Pathogenesis of Systemic Juvenile Idiopathic Arthritis-Associated Lung Disease

系统性幼年特发性关节炎相关肺病的发病机制

• 批准号: 10441762
• 负责人: Grant Sanford Schulert
• 金额: $ 55.16万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-06 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10441762
• 关键词: Affect; Alveolar Macrophages; Anti-Inflammatory Agents; Arthritis; Automobile Driving; Biological; Biological Assay; Biological Models; Biological Products; Biological Response Modifier Therapy; Biology; Bronchoalveolar Lavage Fluid; Cause of Death; Cells; Child; Childhood; Chronic; Clinical; Complication; Data; Data Set; Development; Diagnosis; Disease; Etiology; Experimental Models; Exposure to; Failure; Flow Cytometry; Functional disorder; Gene Expression; Gene Expression Profile; Goals; Immune; Immunobiology; Incidence; Inflammation; Inflammatory; Interferon Type II; Interferons; Interleukin-1; International; Interstitial Lung Diseases; Knowledge; Life; Link; Lung; Lung diseases; Macrophage activation syndrome; Mediator of activation protein; Mission; Modeling; Monoclonal Antibodies; Mus; Nature; Pathogenesis; Pathway interactions; Patients; Phagocytosis; Pharmaceutical Preparations; Phenotype; Population; Public Health; Pulmonary Alveolar Proteinosis; Pulmonary Inflammation; Pulmonology; Recurrence; Reporting; Research; Resolution; Rheumatology; Risk; Role; Signal Transduction; Structure of parenchyma of lung; System; Systemic Therapy; Testing; Translations; United States National Institutes of Health; Work; biomedical referral center; chemokine; clinical care; cohort; cytokine; cytokine release syndrome; experimental study; genetic signature; human disease; human model; in vivo; insight; interstitial; lung development; macrophage; mouse model; novel; novel therapeutics; prevent; prospective; pulmonary function; single-cell RNA sequencing; systemic juvenile idiopathic arthritis; targeted treatment; tool; treatment strategy

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.

项目摘要/摘要