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Role of T-bet B cells in rheumatoid arthritis

Award Number: R01AI175212
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/12/2023
PERIOD OF PERFORMANCE END DATE: 10/31/2028

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Role of T-bet B cells in rheumatoid arthritis - Although new treatments have improved outcomes in rheumatoid arthritis (RA), disability remains high, most patients have ongoing disease activity, and lasting remissions are rare. A major gap in the field is the elusive identity of pathogenic cells driving persistent inflammation and bone erosion. Our lab focuses on the identification of pathogenic B cell subsets in RA, which might drive persistent and aggressive disease. We reported that B cells promote bone erosion by RANKL/TNF-mediated differentiation of monocytes to osteoclasts (OCs) and TNF/CCL3- mediated inhibition of osteoblasts (OBs). Importantly, synovial B cells express much higher levels of these bone pathogenic factors. More recently, we identified a subset of B cells expressing the classic T cell lineage defining transcription factor T-bet enriched in the RA synovium and correlating with disease severity and the abundance of SLAMF7 pro-inflammatory monocytes. We find that synovial T-bet B cells express cytokines influencing OCs/OBs, SLAMF7, and the T- bet inducible chemokine receptor CXCR3. Remarkably, mouse B cells lacking T-bet did not activate OCs or inhibit OBs. Based on our results, the central goal of this proposal is to define how T-bet influences synovial B cell states, mediates B cell-driven bone effects on OCs/OBs, and coordinates B cell pathogenic functions in RA target tissue, contributing to joint erosion and synovial inflammation. We hypothesize that T-bet promotes pathogenic B cell functions in the RA synovium via acquisition of a pro-inflammatory cytokine/chemokine program that orchestrates CXCR3-dependent B cell migration to the synovium and enhances SLAMF7-dependent monocyte activation and bone erosion. We will use deeply characterized RA patient cohorts, high- resolution single cell transcriptomic and spatial analysis of joint target tissue, and novel animal models to track T bet B cells and selectively and conditionally delete T-bet in B cells of mice with collagen induced arthritis. The combination of preclinical and translational studies will facilitate the mechanistic interrogation of T-bet B cell functions in RA via 3 SAs: 1) Determine the mechanisms by which B cell T-bet promotes RA joint erosion; 2) Assess how T-bet B cells impact RA synovial monocyte activation; 3) Examine the role of T-bet in B cells during inflammatory- erosive arthritis in mice. By detailing the functional impact of T-bet B cells, innovative treatments targeting their activity may be a novel path towards preventing bone erosion and conferring lasting clinical remissions.


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: 2026 ( Subtotal = $711,221 )
2026	2026	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Allergy and Infectious Diseases Research	000	3	12/23/2025	NON-COMPETING CONTINUATION	$711,221
														Subtotal = $711,221

Issue Date FY: 2025 ( Subtotal = $683,909 )
2025	2025	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Allergy and Infectious Diseases Research	000	2	10/29/2024	NON-COMPETING CONTINUATION	$683,909
														Subtotal = $683,909

Issue Date FY: 2024 ( Subtotal = $689,965 )
2024	2024	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Allergy and Infectious Diseases Research	000	1	12/12/2023	NEW	$620,968
2024	2024	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Allergy and Infectious Diseases Research	001	1	9/3/2024	NEW	$68,997
														Subtotal = $689,965

Grand Total All Awards = $2,085,095

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Role of T-bet B cells in rheumatoid arthritis

Award Number: R01AI175212

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/12/2023

PERIOD OF PERFORMANCE END DATE: 10/31/2028

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