Role of PTPN2 in rheumatoid arthritis

摘要 这项拨款申请的目的是了解PTPN 2基因的功能丧失遗传变异是如何发生的。 - 编码T细胞蛋白酪氨酸磷酸酶（TC-PTP）-增加类风湿性关节炎（RA）的风险。PTPN2 是普遍存在的，并且在免疫细胞中高度表达，是Janus激酶的关键负调节因子， 信号转导子和转录激活子下游的多种细胞因子受体。为了模拟 PTPN 2自身免疫相关变异体在RA中的作用机制，我们评估了携带Ptpn 2 单倍不足（Ptpn 2 +/-小鼠），其导致与人PTPN 2相当的PTPN 2表达丧失 RA风险变体。我们发现，在SKG RA模型中-以CD 4 T细胞驱动的疾病为特征-部分丧失 PTPN 2功能的降低导致关节炎严重程度的显著增加。通过利用条件Ptpn 2 单倍不足和命运作图小鼠，我们表明SKG.Ptpn2+/-小鼠的表型是由于 增强炎症诱导的FoxP 3+调节性T细胞（Treg）不稳定性，这是一个已知导致转化的过程 将外周FoxP 3 + Treg转化为表达白细胞介素-17（IL-17）的致病性FoxP 3-“exTreg”。我们有证据 Ptpn 2 +/-T细胞转化为产生IL-17的“exTreg”的增强是由于STAT 3的增加， 在用IL-6和潜在的其他炎症诱导因子刺激后，细胞内的蛋白质磷酸化。在这里，我们申请 资助进一步了解PTPN 2在Treg不稳定性和RA发病机制中的作用机制 通过小鼠免疫学和细胞信号传导研究。在目标1和2中，我们将阐明机制和拓扑结构 增强炎症诱导的SKG.Ptpn2+/- Treg的不稳定性和致病性。在目标3中，我们将评估 PTPN 2在Treg中的过表达是否可以逆转由Ptpn 2 +/- in SKG小鼠。我们的长期目标是获得PTPN 2功能遗传学的知识，以发现 个体化和非免疫抑制疗法用于携带遗传PTPN 2风险变体的RA患者。

ABSTRACT The objective of this grant application is to understand how loss-of-function genetic variants of the PTPN2 gene -encoding the T cell-protein tyrosine phosphatase (TC-PTP)- enhance risk of rheumatoid arthritis (RA). PTPN2 is ubiquitous, and very highly expressed in immune cells and is a critical negative regulator of Janus kinases and signal transducers and activators of transcription downstream multiple cytokine receptors. In order to model the mechanism of action of PTPN2 autoimmunity-associated variants in RA, we assessed mice carrying Ptpn2 haploinsufficiency (Ptpn2+/- mice), which causes a loss of expression of PTPN2 comparable to the human PTPN2 RA-risk variants. We found that in the SKG RA model- characterized by CD4 T cell-driven disease- partial loss of function of PTPN2 caused significant enhancement of arthritis severity. By leveraging conditional Ptpn2 haploinsufficiency and fate-mapping mice, we showed that the phenotype of SKG.Ptpn2+/- mice is due to enhanced inflammation-induced FoxP3+ regulatory T cell (Treg) instability, a process known to lead to conversion of peripheral FoxP3+ Treg into pathogenic FoxP3- “exTreg” expressing interleukin-17 (IL-17). We have evidence that the enhanced conversion of Ptpn2+/- Tregs into IL-17-producing “exTreg” is due to increased STAT3 phosphorylation after stimulation with IL-6 and potentially other inflammation-induced factors. Here we apply for funding to further understand the mechanism of action of PTPN2 in Treg instability and the pathogenesis of RA via mouse immunology and cell signaling studies. In Aim 1 and 2 we will elucidate the mechanism and topology of enhanced inflammation-induced instability and pathogenicity of SKG.Ptpn2+/- Treg. In Aim 3 we will assess whether overexpression of PTPN2 in Treg can reverse the Treg and arthritis phenotype induced by Ptpn2+/- in SKG mice. Our long-term goal is to acquire knowledge of PTPN2 functional genetics to enable the discovery of personalized and non-immunosuppressive therapies for RA patients carrying genetic PTPN2 risk variants.