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Differentiation of immune cells and fibrobalsts in inflamed tissue in RA and SLE

Award Number: P01AI148102
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: 06/15/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Differentiation of immune cells and fibrobalsts in inflamed tissue in RA and SLE - ABSTRACT Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are different diseases clinically and the most important tissue damage occurs in joints and kidneys, respectively. Yet, both SLE and RA share a central common theme of adaptive T and B cell interactions that result in autoantibody production. Both tissues develop chronic inflammatory reactions that also include myeloid cell populations, neutrophils and other innate leukocytes. The two diseases cluster in families and share a number of closely related risk alleles suggesting related immune mechanisms. Developing targeted therapies for lupus has been frustrating and while a number of therapies can reduce disease activity in RA, a large unmet need exists in the form of TNF inadequate responders; and there is no cure. Based on the RA/SLE AMP consortium, single cell RNA-seq and CyTOF analysis has phenotypically and transcriptionally identified many unexpected cell types and cell states present in the inflamed kidney in lupus nephritis and RA synovitis. Here, we select a set of important cell populations specific to, or highly enriched in, the involved tissues in both diseases. Given the importance of B cells and antibody production, we focus on the novel subset of age (or autoimmunity) associated B cells (ABC B cells) and B helper T cells including both T follicular helper (Tfh) and the recently discovered T peripheral helper (Tph) T cells in Project 1. The project focuses on defining the relationship of ABC to other B cell populations and examines the role of Tph and Tfh cells in driving ABC B cells and their cross-talk. ABC B cells and Tph/Tfh cells are enriched in both lupus kidney and RA synovium allowing their comparison across diseases. Project 2 examines novel macrophage inflammatory states found in lupus kidney and seeks to define the main activating factors and transcription factors that drive cell state changes to achieve the inflammatory CM4 state that predominates in nephritis. Project 3 examines the fibroblastic stroma that drives inflammation in RA. A population of inflammatory sublining CD90+DR+ fibroblasts is profoundly expanded in RA and implicated in perpetuating inflammation. Project 3 examines the role of a Notch gradient and Notch signaling in driving the differentiation and activation of this population in synovium and kidney and its role in inflammatory arthritis. All 3 projects interact to examine the cell types of interest across diseases, to determine which cells are interacting most closely by integrated imaging analysis. By utilizing the synchronized expert pipelines of the Computational Systems Immunology Core for single cell RNA-seq and image analysis, the data gathered from both diseases and tissues can be effectively compared. All 3 projects focus on determining the drivers and transitions that yield the important cell states that have been discovered directly in the involved tissues. Together, the program will provide new insights into the tissue immunopathology in these human autoimmune diseases and help to unfold new avenues for therapeutic intervention.


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 = $2,491,765 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	5	4/17/2025	NON-COMPETING CONTINUATION	$2,491,765
														Subtotal = $2,491,765

Issue Date FY: 2024 ( Subtotal = $2,491,765 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	4	4/2/2024	NON-COMPETING CONTINUATION	$2,491,765
														Subtotal = $2,491,765

Issue Date FY: 2023 ( Subtotal = $2,491,765 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	3	3/27/2023	NON-COMPETING CONTINUATION	$2,491,765
														Subtotal = $2,491,765

Issue Date FY: 2022 ( Subtotal = $2,491,765 )
2022	2022	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	3/29/2022	NON-COMPETING CONTINUATION	$2,491,765
														Subtotal = $2,491,765

Issue Date FY: 2021 ( Subtotal = $2,511,008 )
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	6/11/2021	NEW	$2,511,008
														Subtotal = $2,511,008

Grand Total All Awards = $12,478,068

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Differentiation of immune cells and fibrobalsts in inflamed tissue in RA and SLE

Award Number: P01AI148102

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: 06/15/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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