Blood immunophenotyping identifies distinct kidney histopathology and outcomes in patients with lupus nephritis
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
- Tusharkanti Ghosh (ORCID: https://orcid.org/0000-0002-7537-6374)
- Michael B. Brenner (ORCID: https://orcid.org/0000-0001-6202-8445)
- Arnon Arazi
- Céline C. Berthier (ORCID: https://orcid.org/0000-0003-3539-1075)
- Kenneth Kalunian (ORCID: https://orcid.org/0000-0003-0261-3102)
- Maureen McMahon (ORCID: https://orcid.org/0000-0002-2910-7640)
- William Apruzzese (ORCID: https://orcid.org/0000-0003-4037-6160)
- Alec Griffith (ORCID: https://orcid.org/0000-0002-4289-3017)
- Joshua M. Keegan
- E. Steve Woodle (ORCID: https://orcid.org/0000-0003-4280-0842)
- Jennifer H. Anolik (ORCID: https://orcid.org/0000-0002-1450-1549)
- Takanori Sasaki (ORCID: https://orcid.org/0000-0001-9720-0698)
- Joel M. Guthridge (ORCID: https://orcid.org/0000-0002-9308-237X)
- Maria Dall’Era (ORCID: https://orcid.org/0000-0001-7439-2316)
- Paul Hoover (ORCID: https://orcid.org/0000-0001-5343-429X)
- Nir Hacohen (ORCID: https://orcid.org/0000-0002-2349-2656)
- Fernanda Payan‐Schober
- María Gutiérrez‐Arcelus (ORCID: https://orcid.org/0000-0001-7898-7691)
- David Wofsy (ORCID: https://orcid.org/0000-0001-8350-3428)
- Thomas Eisenhaure (ORCID: https://orcid.org/0000-0003-3999-3540)
- Jun Inamo (ORCID: https://orcid.org/0000-0002-9927-7936)
- Alice Horisberger (ORCID: https://orcid.org/0000-0002-3732-8662)
- Brandon L. Hancock
- Rebecca T. Beuschel (ORCID: https://orcid.org/0000-0002-3882-457X)
- Andrea Fava (ORCID: https://orcid.org/0000-0001-6738-4836)
- Peter Izmirly (ORCID: https://orcid.org/0000-0001-5445-2182)
- Fan Zhang (ORCID: https://orcid.org/0000-0002-6102-2970)
- David A. Hildeman (ORCID: https://orcid.org/0000-0002-0421-8483)
- Jill P. Buyon (ORCID: https://orcid.org/0000-0002-3852-7129)
- Anne Davidson (ORCID: https://orcid.org/0000-0002-4081-6464)
- Eddie A. James (ORCID: https://orcid.org/0000-0002-7217-5729)
- Kaitlyn Howard (ORCID: https://orcid.org/0000-0002-9398-6176)
- Richard Alan Furie (ORCID: https://orcid.org/0000-0001-6712-1585)
- Jennifer L. Barnas (ORCID: https://orcid.org/0000-0002-6033-4403)
- Soumya Raychaudhuri (ORCID: https://orcid.org/0000-0002-1901-8265)
- Diane L. Kamen (ORCID: https://orcid.org/0000-0002-7698-980X)
- Jeffrey B. Hodgin (ORCID: https://orcid.org/0000-0003-0534-3048)
- Deepak A. Rao (ORCID: https://orcid.org/0000-0001-9672-7746)
- Judith A. James (ORCID: https://orcid.org/0000-0002-9574-7355)
- Chaim Putterman (ORCID: https://orcid.org/0000-0002-3204-6068)
- Betty Diamond (ORCID: https://orcid.org/0000-0002-3250-3804)
- Ekaterina Murzin
- Katie Preisinger
- Michelle Petri (ORCID: https://orcid.org/0000-0003-1441-5373)
- Ye Cao (ORCID: https://orcid.org/0000-0002-1654-9060)
- Robert M. Clancy (ORCID: https://orcid.org/0000-0003-1151-0084)
- Dawit Demeke (ORCID: https://orcid.org/0009-0002-0905-178X)
- Jennifer Grossman
- Mariko Ishimori
- John Pulford
- Michael H. Weisman
- Michael Belmont (ORCID: https://orcid.org/0000-0003-3389-2976)
Institutions
- Broad Institute (US)
- Boston University (US)
- Texas Tech University (US)
- Cedars-Sinai Medical Center (US)
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Albert Einstein College of Medicine (US)
- Northwell Health (US)
- Feinstein Institute for Medical Research (US)
- Montefiore Medical Center (US)
- Harvard University (US)
- Johns Hopkins University (US)
- Colorado School of Public Health (US)
- Medical University of South Carolina (US)
- University of California, Los Angeles (US)
- University of California, San Francisco (US)
- University of Michigan (US)
- Johns Hopkins Medicine (US)
- University of Rochester Medical Center (US)
- Oklahoma Medical Research Foundation (US)
- University of California San Diego (US)
- Zefat Academic College (IL)
- University of Colorado Anschutz Medical Campus (US)
- New York University (US)
- University of Cincinnati Medical Center (US)
- Texas Tech University Health Sciences Center (US)
- University of Lausanne (CH)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-06-19
- DOI
- https://doi.org/10.1172/jci181034
- Citations
- 5
- Primary Topic
- Systemic Lupus Erythematosus Research
- Type
- article
- Field-Weighted Citation Impact
- 8.34
Funders
- National Science Foundation
- Bristol-Myers Squibb
- Pfizer
- GlaxoSmithKline
- Sanofi
- Brigham and Women's Hospital
- Rheumatology Research Foundation
- Harvard University
- Harvard Catalyst
- Lupus Research Alliance
- National Research Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Centre Hospitalier Universitaire Vaudois
- National Institutes of Health
- Takeda Pharmaceuticals International
- National Institute of Allergy and Infectious Diseases
- Janssen Research and Development
- National Center for Advancing Translational Sciences