Pathogenesis of Systemic Juvenile Idiopathic Arthritis-Associated Lung Disease

项目概要/摘要 严重肺部疾病是一种日益被认识到的危及生命的全身性青少年特发性并发症 关节炎（SJIA-LD），代表一种独特的高度炎症性间质性肺病， 每20名SJIA儿童中就有1名。虽然SJIA-LD的病因尚不清楚，但它与巨噬细胞密切相关。 激活综合征（MAS），干扰素γ驱动的SJIA发作性全身性炎症过度 (IFNγ）。我们最近报道，SJIA-LD和MAS具有IFNγ激活的显著特征，支持 该通路在SJIA-LD发病机制中的关键作用。然而，IFNγ激活的机制 驱动SJIA-LD中的肺部炎症的因素尚未探索。此外，抗IL-1疗法的广泛使用， SJIA与SJIA-LD的发生率显著增加有关，包括不同的临床特征， 肺泡蛋白沉积症（PAP）。我们提出的研究提供了一个关键步骤，以确定 SJIA-LD的机制性原因，是制定针对性治疗策略的必要步骤， 最终预防SJIA-LD。本申请的目的是定义MAS和 持续的IFNγ驱动SJIA-LD的发病机制。因此，我们要检验的中心假设是， 持续性IFNγ通路激活导致SJIA-LD肺泡巨噬细胞功能障碍和肺部炎症 并且通过抗IL-1生物治疗而被放大。为了研究SJIA-LD的机制，我们将利用重叠 在我们建立的小鼠模型系统中，直接测试持续性IFNγ对肺组织的影响， 炎症，以及肺泡巨噬细胞功能表型对IL-1信号传导的需求。同时， 我们将确定IFNγ驱动的SJIA-LD患儿肺泡巨噬细胞功能极化表型。 特异性目标1将确定持续的IFNγ激活是否是肺炎症的关键驱动因素， MAS。我们假设在慢性/复发性MAS中持续的IFNγ激活导致了 小鼠的肺部疾病。具体目标2将确定肺泡巨噬细胞重编程的机制， 实验MAS我们假设在MAS期间持续IFNγ激活的情况下，IL-1阻断 将肺泡巨噬细胞重编程为炎症表型并抑制抗炎/消退 和自我平衡功能。具体目标3将定义儿童中IFNγ驱动的肺泡巨噬细胞群 关于SJIA-LD我们假设SJIA-LD中肺泡巨噬细胞亚群显示IFNγ驱动的炎症反应， 阻止正常稳态功能的表型。我们预计，拟议的实验将定义 持续的IFNγ激活和IL-1阻断作为肺部炎症和肺泡炎的驱动因素的功能 MAS和SJIA-LD中的巨噬细胞功能障碍。这些研究将共同推进我们的长期目标， 确定SJIA-LD的原因并开发新的治疗方法。

PROJECT SUMMARY / ABSTRACT Severe lung disease is an increasingly recognized life-threatening complication of systemic juvenile idiopathic arthritis (SJIA-LD), representing a distinct and highly inflammatory interstitial lung disease that affects as many as 1 in 20 children with SJIA. While the etiology of SJIA-LD is unknown, it is strongly linked to macrophage activation syndrome, (MAS), episodic systemic hyperinflammation with SJIA that is driven by interferon gamma (IFNγ). We recently reported that SJIA-LD and MAS share prominent features of IFNγ activation, supporting a key role for this pathway in the pathogenesis of SJIA-LD. However, the mechanisms by which IFNγ activation drives pulmonary inflammation in SJIA-LD is unexplored. In addition, the widespread use of anti-IL-1 therapy for SJIA has been linked to markedly increased incidence of SJIA-LD including distinct clinical features and development of pulmonary alveolar proteinosis (PAP). Our proposed studies provide a critical step to identify the mechanistic causes of SJIA-LD, a necessary step towards developing targeted treatment strategies for and ultimately to prevent SJIA-LD. The objective of this application is to define the mechanisms by which MAS and persistent IFNγ drive the pathogenesis of SJIA-LD. Accordingly, our central hypothesis to be tested is that persistent IFNγ pathway activation leads to alveolar macrophage dysfunction and lung inflammation in SJIA-LD and is amplified by anti-IL-1 biologic therapy. To study the mechanisms of SJIA-LD, we will utilize overlapping approaches in our established mouse model system to directly test effects of persistent IFNγ on pulmonary inflammation, and the requirement of IL-1 signaling for alveolar macrophage functional phenotypes. In parallel, we will define IFNγ-driven functional polarization phenotypes of alveolar macrophages in children with SJIA-LD. Specific Aim 1 will determine whether persistent IFNγ activation is the key driver of lung inflammation during MAS. We hypothesize that persistent IFNγ activation during chronic/recurrent MAS leads to the development of lung disease in mice. Specific Aim 2 will identify mechanisms of alveolar macrophage reprogramming in experimental MAS. We hypothesize that IL-1 blockade in the setting of persistent IFNγ activation during MAS reprograms alveolar macrophages towards inflammatory phenotypes and inhibits anti-inflammatory/resolution and homeostatic functions. Specific Aim 3 will define IFNγ-driven alveolar macrophage populations in children with SJIA-LD. We hypothesize that alveolar macrophage subsets in SJIA-LD display an IFNγ-driven inflammatory phenotype that prevents normal homeostatic functions. We anticipate that the proposed experiments will define the function of persistent IFNγ activation and IL-1 blockade as drivers of lung inflammation and alveolar macrophage dysfunction in MAS and SJIA-LD. Together these studies will advance our long-term goal of identifying the causes of and developing novel treatment approaches for SJIA-LD.