W104 - Inferring Disease Mechanisms in Lupus Nephritis: Lessons from the Accelerating Medicines Partnership (AMP) in SLE Consortium

Paul Hoover – Broad Institute of MIT and Harvard; Thomas Eisenhaure – Broad Institute of MIT and Harvard; Shaun Jackson – University of Washington School of Medicine; Patrick Danaher – NanoString Technologies; Siddarth Gurajala – Brigham and Women’s Hospital; Qian Xiao – Brigham and Women’s Hospital; Jospeh Mears – Brigham and Women’s Hospital; Deepak Rao – Brigham and Women’s Hospital; Celine Berthier – University of Michigan, Ann Arbor; Jeffrey Hodgin – University of Michigan, Ann Arbor; Andrea Fava – Johns Hopkins University; Saori Sakaue – Brigham and Women’s Hospital; William Apruzzese – Brigham and Women’s Hospital; Jennifer Barnas – University of Rochester Medical Center; Derek Fine – Johns Hopkins University; Richard Furie – Feinstein Institutes for Medical Research; David Hildeman – University of Cincinnati College of Medicine; Steve Woodle – University of Cincinnati College of Medicine; Joel Guthridge – Oklahoma Medical Research Foundation; Maria Dall’Era – University of California San Francisco; David Wofsy – University of California San Francisco; Peter Izmirly – New York University School of Medicine; Michael Belmont – New York University School of Medicine; Robert Clancy – New York University School of Medicine; Diane Kamen – Medical University of South Carolina; Chaim Putterman – Albert Einstein College of Medicine and Montefiore Medical Center; Thomas Tuschl – Rockefeller University; Maureen McMahon – University of California Los Angeles; Jennifer Grossman – University of California Los Angeles; Kenneth Kalunian – University of California San Diego School of Medicine; Fernanda Payan-Schober – Texas Tech University Health Sciences Center; Mariko Ishimori – Cedars-Sinai Medical Center; Michael Weisman – Cedars-Sinai Medical Center; Matthias Kretzler – University of Michigan, Ann Arbor; Michael Brenner – Brigham and Women’s Hospital; Soumya Raychaudhuri – Brigham and Women’s Hospital; Judith James – Oklahoma Medical Research Foundation; Jennifer Anolik – University of Rochester Medical Center; Michelle Petri – Johns Hopkins University; Jill Buyon – New York University School of Medicine; Betty Diamond – Feinstein Institutes for Medical Research; Nir Hacohen – Broad Institute of MIT and Harvard; Anne Davidson – Feinstein Institutes for Medical Research

Abstract Text: Gaining insights into the immune mechanisms underlying lupus nephritis (LN) remains a major challenge towards the development of more effective and specific therapies for this potentially fatal disease. We analyzed the single-cell RNA-sequencing data generated as part of the AMP SLE consortium. Kidney biopsies from 156 LN patients and 30 healthy controls were profiled, yielding 73,440 immune cells and 474,873 tissue cells. Our analysis showed that pre-fibrotic disease is dominated by myeloid cells, with an expansion of disease-specific proinflammatory and phagocytic subsets of macrophages, in a manner correlated with disease activity. The emergence of irreversible tissue damage is associated with an increase in the relative frequencies of dendritic cells, B cells, GZMK+CD8+ T cells and memory CD4+ T cells, and a decrease in the interferon response. In vitro experiments, in which cells were stimulated with several different cytokines and lupus-related antigens, and the resulting transcriptional changes were compared to those observed in vivo, suggested that the differentiation of proinflammatory macrophages is driven by TLR7 ligands, while that of phagocytic macrophages is promoted by apoptotic debris. Differential expression analysis of parietal epithelial cells (PECs) identified the upregulation in disease of several receptors whose ligands are expressed by immune cells. Additional analysis suggested that the production of Galectin-9, TWEAK and plasminogen activator, urokinase receptor (PLAUR) by phagocytic macrophages, and of IFNγ by CD8+ T cells, may promote PEC activation, proliferation and migration, leading to glomerulosclerosis. We provide further evidence supporting these predictions by analyzing a spatial transcriptomics dataset of LN samples.