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Citation Information: J Clin Invest. 2025;135(16):e181034. https://doi.org/10.1172/JCI181034.
Abstract
Lupus nephritis (LN) is a frequent manifestation of systemic lupus erythematosus, and fewer than half of patients achieve complete renal response with standard immunosuppressants. Identifying noninvasive, blood-based immune alterations associated with renal injury could aid therapeutic decisions. Here, we used mass cytometry immunophenotyping of peripheral blood mononuclear cells in 145 patients with biopsy-proven LN and 40 healthy controls to evaluate the heterogeneity of immune activation and identify correlates of renal parameters. Unbiased analysis identified 3 immunologically distinct groups of patients that were associated with different patterns of histopathology, renal cell infiltrates, urine proteomic profiles, and treatment response at 1 year. Patients with enriched circulating granzyme B+ T cells showed more active disease and increased numbers of activated CD8+ T cells in the kidney, yet they had the highest likelihood of treatment response. A second group characterized by a high type I interferon signature had a lower likelihood of response to therapy, while a third group appeared immunologically inactive but with chronic renal injuries. The major immunologic axes of variation could be distilled down to 5 simple cytometric parameters that recapitulate several clinical associations, highlighting the potential for blood immunoprofiling to translate to clinically useful noninvasive metrics to assess immune-mediated disease in LN.
Authors
Alice Horisberger, Alec Griffith, Joshua Keegan, Arnon Arazi, John Pulford, Ekaterina Murzin, Kaitlyn Howard, Brandon Hancock, Andrea Fava, Takanori Sasaki, Tusharkanti Ghosh, Jun Inamo, Rebecca Beuschel, Ye Cao, Katie Preisinger, Maria Gutierrez-Arcelus, Thomas M. Eisenhaure, Joel Guthridge, Paul J. Hoover, Maria Dall’Era, David Wofsy, Diane L. Kamen, Kenneth C. Kalunian, Richard Furie, Michael Belmont, Peter Izmirly, Robert Clancy, David Hildeman, E. Steve Woodle, William Apruzzese, Maureen A. McMahon, Jennifer Grossman, Jennifer L. Barnas, Fernanda Payan-Schober, Mariko Ishimori, Michael Weisman, Matthias Kretzler, Celine C. Berthier, Jeffrey B. Hodgin, Dawit S. Demeke, Chaim Putterman, Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Network, Michael B. Brenner, Jennifer H. Anolik, Soumya Raychaudhuri, Nir Hacohen, Judith A. James, Anne Davidson, Michelle A. Petri, Jill P. Buyon, Betty Diamond, Fan Zhang, James A. Lederer, Deepak A. Rao
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