# Pathogenesis of Systemic Juvenile Idiopathic Arthritis-Associated Lung Disease

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $528,880

## Abstract

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 deve...

## Key facts

- **NIH application ID:** 10815635
- **Project number:** 5R01AR079524-03
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Grant Sanford Schulert
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $528,880
- **Award type:** 5
- **Project period:** 2022-04-06 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10815635

## Citation

> US National Institutes of Health, RePORTER application 10815635, Pathogenesis of Systemic Juvenile Idiopathic Arthritis-Associated Lung Disease (5R01AR079524-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10815635. Licensed CC0.

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