Pathogenesis of Systemic Juvenile Idiopathic Arthritis-Associated Lung Disease

项目摘要/摘要 严重肺部疾病是系统性青少年特发性的一种日益公认的危及生命的并发症 关节炎(SJIA-LD)，代表一种独特的高度炎症性间质性肺部疾病， 每20名儿童中就有1名患有SJIA。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)，由干扰素γ驱动的SJIA发作性全身性炎症 (干扰素γ)。我们最近报道了SJIA-LD和MAS具有干扰素γ激活的显著特征，支持 该通路在SJIA-LD发病机制中起关键作用。然而，干扰素γ激活的机制 SJIA-LD对肺部炎症的驱动作用尚不清楚。此外，广泛使用的抗IL-1治疗对 SJIA与SJIA-LD发病率显著增加有关，包括明显的临床特征和 肺泡蛋白沉积症(PAP)的发生。我们建议的研究提供了关键的一步来确定 SJIA-LD的机制原因，为制定有针对性的治疗策略的必要步骤 最终阻止SJIA-LD。本应用程序的目标是定义MAS和 持续性干扰素γ是SJIA-LD发病机制之一。因此，我们要检验的中心假设是 持续干扰素γ途径激活导致肺泡巨噬细胞功能障碍和肺组织炎症 并通过抗IL-1生物疗法扩增。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久性干扰素γ对肺组织的影响的方法 炎症，以及IL-1信号对肺泡巨噬细胞功能表型的要求。同时， 我们将确定干扰素γ驱动的肺泡巨噬细胞功能极化表型。 特异性目标1将确定持续的干扰素γ激活是否是肺部炎症的关键驱动因素 玛斯。我们假设在慢性/复发性大脑中动脉粥样硬化期间持续的干扰素γ激活导致了 小鼠的肺部疾病。特异性目标2将确定肺泡巨噬细胞重编程的机制 实验性多智能体系统。我们假设IL-1在大脑中动脉闭塞期间持续的干扰素γ激活过程中起阻断作用。 肺泡巨噬细胞重新编程为炎症表型并抑制抗炎/分解 和内环境平衡功能。特异性目标3将确定儿童干扰素γ驱动的肺泡巨噬细胞群 与SJIA-LD合作。我们假设肺泡巨噬细胞亚群表现为干扰素γ驱动的炎症。 妨碍正常内环境平衡功能的表型。我们预计，拟议的实验将定义 持续性干扰素γ激活和IL-1阻断在肺部炎症和肺泡炎中的作用 MAS和SJIA-LD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的病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.