Pathogenic role of ILC2 in rheumatoid arthritis

摘要 类风湿性关节炎（RA）的发病机制涉及适应性（例如T细胞和B细胞）之间的复杂相互作用。 和先天性（例如巨噬细胞）免疫细胞和间充质来源的基质细胞（例如局部成纤维细胞样 滑膜细胞[FLS]）。免疫细胞介导的FLS活化在关节炎症和关节炎中起关键作用。 在RA期间销毁。本项目将探索ILC 2亚群激活FLS的新机制， 先天性淋巴样细胞（ILC）。ILC是最近发现的在外周组织中富集的免疫细胞 并作为抵抗感染和肿瘤的第一道局部屏障。已经确定了ILC的四个主要子集， ILC 1、ILC 2、ILC 3和cNK细胞显示出与Th 1、Th 2和Th 17亚群相似的免疫功能 CD 4 T细胞和CD 8杀伤性T细胞。其中，ILC 2与Th 2细胞同源并分泌 在一些实施方案中，细胞因子是“2型细胞因子”，例如白介素-4（IL-4）、IL-5和IL-13，其驱动“2型”免疫应答。的 2型免疫应答被认为是类风湿关节炎中的抗炎性免疫应答，然而，ILC 2 仅在RA中发挥疾病保护作用。这项赠款的目的是收集试点证据， 通过分泌一种表皮生长因子（EGF）类似的分子， 双调蛋白（AREG）。已知ILC 2分泌AREG，其通常有助于维持组织完整性， 它不仅是对感染的反应，而且还涉及慢性炎症背景下器官纤维化的发病机制。 炎症我们已经在关节炎小鼠的关节中发现了高水平的AREG -主要由ILC 2产生， 有初步证据表明，AREG促进关节炎的严重程度和成纤维细胞样的攻击行为， 滑膜细胞（FLS）。因此，我们假设关节局部ILC 2促进RA的疾病活动 通过产生AREG与FLS相互作用。这项拨款申请提出的实验旨在 获得ILC 2通过产生AREG增强小鼠关节炎发展的严格证据（目的 AREG在体外和体内促进FLS的攻击性和关节破坏性行为（目的2）。的 该项目非常适合R21格式，因为其目标是收集支持概念的试验证据 目前被认为是高风险和潜在的违反直觉，但是，如果得到验证，它可能会铺平道路， 通过干扰ILC 2-AREG-FLS轴来治疗RA的新方法。 .

ABSTRACT The pathogenesis of rheumatoid arthritis (RA) involves a complex interplay between adaptive (e.g. T & B cells) and innate (e.g. macrophages) immune cells and mesenchymal-derived stromal cells (e.g. local fibroblast-like synoviocytes [FLS]). Immune cell-mediated activation of FLS plays a key role in joint inflammation and destruction during RA. This project will explore a novel mechanism of activation of FLS by the ILC2 subset of innate lymphoid cells (ILCs). ILCs are recently discovered immune cells that are enriched in peripheral tissues and act as the first local barrier against infections and tumors. Four major subsets of ILCs have been identified, ILC1, ILC2, ILC3 and cNK cells that display immune functions similar to those of Th1, Th2, and Th17 subsets of CD4 T cells and CD8 killer T cells respectively. Of these, ILC2 are homologous to Th2 cells and secrete “type 2 cytokines” such as interleukin-4 (IL-4), IL-5 and IL-13, which drive a “type 2” immune response. The type 2 immune response is considered to be anti-inflammatory in RA, however it remains unclear whether ILC2 exclusively play a disease protective role in RA. The objective of this grant is to collect pilot evidence that ILC2 play a pathogenic role in RA by secreting an epidermal growth factor (EGF)-similar molecule called amphiregulin (AREG). ILC2 are known to secrete AREG which normally helps to maintain tissue integrity in response to infections, but is also implicated in the pathogenesis of organ fibrosis in the context of chronic inflammation. We have found high levels of AREG -mainly produced by ILC2- in the joints of arthritic mice and have preliminary evidence that AREG promotes arthritis severity and the aggressive behavior of fibroblast-like synoviocytes (FLS) in vitro. We thus hypothesize that joint-localized ILC2 promote disease activity in RA through interaction with FLS via production of AREG. This grant application proposes experiments aimed to obtain rigorous evidence that ILC2 enhance development of arthritis in mice through production of AREG (Aim 1), and that AREG promotes aggressive and joint-destructive behavior in FLS in vitro and in vivo (Aim 2). The project fits well with the R21 format because the objective is to collect pilot evidence in support of a concept that is currently considered high risk and potentially counterintuitive, however, if validated, it might pave the way to novel therapeutic approaches to RA via interference with the ILC2-AREG-FLS axis. .