PTPN22 deficiency cooperates with the CD45 E613R allele to break tolerance on a non-autoimmune background.
PTPN22 deficiency cooperates with the CD45 E613R allele to break tolerance on a non-autoimmune background.
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DOI：
10.4049/jimmunol.0803317
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发表时间：
2009-04-01
期刊：
影响因子：
--
通讯作者：
Weiss A
中科院分区：
文献类型：
--
作者：
Zikherman J;Hermiston M;Steiner D;Hasegawa K;Chan A;Weiss A
Pep和CD 45是酪氨酸磷酸酶，其靶标包括Src家族激酶，抗原受体信号传导的关键介质。PTPN 22是编码人类Pep直系同源物Lyp的基因，在复杂的遗传背景下，PTPN 22的多态性赋予对多种人类自身免疫性疾病的易感性。然而，R620 W风险等位基因的功能意义尚不清楚。我们报告，在Jurkat细胞中野生型或R620 W Pep/Lyp的错误表达，在其结合伴侣Csk的背景下，揭示了作为亚型的风险等位基因。先前已经表明，尽管B6背景下的Pep缺陷小鼠具有超应答记忆T细胞，但自身免疫性不发展。在CD 45跨膜楔结构域（E613 R）中含有点突变的小鼠在混合129/B6背景下发生B细胞驱动的狼疮样疾病，但在B6背景下不发生。我们研究了Pep缺乏作为非自身免疫性B6背景下CD 45 E613 R突变的遗传修饰剂的能力，以了解复杂的易感基因座如何在自身免疫中相互作用。在这里，我们报告说，双突变小鼠开发狼疮样疾病以及淋巴结病，多克隆淋巴细胞活化，加速记忆T细胞的形成。在抗原受体刺激后，双突变小鼠中的外周B细胞表型复制高反应性CD 45 E613 R B细胞，而外周T细胞的反应类似于Pep−/− T细胞。这些研究表明，敏感微环境中的Pep−/− T细胞可以驱动高反应性CD 45 E613 R B细胞破坏耐受性。
Pep and CD45 are tyrosine phosphatases whose targets include the Src-family kinases, critical mediators of antigen receptor signaling. A polymorphism in PTPN22, the gene that encodes the human Pep ortholog Lyp, confers susceptibility to multiple human autoimmune diseases in the context of complex genetic backgrounds. However, the functional significance of the R620W risk allele is not clear. We report that misexpression of wild type or R620W Pep/Lyp in Jurkat cells, in the context of its binding partner Csk, unmasks the risk allele as a hypomorph. It has been shown previously that, although Pep deficient mice on the B6 background have hyper-responsive memory T cells, autoimmunity does not develop. Mice containing a point mutation in the CD45 juxtamembrane wedge domain (E613R) develop a B cell-driven lupus-like disease on the mixed 129/B6 background, but not on the B6 background. We studied the ability of Pep deficiency to act as a genetic modifier of the CD45 E613R mutation on the non-autoimmune B6 background in order to understand how complex susceptibility loci might interact in autoimmunity. Here we report that double mutant mice develop a lupus-like disease as well as lymphadenopathy, polyclonal lymphocyte activation, and accelerated memory T cell formation. Following antigen receptor stimulation, peripheral B cells in the double mutant mice phenocopy hyper-responsive CD45 E613R B cells, whereas peripheral T cells respond like Pep−/− T cells. These studies suggest that Pep−/− T cells in the context of a susceptible microenvironment can drive hyper-responsive CD45 E613R B cells to break tolerance.
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