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Pathogenesis of Systemic Juvenile Idiopathic Arthritis-Associated Lung Disease

Award Number: R01AR079524
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/06/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Pathogenesis of Systemic Juvenile Idiopathic Arthritis-Associated Lung Disease - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $474,257 )
2026	2026	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	5/5/2026	NON-COMPETING CONTINUATION	$24,960
2026	2026	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	1/27/2026	NON-COMPETING CONTINUATION	$449,297
														Subtotal = $474,257

Issue Date FY: 2025 ( Subtotal = $525,487 )
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	4/30/2025	NON-COMPETING CONTINUATION	$525,487
														Subtotal = $525,487

Issue Date FY: 2024 ( Subtotal = $528,880 )
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	6/13/2024	NON-COMPETING CONTINUATION	$38,165
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	2/23/2024	NON-COMPETING CONTINUATION	$490,715
														Subtotal = $528,880

Issue Date FY: 2023 ( Subtotal = $547,211 )
2023	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	3/26/2023	NON-COMPETING CONTINUATION	$547,211
														Subtotal = $547,211

Issue Date FY: 2022 ( Subtotal = $551,577 )
2022	2022	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	4/6/2022	NEW	$551,577
														Subtotal = $551,577

Grand Total All Awards = $2,627,412

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Pathogenesis of Systemic Juvenile Idiopathic Arthritis-Associated Lung Disease

Award Number: R01AR079524

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/06/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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