Insights from Comparison of the Renal and Skin Single Cell Transcriptomes in Lupus Nephritis

Abstract

Lupus nephritis (LN) occurs in up to 50% of patients with systemic lupus erythematosus (SLE), and is a major contributor to mortality and morbidity. LN presents as a highly heterogeneous disease both in histopathology and response to therapy. The molecular and cellular processes leading to renal damage and to the heterogeneity of the disease are not well understood. To elucidate the processes underpinning the heterogeneity of LN, we applied singlecell RNA-sequencing (scRNA-seq) to renal biopsies from LN patients. Skin biopsies were evaluated as a source of biomarkers for monitoring kidney disease. Type-I interferon (IFN) response signatures were identified in tubular cells and keratinocytes, differentiating LN patients from healthy controls. Non-responders associated with higher IFN signatures in both tissue compartments. Moreover, non-response was also associated with a fibrotic signature in the tubular cells. Receptor-ligand interaction analysis indicated that the fibrotic process is likely mediated by FGF receptors with the initiating signal originating from infiltrating leukocytes. Differential expression analysis of tubular cells between proliferative and membranous LN pointed to several fibrosis-relevant pathways, which may offer insight into their histological differences. In summary, scRNA-seq was applied to LN to deconstruct its heterogeneity and provide novel targets for personalized approaches to therapy.

Accelerating Medicines Partnership: Organizational Structure and Preliminary Data From the Phase 1 Studies of Lupus Nephritis

“…Preliminary analysis of small numbers of LN patients with available follow-up data found that tubular cells from patients who did not respond to conventional therapy at 6 months post biopsy showed a higher IFN score and increased expression of genes encoding extracellular matrix (ECM) proteins and ECM interaction proteins, suggesting a fibrotic process. A trend toward up-regulation of both ECM pathways was also observed in keratinocytes of nonresponders (32). Exploration of the cellular interactions between various cell types in the kidney and skin suggest that the fibrotic process may be mediated through fibroblast growth factor receptors on the tubular cells whose ligand is expressed in leukocytes.…”

Latent factor modelling of scRNA-seq data uncovers novel pathways dysregulated in cell subsets of autoimmune disease patients

“…Single-cell RNA-sequencing (scRNA-seq) is a powerful technique that enables gene expression measurements in thousands of individual cells. Resolving cellular heterogeneity by scRNA-seq has enabled groundbreaking discovery in the biomedical domain, such as finding key disease drivers in cancer 1-3 , neurodegeneration 4,5 and immune-mediated diseases [6][7][8][9] . From a data analysis standpoint, a crucial step in a standard scRNA-seq pipeline 10 is clustering, where discrete cell populations sharing a common transcriptional profile are defined.…”