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.

Grant Number: 5P01AI148102-05
NIH Institute/Center: NIH
Principal Investigator: Michael Brenner