Integrated urine proteomics and renal single-cell genomics identify an IFN-γ response gradient in lupus nephritis
Open Access
- 18 June 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 5 (12)
- https://doi.org/10.1172/jci.insight.138345
Abstract
Lupus nephritis, one of the most serious manifestations of systemic lupus erythematosus (SLE), has a heterogeneous clinical and pathological presentation. For example, proliferative nephritis identifies a more aggressive disease class that requires immunosuppression. However, the current classification system relies on the static appearance of histopathological morphology, which does not capture differences in the inflammatory response. Therefore, a biomarker grounded in the disease biology is needed in order to understand the molecular heterogeneity of lupus nephritis and identify immunologic mechanism and pathways. Here, we analyzed the patterns of 1000 urine protein biomarkers in 30 patients with active lupus nephritis. We found that patients stratify over a chemokine gradient inducible by IFN-gamma. Higher values identified patients with proliferative lupus nephritis. After integrating the urine proteomics with the single-cell transcriptomics of kidney biopsies, we observed that the urinary chemokines defining the gradient were predominantly produced by infiltrating CD8(+) T cells, along with natural killer and myeloid cells. The urine chemokine gradient significantly correlated with the number of kidney-infiltrating CD8(+) cells. These findings suggest that urine proteomics can capture the complex biology of the kidney in lupus nephritis. Patient-specific pathways could be noninvasively tracked in the urine in real time, enabling diagnosis and personalized treatment.Funding Information
- Accelerating Medicines Partnership (AMP) Rheumatoid Arthritis and Lupus Network (UH2-AR067676,UH2-AR067677,UH2-AR067679,UH2-AR067681,UH2-AR067685,UH2- AR067688,UH2-AR067689,UH2-AR067690,UH2-AR067691,UH2-AR067694,UM2- AR067678,, AR074096)
- NIH (AR 69572)
This publication has 49 references indexed in Scilit:
- INTERFEROME v2.0: an updated database of annotated interferon-regulated genesNucleic Acids Research, 2012
- Precise probes of type II interferon activity define the origin of interferon signatures in target tissues in rheumatic diseasesProceedings of the National Academy of Sciences of the United States of America, 2012
- American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritisArthritis Care & Research, 2012
- Urinary Vascular Cell Adhesion Molecule, But Not Neutrophil Gelatinase-associated Lipocalin, Is Associated with Lupus NephritisThe Journal of Rheumatology, 2012
- Netting Neutrophils Induce Endothelial Damage, Infiltrate Tissues, and Expose Immunostimulatory Molecules in Systemic Lupus ErythematosusThe Journal of Immunology, 2011
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005
- Coordinate overexpression of interferon‐α–induced genes in systemic lupus erythematosusArthritis & Rheumatism, 2004
- Interferon and Granulopoiesis Signatures in Systemic Lupus Erythematosus BloodThe Journal of Experimental Medicine, 2003
- Cytokine balance in kidney tissue from lupus nephritis patientsRheumatology, 2003
- The combination of polymorphisms within interferon‐γ receptor 1 and receptor 2 associated with the risk of systemic lupus erythematosusFEBS Letters, 1999