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Th113 - Deep Immunophenotyping Reveals Cellular Phenotypes in Peripheral Blood Associated with Specific Patterns of Kidney Injury in Lupus Nephritis

Thursday, June 22, 2023
7:30 AM – 7:30 PM  
Alec Griffith – Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; Joshua Keegan – Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; Kaitlyn Howard – Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; John Pulford – Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; Ekaterina Murzin – Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; Brandon Hancock – Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; Tusharkanti Ghosh – Colorado School of Public Health, University of Colorado, Anschutz Medical Campus, CO, USA; Takanori Sasaki – Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; Andrea Fava – Johns Hopkins University, Baltimore, MD, USA; Maria Gutierrez-Arcelus – Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Thomas M. Eisenhaure – Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Joel Guthridge – Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Arnon Arazi – The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA; Paul J. Hoover – Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; Maria Dall’Era – University of California San Francisco, San Francisco, CA, USA; David Wofsy – University of California San Francisco, San Francisco, CA, USA; Diane L. Kamen – Medical University of South Carolina, Charleston, SC, USA; Kenneth C. Kalunian – University of California, San Diego School of Medicine, La Jolla, CA, USA; Richard Furie – The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA; Michael Belmont – New York University School of Medicine, New York, NY, USA; Peter Izmirly – New York University School of Medicine, New York, NY, USA; Robert Clancy – New York University School of Medicine, New York, NY, USA; David Hildeman – University of Cincinnati College of Medicine, Cincinnati, OH, USA; Steve Woodle – University of Cincinnati College of Medicine, Cincinnati, OH, USA; William Apruzzese – Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; Maureen A. McMahon – University of California, Los Angeles, CA, USA; Jennifer Grossman – University of California, Los Angeles, CA, USA; Jennifer L. Barnas – University of Rochester Medical Center, Rochester, NY, USA; Fernanda Payan-Schober – Texas Tech University Health Sciences Center, El Paso, TX, USA; Mariko Ishimori – Cedars-Sinai Medical Center, Los Angeles, CA, USA; Michael Weisman – Cedars-Sinai Medical Center, Los Angeles, CA, USA; Matthias Kretzler – University of Michigan, Ann Arbor, MI, USA; Celine C. Berthier – University of Michigan, Ann Arbor, MI, USA; Jeffrey Hodgin – University of Michigan, Ann Arbor, MI, USA; Chaim Putterman – Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA; Nir Hacohen – Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Michael B. Brenner – Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; Jennifer H. Anolik – University of Rochester Medical Center, Rochester, NY, USA; Anne Davidson – The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA; Judith A. James – Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Soumya Raychaudhuri – Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; Michelle A. Petri – Johns Hopkins University, Baltimore, MD, USA; Jill P. Buyon – New York University School of Medicine, New York, NY, USA; Betty Diamond – The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA; The Accelerating Medicines Partnership (AMP) RA/SLE Network – Multiple sites; Fan Zhang – * co-senior author – School of Medicine, University of Colorado, Anschutz Medical Campus, CO, USA; James A. Lederer – * co-senior author – Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; Deepak A. Rao – * co-senior author – Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
Abstract Text: Lupus nephritis (LN) is a severe complication of systemic lupus requiring renal biopsy to guide treatment decisions. Defining LN heterogeneity using a non-invasive approach is a pressing need to improve treatment. We applied mass cytometry using four 48-marker panels to characterize peripheral blood mononuclear cells (PBMC) from 140 patients with biopsy-proven LN and 40 controls enrolled in the Accelerating Medicines Partnership RA/SLE Network. We projected cells in a reduced dimensional space and implemented covarying neighborhood analysis (CNA) to identify cell ‘neighborhoods’ associated with clinical features. Compared to controls, LN patients displayed significant enrichment of cells expressing interferon (IFN)-induced proteins including MX1 and Siglec1, reflecting a cytometric detection of an IFN signature. Comparing patients with proliferative LN (class III/IV+/-V, n=94) versus membranous LN (class V, n=46), we observed enrichment of a specific naive B cell population characterized as CD23- and CD21dim, in proliferative LN patients (p.adj=0.02). These cells were distinct from CD11c+ B cells and were also associated with increased histologic NIH activity index and with anti-dsDNA antibody, even after adjusting for immunosuppression. To further understand LN heterogeneity, we clustered patients and controls based on proportions of immune cell subsets using k-means clustering. We identified two major clusters: cluster1 included only LN patients, and cluster 2 included controls and 26 LN patients. Patients from cluster2 had significantly lower clinical extrarenal activity (p.adj=0.01) and IFN-induced protein expression (p.adj < 0.001) and higher histologic chronicity (p.adj < 0.001). These results nominate potential biomarkers associated with LN heterogeneity and highlight altered naive B cell activation in proliferative LN.