Urine Proteomics and Renal Single‐Cell Transcriptomics Implicate Interleukin‐16 in Lupus Nephritis

作者：Andrea Fava, Deepak A. Rao, Chandra Mohan, Ting Zhang, Avi Z. Rosenberg, Paride Fenaroli, H. Michael Belmont, Peter Izmirly, Robert M. Clancy, Jose M. Monroy‐Trujillo, Derek M. Fine, Arnon Arazi, Céline C. Berthier, Anne Davidson, Judith A. James, Betty Diamond, Nir Hacohen, David Wofsy, Soumya Raychaudhuri, William Apruzzese, the Accelerating Medicines Partnership in Rheumatoid Arthritis and Systemic Lupus Erythematosus Network, Jill P. Buyon, Michelle Petri · 发表于：Arthritis & Rheumatology · 年份：2021 · DOI：10.1002/art.42023 · 被引用次数：96 · 研究领域：Whipple's Disease and Interleukins、Hypertrophic osteoarthropathy and related conditions、Systemic Lupus Erythematosus Research

OBJECTIVE: Current lupus nephritis (LN) treatments are effective in only 30% of patients, emphasizing the need for novel therapeutic strategies. We undertook this study to develop mechanistic hypotheses and explore novel biomarkers by analyzing the longitudinal urinary proteomic profiles in LN patients undergoing treatment. METHODS: We quantified 1,000 urinary proteins in 30 patients with LN at the time of the diagnostic renal biopsy and after 3, 6, and 12 months. The proteins and molecular pathways detected in the urine proteome were then analyzed with respect to baseline clinical features and longitudinal trajectories. The intrarenal expression of candidate biomarkers was evaluated using single-cell transcriptomics of renal biopsy sections from LN patients. RESULTS: Our analysis revealed multiple biologic pathways, including chemotaxis, neutrophil activation, platelet degranulation, and extracellular matrix organization, which could be noninvasively quantified and monitored in the urine. We identified 237 urinary biomarkers associated with LN, as compared to controls without systemic lupus erythematosus. Interleukin-16 (IL-16), CD163, and transforming growth factor β mirrored intrarenal nephritis activity. Response to treatment was paralleled by a reduction in urinary IL-16, a CD4 ligand with proinflammatory and chemotactic properties. Single-cell RNA sequencing independently demonstrated that IL16 is the second most expressed cytokine by most infiltrating immune cells in L...