Integrated urine proteomics and renal single-cell genomics identify an IFN-γ response gradient in lupus nephritis

Andrea Fava, Jill Buyon, Chandra Mohan, Ting Zhang, H. Michael Belmont, Peter Izmirly, Robert Clancy, Jose Monroy Trujillo, Derek Fine, Yuji Zhang, Laurence Magder, Deepak A. Rao, Arnon Arazi, Celine C. Berthier, Anne Davidson, Betty Diamond, Nir Hacohen, David Wofsy, William Apruzzese, Soumya RaychaudhuriMichelle Petri

Research output: Contribution to journalArticlepeer-review

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-γ. 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.

Original languageEnglish (US)
Article number137788
JournalJCI Insight
Volume5
Issue number12
DOIs
StatePublished - Jun 18 2020

ASJC Scopus subject areas

  • Medicine(all)

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