Assistant Professor The Feinstein Institutes for Medical Research ACTON, Massachusetts, United States
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.
