College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China; Research Institute of McGill University Health Centre, Child Health and Human Development Program, 1001 Decarie Boulevard, Montreal, QC H4A 3J1, Canada.
Research Institute of McGill University Health Centre, Child Health and Human Development Program, 1001 Decarie Boulevard, Montreal, QC H4A 3J1, Canada.
J Autoimmun. 2017 May;79:74-83. doi: 10.1016/j.jaut.2017.01.009. Epub 2017 Feb 22.
The C1858T single nucleotide polymorphism (SNP) in PTPN22 (protein tyrosine phosphatase nonreceptor 22) leads to the 620 Arg to Trp polymorphism in its encoded human protein LYP. This allelic variant is associated with multiple autoimmune diseases, including type 1 diabetes (T1D), Crohn's disease, rheumatoid arthritis and systemic lupus erythematosus. However, the underlying mechanisms are poorly understood. To study how this polymorphism influences the immune system, we generated a mouse strain with a knock-in of the Trp allele, imitating the human disease-associated variant. We did not find significant difference between the polymorphic and the wild type mice on the proportion of total CD4 T cell, CD8 T cell, NK cell, memory T lymphocyte, macrophage, dendritic cells in both peripheral lymph nodes and spleen. However, macrophages from Trp/Trp mice showed altered morphology and enhanced function, including higher expression of MHCII and B7 molecules and increased phagocytic ability, which further leads to a higher T-cell activation by specific antigen. Our model shows no alteration in immune cell profile by the Trp allele, but brings up macrophages as an important player to consider in explaining the PTPN22 Trp allele effect on autoimmune disease risk.
C1858T 单核苷酸多态性（SNP）在 PTPN22（蛋白酪氨酸磷酸酶非受体 22）中导致其编码的人类蛋白质 LYP 中的 620 精氨酸到色氨酸多态性。这种等位基因变体与多种自身免疫性疾病有关，包括 1 型糖尿病（T1D）、克罗恩病、类风湿关节炎和系统性红斑狼疮。然而，其潜在机制尚不清楚。为了研究这种多态性如何影响免疫系统，我们生成了一种携带 Trp 等位基因敲入的小鼠品系，模拟人类疾病相关的变体。我们没有发现多态性和野生型小鼠在外周淋巴结和脾脏中的总 CD4 T 细胞、CD8 T 细胞、NK 细胞、记忆 T 淋巴细胞、巨噬细胞、树突状细胞的比例上有显著差异。然而，Trp/Trp 小鼠的巨噬细胞表现出改变的形态和增强的功能，包括 MHCII 和 B7 分子的更高表达和增强的吞噬能力，这进一步导致特定抗原的 T 细胞激活增加。我们的模型显示 Trp 等位基因对免疫细胞谱没有改变，但提出了巨噬细胞作为一个重要的参与者来解释 PTPN22 Trp 等位基因对自身免疫性疾病风险的影响。
