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IRF5 and Macrophage Activation Syndrome in systemic Juvenile Idiopathic Arthritis

Award Number: R01AR076242
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: 07/24/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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IRF5 and Macrophage Activation Syndrome in systemic Juvenile Idiopathic Arthritis - Project Summary Macrophage Activation Syndrome (MAS) is an acute complication associated with rheumatic diseases. MAS is most commonly seen in patients with systemic juvenile idiopathic arthritis (sJIA) and pediatric lupus, however MAS can develop after viral infections, such as with EBV. MAS involves the accumulation of activated macrophages in the bone marrow, spleen and liver that have phagocytosed red blood cells (RBCs) and leukocytes. MAS is associated with increased inflammatory cytokines, cytopenias such as anemia and thrombocytopenia, and high serum ferritin. In the absence of treatment, MAS can be fatal, and most death in sJIA are due to MAS. Thus, understanding the mechanisms underlying MAS in rheumatic and inflammatory diseases is important for the development of new methods of therapeutic intervention. To identify novel pathways contributing to MAS, we focused on the identification of pathologic macrophages in a mouse model of MAS. As the phagocytosis of RBCs, platelets, and leukocytes can be a major contributor to the acute cytopenia seen in MAS, we reasoned that specialized phagocytes may be involved in disease pathogenesis. We found that chronic signaling via endosomal TLR7 and TLR9 directly induced differentiation of a novel macrophage population termed inflammatory hemophagocytes (iHPC), which differentiated from Ly6Chi monocytes. Transgenic overexpression of TLR7 not only caused the development of iHPC, but also caused a lethal MAS-like disease that could be rescued by iHPC depletion. MAS secondary to sJIA and to viral infection is associated with variants in the gene encoding IRF5, a transcription factor activated downstream of TLR signaling in monocytes and macrophages. Our preliminary data show that IRF5 also participates in TLR7- induced iHPC differentiation both in vitro and in vivo, and that IRF5 is hyper-activated in iHPC in our mouse model of TLR7-induced MAS. The premise of this application is that IRF5 signaling downstream of endosomal TLR7 and TLR9 is a critical component of iHPC differentiation and MAS. In this proposal we will 1) Test the hypothesis that IRF5 is required for iHPC differentiation and disease in a mouse model of TLR7-driven MAS, 2) Determine the mechanisms by which IRF5 participates in iHPC differentiation, and 3) Test the hypothesis that IRF5 is constitutively activated in iHPC and/or monocytes from sJIA patients with MAS. Successful completion of these studies will determine whether IRF5 is a viable therapeutic target for MAS in sJIA and other autoimmune diseases.


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: 2025 ( Subtotal = $0 )
2025	2023	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	5/6/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $960,789 )
2023	2023	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	8/17/2023	SUPPLEMENT FOR EXPANSION	$383,657
2023	2023	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	6/16/2023	NON-COMPETING CONTINUATION	$577,132
														Subtotal = $960,789

Issue Date FY: 2022 ( Subtotal = $577,613 )
2022	2022	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	7/11/2022	NON-COMPETING CONTINUATION	$577,613
														Subtotal = $577,613

Issue Date FY: 2021 ( Subtotal = $571,447 )
2021	2021	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	7/21/2021	NON-COMPETING CONTINUATION	$571,447
														Subtotal = $571,447

Issue Date FY: 2020 ( Subtotal = $589,776 )
2020	2020	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	6/22/2020	NON-COMPETING CONTINUATION	$589,776
														Subtotal = $589,776

Issue Date FY: 2019 ( Subtotal = $609,313 )
2019	2019	BENAROYA RESEARCH INSTITUTE AT VIRGINIA MASON	1201 9TH AVE	SEATTLE	WA	98101	KING	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	7/24/2019	NEW	$609,313
														Subtotal = $609,313

Grand Total All Awards = $3,308,938

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IRF5 and Macrophage Activation Syndrome in systemic Juvenile Idiopathic Arthritis

Award Number: R01AR076242

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: 07/24/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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