A disease-associated PTPN22 variant promotes systemic autoimmunity in murine models
A disease-associated PTPN22 variant promotes systemic autoimmunity in murine models
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DOI：
10.1172/jci66963
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发表时间：
2013-05-01
影响因子：
15.9
通讯作者：
Rawlings, David J.
中科院分区：
文献类型：
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作者：
Dai, Xuezhi;James, Richard G.;Rawlings, David J.
多种自身免疫性疾病，包括 1 型糖尿病、类风湿性关节炎、格雷夫斯病和系统性红斑狼疮，都与编码蛋白 LYP 的蛋白酪氨酸磷酸酶非受体 22 (PTPN22) 的等位基因变异有关。为了模拟人类疾病相关变体 LYP-R620W，我们生成了表达小鼠直系同源 PEST 结构域磷酸酶 (PEP) 中类似突变 R619W 的敲入小鼠。与之前的报告相反，我们发现该变体表现出正常的蛋白质稳定性，但显着改变了淋巴细胞功能。衰老的敲入小鼠表现出效应 T 细胞扩增和过渡、生发中心和与年龄相关的 B 细胞扩增，以及自身抗体和全身自身免疫的发展。此外，PEP-R619W 影响 B 细胞选择和 B 谱系限制性变异表达，并足以促进自身免疫。与这些特征一致，PEP-R619W 淋巴细胞对抗原受体与酪氨酸磷酸化底物的独特特征的结合反应过度。因此，PEP-R619W 独特地调节 T 和 B 细胞稳态，导致耐受性和自身免疫性丧失。
Multiple autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, Graves disease, and systemic lupus erythematosus, are associated with an allelic variant of protein tyrosine phosphatase nonreceptor 22 (PTPN22), which encodes the protein LYP. To model the human disease-linked variant LYP-R620W, we generated knockin mice expressing the analogous mutation, R619W, in the murine ortholog PEST domain phosphatase (PEP). In contrast with a previous report, we found that this variant exhibits normal protein stability, but significantly alters lymphocyte function. Aged knockin mice exhibited effector T cell expansion and transitional, germinal center, and age-related B cell expansion as well as the development of autoantibodies and systemic autoimmunity. Further, PEP-R619W affected B cell selection and B lineage-restricted variant expression and was sufficient to promote autoimmunity. Consistent with these features, PEP-R619W lymphocytes were hyperresponsive to antigen-receptor engagement with a distinct profile of tyrosine-phosphorylated substrates. Thus, PEP-R619W uniquely modulates T and B cell homeostasis, leading to a loss in tolerance and autoimmunity.