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Publications

Journal Article Ahead of print

PubMed: 42055919 DOI: 10.1016/j.ard.2026.03.004

Deep profiling of lupus nephritis kidneys reveals dynamic changes in myeloid cells associated with disease progression.

Ann Rheum Dis

Authors: Paul J Hoover, Thomas M Eisenhaure, Jeffrey Hodgin, William Apruzzese, Joseph Mears, Michael Peters, Tony Jones, Sujal I Shah, Haniya Kamal, Rollin Leavitt, Shaun W Jackson, Patrick Danaher, Deepak A Rao, Qian Xiao, Siddarth Gurajala, Junting Ai, Andrea Fava, Celine C Berthier, Alice Horisberger, Jennifer L Barnas, Peter M Izmirly, H Michael Belmont, Robert Clancy, Richard Furie, Cynthia Aranow, Joel M Guthridge, Maria Dall'Era, David Wofsy, Diane L Kamen, Kenneth C Kalunian, Maureen A McMahon, Jennifer Grossman, Fernanda Payan-Schober, David A Hildeman, E Steve Woodle, Chaim Putterman, Matthias Kretzler, Marcus R Clark, Soumya Raychaudhuri, Judith A James, Jennifer H Anolik, Michelle A Petri, Jill P Buyon, Betty Diamond, Anne Davidson, Nir Hacohen, Arnon Arazi

Affiliations

  • Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
  • Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA; Seattle Children's Research Institute, Seattle, Washington, USA.
  • Bruker Spatial Biology, Seattle, Washington, USA.
  • Department of Medicine, University of Chicago, Chicago, Illinois, USA.
  • Division of Rheumatology, Johns Hopkins University, Baltimore, Maryland, USA.
  • Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
  • Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, New York, USA.
  • Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York, New York, USA.
  • The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, USA.
  • Arthritis & Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
  • Department of Medicine, University of California San Francisco, San Francisco, California, USA.
  • Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
  • Division of Rheumatology, Autoimmunity, and Inflammation, University of California San Diego School of Medicine, La Jolla, California, USA.
  • Department of Medicine, University of California Los Angeles, Los Angeles, California, USA.
  • Department of Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA.
  • Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
  • Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
  • Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, USA.
  • Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, USA.

Abstract

OBJECTIVES

Lupus nephritis (LN) is a common, potentially fatal manifestation of systemic lupus erythematosus. We aimed to gain new insights into the immune responses underlying LN and their relation to the histologic heterogeneity observed in this disease, focusing on myeloid cells.

METHODS

We used single-cell RNA-sequencing (scRNA-seq) data of dissociated kidney samples from 156 patients with LN and 30 healthy individuals. We applied spatial transcriptomics (ST), utilising a gene panel designed to capture all myeloid subsets identified in the scRNA-seq data, to profile kidney samples acquired from 6 patients with LN and 2 controls.

RESULTS

We generated a catalogue of the myeloid subsets found in LN kidneys. Our analyses indicated that an increase in irreversible tissue damage, as measured by the National Institutes of Health chronicity index (CI), is associated with a gradual switch of the local immune response from one dominated by monocytes and macrophages to one featuring expanded CD4 T, GZMK + CD8 T, B, and dendritic cells, with a parallel decrease in the interferon response. In proliferative/mixed LN only, the degree of active inflammation correlates with the expansion of disease-specific macrophage (DMac) subsets, which later contract as the CI increases. Trajectory analysis of the scRNA-seq data suggested that DMacs arise from both infiltrating monocytes and tissue-resident macrophages; this was supported by the ST data, as well as cell cultures. DMacs are implied to interact with parietal epithelial cells, promoting the development of glomerulosclerosis.

CONCLUSIONS

We suggest a detailed picture of the changes in the kidney immune mechanisms in LN as this disease progresses.

MeSH

Cells, Genes, Monocytes, Macrophages, Disease Progression, Lupus Nephritis, Kidney, Myeloid Cells, Immunity, Tissues, Nephritis