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Impact of Loss-of-function NADPH Oxidase Variants on B cell Activation in SLE

Award Number: R01AR075813
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: 02/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Impact of Loss-of-function NADPH Oxidase Variants on B cell Activation in SLE - Project abstract Genome-wide association studies (GWAS) have identified immune pathways linked to the pathogenesis of systemic lupus erythematosus (SLE). However, despite these insights, our understanding of how individual genetic variants promote autoimmunity remains poor. Loss-of-function mutations in genes of the phagocytic NADPH oxidase complex (NOX2), including NCF1 and NCF2, have been linked with the pathogenesis of SLE and other humoral autoimmune diseases. The current model for how reduced NOX2 activity promotes lupus development focuses on defects in the clearance of apoptotic material by phagocytic myeloid lineages. While myeloid defects likely contribute to disease risk, we hypothesize that a parallel B cell-intrinsic mechanism underlies the profound increase risk of SLE in human carriers of NCF1 and NCF2 variants. In addition to the production of pathogenic autoantibodies, recent studies have demonstrated that B cells can promote lupus pathogenesis by initiating immune tolerance breaks and facilitating the generation of spontaneous germinal centers (GC). The activation of autoreactive B cells in SLE requires B cell-intrinsic expression of the endosomal toll-like receptors TLR7 and TLR9, and our published and preliminary data show that reduced NOX2 activity results in dysregulated endosomal TLR signaling by impacting non-canonical autophagy pathways. Based on these data, we hypothesize that a B cell-specific reduction in NOX2 activity will result in enhanced TLR- dependent GC formation and the development of humoral autoimmunity. We will test this idea via parallel in vivo and in vitro mechanistic studies. In Aim 1, we will test whether B cell-intrinsic deletion NOX2 component genes results in enhanced TLR-dependent GC responses using a well-characterized model of viral infection. In Aim 2, we will study whether reduced NOX2 activity promotes autoantibody production and humoral autoimmunity in murine SLE. Finally, in Aim 3, we will use biochemical and cell imaging approaches to test whether NAPDH oxidase activity impacts B cell TLR signaling and non-canonical autophagy pathways using both murine genetic models and gene-edited human B cells. Together, these studies promise to advance our understanding of lupus pathogenesis and may inform the design of future targeted therapies for human SLE.


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 = $520,458 )
2025	2025	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	1/9/2025	NON-COMPETING CONTINUATION	$482,898
2025	2025	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	5	6/4/2025	NON-COMPETING CONTINUATION	$37,560
2025	2024	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	5/7/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $520,458

Issue Date FY: 2024 ( Subtotal = $581,601 )
2024	2024	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	6/19/2024	NON-COMPETING CONTINUATION	$37,560
2024	2024	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	1/4/2024	NON-COMPETING CONTINUATION	$482,898
2024	2024	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	4	6/24/2024	SUPPLEMENT FOR EXPANSION	$61,143
														Subtotal = $581,601

Issue Date FY: 2023 ( Subtotal = $536,554 )
2023	2023	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	2/28/2023	NON-COMPETING CONTINUATION	$536,554
														Subtotal = $536,554

Issue Date FY: 2022 ( Subtotal = $531,189 )
2022	2022	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	2/22/2022	NON-COMPETING CONTINUATION	$482,897
2022	2022	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	5/24/2022	NON-COMPETING CONTINUATION	$48,292
														Subtotal = $531,189

Issue Date FY: 2021 ( Subtotal = $536,554 )
2021	2021	SEATTLE CHILDREN'S HOSPITAL	4800 SAND PT WAY NE	SEATTLE	WA	98105	KING	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	1/29/2021	NEW	$536,554
														Subtotal = $536,554

Grand Total All Awards = $2,706,356

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Impact of Loss-of-function NADPH Oxidase Variants on B cell Activation in SLE

Award Number: R01AR075813

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: 02/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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