Role of PTPN2 in rheumatoid arthritis

摘要 这项拨款申请的目的是了解PTPN2基因功能丧失的遗传变异如何 -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 普遍存在，在免疫细胞中高度表达，是Janus激酶和JANUS蛋白的关键负调节因子 信号转导和转录激活子下游的多个细胞因子受体。为了建立模型， PTPN2自身免疫相关变异体在RA中的作用机制我们评估了携带PTPN2的小鼠 单倍体功能不全(PTPN2+/-小鼠)，导致与人类PTPN2相当的PTPN2表达缺失 RA风险变种。我们发现，在以CD4T细胞驱动的疾病为特征的SKG RA模型中，部分丢失 PTPN_2的功能减弱导致关节炎的严重程度显著增加。通过利用有条件的PTPN2 单倍体不足和命运映射小鼠，我们发现SKG.Ptpn2+/-小鼠的表型是由于 炎症诱导的FoxP3+调节性T细胞(Treg)不稳定增强，这是一个已知导致转换的过程 外周血中的FoxP3+Treg转化为致病的FoxP3-表达IL-17的ExTreg。我们有证据 PTPN2+/-Tregs转化为产生IL-17的“exTreg”的增强是由于STAT3的增加 IL-6和潜在的其他炎症诱导因子刺激后的磷酸化。我们在这里申请 进一步了解PTPN2在Treg不稳定和RA发病机制中的作用机制 通过小鼠免疫学和细胞信号研究。在目标1和2中，我们将阐明机制和拓扑 增强炎症诱导的不稳定性和致病性。在目标3中，我们将评估 PTPN_2在Treg中过表达能否逆转PTPN_2+/-诱导的Treg和关节炎表型 SKG小鼠。我们的长期目标是获得PTPN2功能遗传学的知识，以便能够发现 携带PTPN2基因变异的RA患者的个人化和非免疫抑制治疗。

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.