TY - JOUR
T1 - Proximity extension assay proteomics and renal single cell transcriptomics uncover novel urinary biomarkers for active lupus nephritis
AU - Li, Yaxi
AU - Tang, Chenling
AU - Vanarsa, Kamala
AU - Thai, Nga
AU - Castillo, Jessica
AU - Lea, Gabrielle Alexis Braza
AU - Lee, Kyung Hyun
AU - Kim, Soojin
AU - Pedroza, Claudia
AU - Wu, Tianfu
AU - Saxena, Ramesh
AU - Mok, Chi Chiu
AU - Mohan, Chandra
N1 - Publisher Copyright:
© 2024 Elsevier Ltd
PY - 2024/2
Y1 - 2024/2
N2 - Objective: To identify urinary biomarkers that can distinguish active renal involvement in Lupus Nephritis (LN), a severe manifestation of systemic lupus erythematosus (SLE). Methods: Urine from 117 subjects, comprised of inactive SLE, active non-renal lupus, active LN, and healthy controls, were subjected to Proximity Extension Assay (PEA) based comprehensive proteomics followed by ELISA validation in an independent, ethnically diverse cohort. Proteomic data is also cross-referenced to renal transcriptomic data to elucidate cellular origins of biomarkers. Results: Systems biology analyses revealed progressive activation of cytokine signaling, chemokine activity and coagulation pathways, with worsening renal disease. In addition to validating 30 previously reported biomarkers, this study uncovers several novel candidates. Following ELISA validation in an independent cohort of different ethnicity, the six most discriminatory biomarkers for active LN were urinary ICAM-2, FABP4, FASLG, IGFBP-2, SELE and TNFSF13B/BAFF, with ROC AUC ≥80%, with most correlating strongly with clinical disease activity. Transcriptomic analyses of LN kidneys mapped the likely origin of these proteins to intra-renal myeloid cells (CXCL16, IL-1RT2, TNFSF13B/BAFF), T/NK cells (FASLG), leukocytes (ICAM2) and endothelial cells (SELE). Conclusion: In addition to confirming the diagnostic potential of urine ALCAM, CD163, MCP1, SELL, ICAM1, VCAM1, NGAL and TWEAK for active LN, this study adds urine ICAM-2, FABP4, FASLG, IGFBP-2, SELE, and TNFSF13B/BAFF as additional markers that warrant systematic validation in larger cross-sectional and longitudinal cohorts.
AB - Objective: To identify urinary biomarkers that can distinguish active renal involvement in Lupus Nephritis (LN), a severe manifestation of systemic lupus erythematosus (SLE). Methods: Urine from 117 subjects, comprised of inactive SLE, active non-renal lupus, active LN, and healthy controls, were subjected to Proximity Extension Assay (PEA) based comprehensive proteomics followed by ELISA validation in an independent, ethnically diverse cohort. Proteomic data is also cross-referenced to renal transcriptomic data to elucidate cellular origins of biomarkers. Results: Systems biology analyses revealed progressive activation of cytokine signaling, chemokine activity and coagulation pathways, with worsening renal disease. In addition to validating 30 previously reported biomarkers, this study uncovers several novel candidates. Following ELISA validation in an independent cohort of different ethnicity, the six most discriminatory biomarkers for active LN were urinary ICAM-2, FABP4, FASLG, IGFBP-2, SELE and TNFSF13B/BAFF, with ROC AUC ≥80%, with most correlating strongly with clinical disease activity. Transcriptomic analyses of LN kidneys mapped the likely origin of these proteins to intra-renal myeloid cells (CXCL16, IL-1RT2, TNFSF13B/BAFF), T/NK cells (FASLG), leukocytes (ICAM2) and endothelial cells (SELE). Conclusion: In addition to confirming the diagnostic potential of urine ALCAM, CD163, MCP1, SELL, ICAM1, VCAM1, NGAL and TWEAK for active LN, this study adds urine ICAM-2, FABP4, FASLG, IGFBP-2, SELE, and TNFSF13B/BAFF as additional markers that warrant systematic validation in larger cross-sectional and longitudinal cohorts.
KW - Biomarker
KW - Lupus nephritis
KW - Proximity extension assay
KW - Transcriptomics
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U2 - 10.1016/j.jaut.2023.103165
DO - 10.1016/j.jaut.2023.103165
M3 - Article
C2 - 38194790
AN - SCOPUS:85181828780
SN - 0896-8411
VL - 143
JO - Journal of Autoimmunity
JF - Journal of Autoimmunity
M1 - 103165
ER -