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Tubular cell and keratinocyte single-cell transcriptomics in lupus nephritis

Comment on: Tubular cell and keratinocyte single-cell transcriptomics applied to lupus nephritis reveal type I IFN and fibrosis relevant pathways. Dar E, et al. Nat Immunol. 2019;20:915-927.

Commented by: Maria G. Tektonidou, MD, PhD, Associate Professor of Rheumatology. Head of Rheumatology Unit, First Department of Propaedeutic Internal Medicine, School of Medicine, University of Athens, Greece

Growing evidence has shown an increased expression of type I interferon (IFN) signature-regulated genes in blood and tissue cells from patients with SLE and mouse models, and IFN levels have been associated with disease flares in lupus nephritis (LN)(1, 2). Upregulation of IFN- responsive genes in keratinocytes from patients with LN compared with healthy control subjects has also been previously demonstrated (3).

In this study (4), single-cell RNA sequencing (scRNA-seq) was applied to 21 renal biopsies from patients with LN and in skin biopsies from 17 of 21 patients obtained at the time of the renal biopsy as a potential source of diagnostic and prognostic markers of renal disease.

Type I IFN-response genes in tubular cells (p=1.4×10-11) and keratinocytes (p=3.3×10-10) from patients with LN were much more highly expressed than those of healthy control subjects. An IFN-response score was developed for each patient using the tubular expression of IFN- response genes, and it was found that patients who did not respond to treatment had significantly higher IFN-response scores compared with those who were either partial (50% reduction in proteinuria at 6 months post-biopsy) or complete responders (urine protein/creatinine ratio (p=0.04).

Differential expression on tubular cells from patients with proliferative LN (class III or class IV) and those with membranous disease (class V) was performed to determine whether there are specific pathways involved in each class. Pathway enrichment analysis of the upregulated genes in proliferative class disease revealed increased type I IFN and tumor necrosis factor (TNF) family signaling compared with tubular cells from the membranous class.

In addition, an elevated IFN-response signature was also observed in keratinocytes from patients with LN compared with healthy control subjects, indicative of a systemic response to IFN. Keratinocytes from patients with proliferative disease also showed an upregulation of several pathways, including type I IFN signaling and antigen presentation, compared with keratinocytes from membranous disease. It was also found that the tubular IFN-response score at the time of biopsy predicted patient response to treatment 6months after biopsy. The keratinocyte IFN-response score did not significantly predict response to treatment, potentially explained by a weaker signal than that observed in the tubular cells.

The clinical importance of the above observations may include the following:

  • In addition to clinical and renal biopsy predictors, further measures are needed for a better assessment of LN prognosis and treatment decisions.
  • Although tubulointerstitial infiltrates and fibrosis have been recognized as predictors of poor response to treatment and long- term outcomes (5), the underlying mechanisms initiating and promoting fibrosis are not fully understood.
  • Single-cell RNA sequencing (scRNA-seq) yields valuable information about intercellular signaling responses and cell-type- specific pathways that may underlie the histologic heterogeneity of LN and may represent potential prognostic markers (6). The potential adjunctive role of skin biopsies has also been discussed.

References

  1. Elkon KB, et al. Type I interferon and systemic lupus erythematosus. J Interferon Cytokine Res.2011; 31:803–812
  2. Mohan C, Putterman C. Genetics and pathogenesis of systemic lupus erythematosus and lupus nephritis. Nat Rev Nephrol. 2015;11:329–341
  3. Der E, et al. Single cell RNA sequencing to dissect the molecular heterogeneity in lupus nephritis. JCI Insight. 2017 May 4;2(9)
  4. Dar E, et al. Tubular cell and keratinocyte single-cell transcriptomics applied to lupus nephritis reveal type I IFN and fibrosis relevant pathways. Nat Immunol. 2019;20:915-927.
  5. Hsieh C, etal. Predicting outcomes of lupus nephritis with tubulointerstitial infammation and scarring. Arthritis Care Res. (Hoboken) 2011;63:865–874.
  6. Park J, et al. Single-cell transcriptomics of the mouse kidney reveals potential cellular targets of kidney disease. Scienze 2018;360(6390):758-763.

A high burden of SLE risk genes is associated with persistent activation of the interferon system in patients with lupus.

25 May 2026

Comment on: Single-cell RNA-seq reveals a persistent interferon signature in immune cells from  systemic lupus erythematosus patients with high versus low polygenic risk scores despite antimalarial  treatment. J Autoimmun. 2026 May 12:161:103575. doi: 10.1016.  Commented by: Lars Rönnblom, Department of Medical Sciences, Uppsala University, Sweden.    Genome-wide association studies have identified more than 300 loci associated to increased risk for  SLE. For the majority of the gene variants in these loci the functional consequences in the SLE disease  process are unknown. However, a large proportion of identified risk genes are connected to the  interferon signaling pathway and contribute to the interferon signature in SLE. Calculating a polygenic  risk score (PRS) is a method to quantify the cumulative genetic burden in a single patient and studies  have shown that patients with a high PRS have a more severe disease phenotype with increased  organ damage and reduced survival, compared to individuals with a low PRS.   Antimalarial therapy is a well-established treatment of SLE and have shown efficacy in a large  proportion of patients. The therapeutic effect is partly mediated by down regulation of the activated  interferon system, which is connected to clinical response. However, despite therapeutic  concentrations of hydroxychloroquine, many patients still have flares and accumulation of organ  damage. The main objective of the present study was therefore to clarify if antimalarial treatment has  different effects in patients with a high or a low PRS.  SLE patients in remission with a high or a low PRS were compared in gene expression profile at single  cell level on peripheral blood mononuclear cells. A total of 6 healthy controls and 16 matched  patients treated with similar antimalarial doses, but no corticosteroids, were investigated. On  average, 9636 cells were analyzed from each donor and 2724 genes detected per cell. Despite similar  clinical picture, patients with a high PRS had a prominent interferon signature across multiple  immune cell types, compared to patients with a low PRS who had a weak expression of interferon  stimulated genes only in monocytes. Pathway analysis revealed that the interferon signaling pathway 

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