Functional plasticity of Th17 in arthritis

摘要 本基金申请的目的是探索Th 17在关节炎中的可塑性。白细胞介素-17A（IL-17 A） 产生Th 17的细胞因子通常大量存在于类风湿和银屑病患者的滑膜中 关节炎然而，IL 17 A的靶向通常不足以完全控制这些病症中的关节炎症。 一种可能的情况是，在关节炎症恶化的情况下，Th 17经历转化为Th 17。 致病性IL 17 A阴性细胞群，统称为exTh 17。Th 17向exTh 17的转化具有 在神经炎症和感染的背景下被记录，并描述了局部产生的IL-7 作为肺中Th 17可塑性的关键启动子。然而，Th 17可塑性在关节炎中的发生及其 在持续滑膜炎症中的潜在作用仍然未知。 我们建立了一种新的自身免疫性关节炎的命运映射小鼠模型， Th 17转化为exTh 17，收集的初步数据表明Th 17经历了IL 17 A的显著损失 表达和转化为exTh 17在滑膜炎症的情况下。我们还确定了候选人 exTh 17亚群可能导致关节炎症持续存在，尽管它们丧失了IL 17 A 表情在这里，我们将利用我们的小鼠模型来收集关于免疫调节和/或免疫抑制的初步证据。 exTh 17在滑膜自身免疫性炎症中的致病作用（Aim 1）。此外，我们还将探讨IL-7或 由滑膜成纤维细胞产生的其它因子在诱导Th 17转化为exTh 17中起作用（目的2）。 我们的长期目标是利用疾病不同阶段局部免疫细胞表型的知识， 使关节炎的阶段特异性和个性化治疗能够最小化非特异性免疫抑制。

ABSTRACT The objective of this grant application is to explore the plasticity of Th17 in arthritis. Interleukin-17A (IL-17A) producing Th17 are present often in large numbers in the synovium of patients with rheumatoid and psoriatic arthritis. However, targeting of IL17A is generally insufficient to fully control joint inflammation in these conditions. One potential scenario is that in the context of worsening joint inflammation, Th17 undergo conversion into pathogenic IL17A-negative cell populations, collectively called exTh17. The conversion of Th17 into exTh17 has been documented in the context of neuroinflammation and infections, and locally produced IL-7 was described as a key promoter of Th17 plasticity in the lung. However, the occurrence of Th17 plasticity in arthritis and its potential role in perpetuating synovial inflammation remain unknown. We generated a novel fate-mapping mouse model of autoimmune arthritis, which allows to follow the conversion of Th17 into exTh17, and collected preliminary data suggesting that Th17 undergo significant loss of IL17A expression and conversion into exTh17 in the context of synovial inflammation. We also identified candidate exTh17 subpopulations which might contribute to perpetuate joint inflammation despite their loss of IL17A expression. Here we will leverage our mouse model to collect pilot evidence about the immunoregulatory and/or pathogenic role of exTh17 in synovial autoimmune inflammation (Aim 1). Also, we will explore whether IL-7 or other factors produced by synovial fibroblast play a role in inducing conversion of Th17 into exTh17 (Aim 2). Our long-term goal is to leverage knowledge of local immune cell phenotypes at various stages of disease to enable stage-specific and personalized therapies of arthritis to minimize non specific immunosuppression.