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Investigating Mucosal Breaks in the Initiation and Progression of Rheumatoid Arthritis

Award Number: R01AR078268
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Investigating Mucosal Breaks in the Initiation and Progression of Rheumatoid Arthritis - Rheumatoid arthritis (RA) is an autoimmune synovitis that affects 0.5% of the world population. RA is characterized by intermittent flares of clinical arthritis that is thought to be mediated in part by anti- citrullinated protein autoimmune responses. The best established environmental risk factors for developing RA include cigarette smoking and periodontal disease, suggesting oral mucosa is a critical site for disease initiation. Nevertheless, the mechanisms by which these environmental exposures lead to RA development and progression remain poorly understood. We have established a clinical and technical protocol for repeated home finger stick blood collection in RA patients to allow for longitudinal RNA sequencing (RNAseq). Using this novel approach, we recently discovered bacteria characteristic of human oral mucosa in the blood of anti-CCP+ RA patients, followed by activation of a signature B cell immune response 3 weeks later, and then clinical flare of disease activity 2 weeks after that. We also investigated B cell responses to these pathogens. We demonstrated elevations in IgA blood plasmablasts both in pre-clinical RA as well as in established RA, with the continual re-activation of a distinct set of IgA/IgG plasmablast clonal families in established RA suggesting a persistent mucosally-driven germinal center reaction. We demonstrate that the recombinant Mabs encoded by the persistently reactivated IgA/G plamablast clonal families encode antibodies that react with both human citrullinated antigens and citrullinated isoforms of oral bacteria identified in the blood of patients antecedent to flares. We anticipate that RA plasmablast Mabs with distinct specificities, either alone or in immune complexes, mediate activation of distinct cellular responses that promote synovitis and tissue destruction in RA. This R01 proposal will test the hypothesis that mucosal breaks trigger plasmablast responses that encode anti-bacterial antibodies that cross-react with host citrullinated antigens. We further hypothesize that mucosal bacteria-induced ACPA activate cellular responses, including macrophage TNF production, NETosis and osteoclast activation, which promote synovitis and joint tissue destruction in RA. Aim 1 will identify the antibody repertoires responsive to pre-flare bacteremia in two independent cohorts of RA patients. Aim 2 will characterize RA plasmablast IgA/G Mabs and sera for reactivity to citrullinated isoforms of bacterial species derived from subgingival collections. Aim 3 will characterize periodontitis tissue for evidence of RA-related autoimmunity. Aim 4 will determine the mechanisms by which cross reactive Mabs, either alone or in immune complexes, mediate arthritis. Success of this proposal would demonstrate that citrullinated periodontal bacteria and mucosal breaks play a key role in mediating RA flare, findings that could lead to development of new diagnostic and therapeutic approaches.


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 = $581,707 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	4/29/2025	NON-COMPETING CONTINUATION	$581,707
														Subtotal = $581,707

Issue Date FY: 2024 ( Subtotal = $593,790 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	6/6/2024	NON-COMPETING CONTINUATION	$42,851
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	5/2/2024	NON-COMPETING CONTINUATION	$550,939
														Subtotal = $593,790

Issue Date FY: 2023 ( Subtotal = $624,190 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	4/19/2023	NON-COMPETING CONTINUATION	$624,190
														Subtotal = $624,190

Issue Date FY: 2022 ( Subtotal = $629,632 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	4/29/2022	NON-COMPETING CONTINUATION	$629,632
														Subtotal = $629,632

Issue Date FY: 2021 ( Subtotal = $661,782 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	6/23/2021	NEW	$661,782
														Subtotal = $661,782

Grand Total All Awards = $3,091,101

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Investigating Mucosal Breaks in the Initiation and Progression of Rheumatoid Arthritis

Award Number: R01AR078268

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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