Autoimmunity-Associated B Cells in Lupus Nephritis

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PROJECT SUMMARY/ABSTRACT This proposal details a five-year research and career development plan with a scientific focus on autoimmunity-associated B cells (ABC), a subset of cells that is expanded during lupus disease activity and can differentiate into autoantibody-producing plasma cells (PC). These cells are found in the kidneys of lupus nephritis patients. The long-term objective of the study is to understand signals that regulate the development of ABC and autoreactive PC in lupus nephritis patients in hopes of identifying new therapeutic targets. Preliminary data suggest that ABC develop after B cell activation in the presence of interferon-gamma (IFN-γ) and interleukin 21. ABC are hyper-responsive to type III interferon (IFN-λ). PC differentiation can be promoted by IFN-λ in healthy B cells. In this application, Aim 1 will determine how interferon lambda (IFN-λ) promotes ABC differentiation to PC by examining epigenetic and gene expression changes in B cells treated with IFN-λ. Aim 2 will define the relationships between ABC and their cellular neighbors in the renal microenvironment. In particular, the developmental relationship between ABC and other B cells in the kidneys of lupus nephritis patients will be examined using transcriptomic approaches. A gene expression map of the cellular neighbors of ABC and PC in the lupus nephritis renal microenvironment will be created using spatial transcriptomic analysis. This will identify factors that may be promoting the development of autoimmunity in lupus nephritis. This project will allow Dr. Jennifer Barnas, MD, PhD to develop her skill set in molecular techniques such epigenomics, spatial and single cell transcriptomics and biostatistical anlaysis of these large data sets under the mentorship of Dr. Jennifer Anolik, an expert in lupus B cell biology, Dr. Martha Susiarjo, an expert in epigenetic regulation of disease, and Dr. Andrew McDavid, a computational biologist with extensive experience in single- cell analysis of immune cells. Dr. Barnas will use these techniques to develop an independent research program at University of Rochester and apply for NIH R01 funding to study B cell activation pathways and PC development in autoimmune disease. This work will inform the origin of ABCs and establish whether pathways revealed by in vitro studies are functioning in clinically relevant tissue samples.