TY - JOUR
T1 - Integrated urine proteomics and renal single-cell genomics identify an IFN-γ response gradient in lupus nephritis
AU - Fava, Andrea
AU - Buyon, Jill
AU - Mohan, Chandra
AU - Zhang, Ting
AU - Belmont, H. Michael
AU - Izmirly, Peter
AU - Clancy, Robert
AU - Trujillo, Jose Monroy
AU - Fine, Derek
AU - Zhang, Yuji
AU - Magder, Laurence
AU - Rao, Deepak A.
AU - Arazi, Arnon
AU - Berthier, Celine C.
AU - Davidson, Anne
AU - Diamond, Betty
AU - Hacohen, Nir
AU - Wofsy, David
AU - Apruzzese, William
AU - Raychaudhuri, Soumya
AU - Petri, Michelle
N1 - Publisher Copyright:
© 2020, American Society for Clinical Investigation.
PY - 2020/6/18
Y1 - 2020/6/18
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.138345
DO - 10.1172/jci.insight.138345
M3 - Article
C2 - 32396533
AN - SCOPUS:85086748812
SN - 2379-3708
VL - 5
JO - JCI Insight
JF - JCI Insight
IS - 12
M1 - 137788
ER -