多态性rs34933034(优势率(OR) = 1.32;P = 1.04×10−9)上。这个风险等位基因与CSK的表达增加有关,还能增加Lyn的磷酸化作用的抑制程度。相对于携带非风险型单倍体的个体,在该风险等位基因的携带者体内,B细胞受体(BCR)介导的成熟B细胞的活化程度增强,以及免疫球蛋白M(IgM)的浓度升高。此外,在风险等位基因的携带者的脐带血中发现移行的B细胞的碎片加倍,这是由于后期扩张的移行细胞被选择机制靶定的结果。这些结果表明Lyp-Csk复合物通过调控B细胞的成熟和活化,来增强机体对狼疮的敏感性。

英文原稿


[Title]: CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation

[Authors]: Nataly Manjarrez-Orduño, Emiliano Marasco, Sharon A Chung, Matthew S Katz, Jenna F Kiridly, Kim R Simpfendorfer, Jan Freudenberg, David H Ballard, Emil Nashi, Thomas J Hopkins, Deborah S Cunninghame Graham, Annette T Lee, Marieke J H Coenen, Barbara Franke, Dorine W Swinkels, Robert R Graham, Robert P Kimberly, Patrick M Gaffney, Timothy J Vyse, Timothy W Behrens, Lindsey A Criswell, Betty Diamond & Peter K Gregersen

[Abstract]: The c-Src tyrosine kinase, Csk, physically interacts with the intracellular phosphatase Lyp (encoded by PTPN22) and can modify the activation state of downstream Src kinases, such as Lyn, in lymphocytes. We identified an association of CSK with systemic lupus erythematosus (SLE) and refined its location to the intronic polymorphism rs34933034 (odds ratio (OR) = 1.32; P = 1.04 × 10−9). The risk allele at this SNP is associated with increased CSK expression and augments inhibitory phosphorylation of Lyn. In carriers of the risk allele, there is increased B-cell receptor (BCR)-mediated activation of mature B cells, as well as higher concentrations of plasma immunoglobulin M (IgM), relative to individuals with the non-risk haplotype. Moreover, the fraction of transitional B cells is doubled in the cord blood of carriers of the risk allele, due to an expansion of late transitional cells in a stage targeted by selection mechanisms. This suggests that the Lyp-Csk complex increases susceptibility to lupus at multiple maturation and activation points in B cells.

原文地址

http://www.nature.com/ng/journal/v44/n11/full/ng.2439.html

 

本站声明: 生物文库所有文章欢迎转载,所有文章未说明,均属于原创,转载均请注明出处。
本文链接: http://www.bioku.cn/201301/csk-gene-bcell-lyp-csk-complex-sle/
版权所有: 生物文库 - 生物医学、生物技术核心期刊文摘

留言


3 − 一 =


沪ICP备12028140号
点击这里给我发消息   点击这里给我发消息