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Mechanisms of DNA-Specific Autoimmunity in Systemic Lupus Erythematosus

Award Number: R01AR071703
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: 06/01/2018
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Mechanisms of DNA-Specific Autoimmunity in Systemic Lupus Erythematosus - PROJECT SUMMARY/ABSTRACT The hallmark of systemic lupus erythematosus (SLE) is the production of antibodies (Abs) to nuclear antigens such as ribonucleoproteins and chromatin. High-affinity IgG Abs to double-stranded DNA (dsDNA) are associated with more severe disease and the development of lupus nephritis (LN). DNASE1L3 is a unique secreted DNase that is capable of digesting DNA packaged in chromatin, and null mutations in human DNASE1L3 cause monogenic early-onset SLE with anti-DNA reactivity. Similar to humans, DNASE1L3-deficient mice rapidly develop Abs to chromatin and dsDNA. Our analysis of this model revealed that the anti-DNA Ab response arises from the short-lived extrafollicular plasmablasts supported by the extrafollicular helper T cell (EF-TFH) subset. Confirming the relevance of DNASE1L3 to human patients with sporadic SLE, we demonstrated that many SLE patients with LN have reduced DNASE1L3 activity, which is associated with the presence of blocking Abs to DNASE1L3. These results suggest that by blocking D1L3, anti-D1L3 Abs facilitate autoreactivity to chromatin and thereby contribute to SLE pathogenesis. In this cycle of the award, these advances will be leveraged to dissect the mechanisms and clinical consequences of anti-DNA responses in SLE patients with autoantibody-mediated D1L3 deficiency. The project will continue the team effort that includes experimental immunology (Reizis), human SLE phenotyping and biobanking (Buyon), and immune repertoires analysis (Ippolito). In Aim 1, we will further characterize the dynamics and clinical correlates of anti-DNASE1L3 Abs in SLE patients, and analyze their role in the control of cell-free DNA. In Aim 2, we will clone anti-DNASE1L3 Abs from SLE patients and analyze their reactivity spectrum and pathogenic potential in vivo. In Aim 3, we will use single-cell TCR sequencing to characterize the autoreactive T cell clones in SLE patients with Ab-mediated blockade of DNASE1L3, and in DNASE1L3-deficient mice. Collectively, these studies should provide insights into the origin and mechanisms of the pathogenic anti-DNA responses in SLE, and facilitate more targeted approaches towards their therapeutic blockade.


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 = $629,341 )
2025	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	7	3/24/2025	NON-COMPETING CONTINUATION	$629,341
2025	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	6	2/25/2025	COMPETING CONTINUATION	$11,800
2025	2022	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	2/25/2025	NON-COMPETING CONTINUATION	-$11,800
														Subtotal = $629,341

Issue Date FY: 2024 ( Subtotal = $717,625 )
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	6	6/26/2024	COMPETING CONTINUATION	$0
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	3/27/2024	COMPETING CONTINUATION	$717,625
														Subtotal = $717,625

Issue Date FY: 2022 ( Subtotal = $493,805 )
2022	2022	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	5/3/2022	NON-COMPETING CONTINUATION	$44,894
2022	2022	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	3/24/2022	NON-COMPETING CONTINUATION	$448,911
														Subtotal = $493,805

Issue Date FY: 2021 ( Subtotal = $481,823 )
2021	2021	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	6/7/2021	NON-COMPETING CONTINUATION	$34,770
2021	2021	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	3/18/2021	NON-COMPETING CONTINUATION	$447,053
														Subtotal = $481,823

Issue Date FY: 2020 ( Subtotal = $496,333 )
2020	2020	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	4/21/2020	NON-COMPETING CONTINUATION	$496,333
														Subtotal = $496,333

Issue Date FY: 2019 ( Subtotal = $494,008 )
2019	2019	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	5/21/2019	NON-COMPETING CONTINUATION	$494,008
														Subtotal = $494,008

Issue Date FY: 2018 ( Subtotal = $508,116 )
2018	2018	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	6/1/2018	NEW	$508,116
														Subtotal = $508,116

Grand Total All Awards = $3,821,051

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Mechanisms of DNA-Specific Autoimmunity in Systemic Lupus Erythematosus

Award Number: R01AR071703

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: 06/01/2018

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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