Blood immunophenotyping identifies distinct kidney histopathology and outcomes in patients with lupus nephritis
Alice Horisberger, … , James A. Lederer, Deepak A. Rao
Alice Horisberger, … , James A. Lederer, Deepak A. Rao
Published June 19, 2025
Citation Information: J Clin Invest. 2025;135(16):e181034. https://doi.org/10.1172/JCI181034.
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Research Article Autoimmunity Immunology

Blood immunophenotyping identifies distinct kidney histopathology and outcomes in patients with lupus nephritis

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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Figure 2

Association of circulating immune cell subsets with histologic patterns of active LN.

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Association of circulating immune cell subsets with histologic patterns ...
(A) Heatmap showing associations between circulating blood cell types (y axis) and LN histologic patterns (x axis). CNA was used to test for associations, adjusting for demographic factors (age, sex, ethnicity, and race) and history of previous biopsy. Purple and light purple represent global adjusted CNA P values, with asterisks indicating significant local associations (FDR < 0.05). (B–D) B cell associations with LN histologic class (n = 124) (B), NIH renal activity index (n = 111) (C), and glomerular fibrinoid necrosis as defined by the NIH renal activity index (n = 90) (D); C includes a violin plot illustrating contributions of individual B cell clusters to the NIH activity index association. (E) Violin plots depicting selected protein expression levels in specific B cell clusters. (F) Scatterplot showing selected protein expression in B cell clusters B0 and B3. E and F include all subjects (LN = 145, controls = 40). (G) Proportion of B cell cluster B3 (percentage of total B cells) associated with LN histologic class (n = 140), renal activity index (n = 124), complement levels (n = 138), and longitudinal changes in non-responders (n = 19) versus complete responders (n = 23). Cross-sectional analyses used linear models, while longitudinal analyses used mixed-effects models with patients as a random effect. (H) Top correlations between B panel marker expression and the main axis of variation from the NIH activity index B cell association, using Spearman’s ρ correlations. (I) Association of myeloid cells with glomerular fibrinoid necrosis (n = 78). (J) Association of T cells with renal interstitial inflammation (n = 82). (A–D, G, I, and J) All cross-sectional statistical analyses shown were adjusted for demographic factors (age, sex, ethnicity, and race) and history of previous biopsy.