Immune Cell Heterogeneity in Lupus Nephritis Kidneys and Its Relation to Histopathological Features

Arnon Arazi¹, Joseph Mears², Thomas Eisenhaure³, Qian Xiao⁴, Paul Hoover⁴, Deepak Rao⁴, Celine Berthier⁵, Andrea Fava⁶, Siddarth Gurajala⁴, Michael Peters³, Tony Jones³, William Apruzzese⁴, Jennifer Barnas⁷, Richard Furie⁸, Anne Davidson⁹, David Hildeman¹⁰, Judith James¹¹, Joel Guthridge¹¹, Maria Dall'Era¹², David Wofsy¹³, Peter Izmirly¹⁴, H Michael Belmont¹⁵, Robert Clancy¹⁴, Diane Kamen¹⁶, Chaim Putterman¹⁷, Thomas Tuschl¹⁸, Maureen McMahon¹⁹, Jennifer Grossman¹⁹, Kenneth Kalunian²⁰, Michael Weisman²¹, Matthias Kretzler⁵, Michael Brenner²², Jennifer Anolik²³, Michelle Petri²⁴, Jill Buyon¹⁴, Soumya Raychaudhuri⁴, Nir Hacohen³, Betty Diamond⁹ and the Accelerating Medicines Partnership RA/SLE Network³, ¹Feinstein Institutes for Medical Research, Melrose, MA, ²Michigan University, Ann Arbor, MI, ³Broad Institute, Cambridge, MA, ⁴Brigham and Women's Hospital, Boston, MA, ⁵University of Michigan, Ann Arbor, MI, ⁶Johns Hopkins University, Baltimore, MD, ⁷University of Rochester, Rochester, NY, ⁸Northwell Health, Great Neck, NY, ⁹Feinstein Institutes for Medical Research, Manhasset, NY, ¹⁰Cincinnati Children's Hospital, Cincinnati, OH, ¹¹Oklahoma Medical Research Foundation, Oklahoma City, OK, ¹²University of California, Division of Rheumatology, San Francisco, CA, ¹³University of California San Francisco, SF, CA, ¹⁴NYU Grossman School of Medicine, New York, NY, ¹⁵NYU School of Medicine, New York, NY, ¹⁶Medical University of South Carolina, Charleston, SC, ¹⁷Albert Einstein College of Medicine, Bronx, NY, ¹⁸Rockefeller University, New York, NY, ¹⁹University of California Los Angeles, Los Angeles, CA, ²⁰University of California San Diego, La Jolla, CA, ²¹Adjunct Professor of Medicine, Stanford University; Distinguished Professor of Medicine Emeritus, David Geffen School of Medicine at UCLA, Los Angeles, CA, ²²Brigham and Women's Hospital, Harvard Medical School, Boston, MA, ²³University of Rochester Medical Center, Rochester, NY, ²⁴Johns Hopkins University School of Medicine, Division of Rheumatology, Baltimore, MD

Meeting: ACR Convergence 2022

Keywords: autoimmune diseases, Bioinformatics, Lupus nephritis, Systemic lupus erythematosus (SLE), Systems-based Studies

Session Information

Date: Sunday, November 13, 2022

Title: SLE – Etiology and Pathogenesis Poster

Session Type: Poster Session B

Session Time: 9:00AM-10:30AM

Background/Purpose: Lupus nephritis (LN) is characterized by considerable variability in its clinical manifestations and histopathological findings. Understanding the cellular and molecular mechanisms underlying this heterogeneity is key for the development of personalized treatments for LN.

Methods: Droplet-based single-cell RNA-sequencing was applied to the analysis of dissociated kidney samples, collected from 155 LN patients with active kidney disease and 30 living donor controls as part of a large-scale, multi-center study. 73,440 immune cells passing quality control were identified, spanning 134 cell subsets, representing various populations of tissue-resident and infiltrating leukocytes, as well as the activation states these cells assume as part of their disease-related activation and differentiation (Fig. 1). Principal component analysis (PCA) was used to characterize the variability in cell subset frequencies across the LN patients. Relationships between the resulting principal components (PCs) and the demographic, clinical and histopathological features of the patients were then assessed.

Results: The first PC (PC1), explaining 33% of the total variability in cell subset frequencies, reflected the balance between lymphocytes and monocytes/macrophages. The second PC (PC2), explaining an additional 21% of the total variability, represented the degree of macrophage differentiation to an alternatively activated phagocytic profile. The third and fourth PCs, bringing the total explained variability to 74%, were related to the balance between cell-mediated and humoral immune responses. PC1 was significantly correlated with the Chronicity index, such that patients with a higher percentage of lymphocytes compared to monocytes/macrophages had a higher Chronicity score (rho = -0.439, p-value < 0.001; Fig. 2A). A high degree of macrophage differentiation, as represented by PC2, was associated with a high Activity score (rho = -0.495, p-value < 0.001; Fig. 2B), and, in addition, with proliferative or mixed histology class, compared to pure membranous nephritis (p-value = 0.001, Kruskal–Wallis test). We further identified a significant correlation of these PCs with age; specifically, older patients had a higher relative frequency of lymphocytes compared to monocytes/macrophages, a lesser degree of macrophage differentiation, and a higher representation of cells putatively involved in a humoral immune response compared to a cell-mediated one.

Conclusion: These results identify distinct leukocyte populations active in different LN patients and, possibly, different stages of disease, and suggest potential therapeutic targets, that must be validated in mechanistic studies. This approach may pave the way to personalized treatment of LN.

Figure 1. Single-cell RNA-sequencing was used to profile immune cells isolated from the kidneys of LN patients and healthy controls. Five main lineages of cells were identified, as shown in a Uniform Manifold Approximation and Projection (UMAP) plot: myeloid cells, T/NK cells, B cells, plasma cells and dividing cells. The cells of each lineage were further split into finer subsets of cells (color-coded).

Figure 2. PCA was used to characterize the variability in cell subset frequencies across LN patients. (A) The first PC, representing the balance between lymphoid cells and monocytes/macrophages, was found to be significantly correlated with the Chronicity index. (B) The second PC, representing the degree of macrophage differentiation, was found to be significantly correlated with the Activity index. Shown in each case are the Spearman correlation and its associated p-value.

Disclosures: A. Arazi, None; J. Mears, None; T. Eisenhaure, None; Q. Xiao, None; P. Hoover, Sanofi, Third Rock Ventures; D. Rao, Janssen, Merck, Bristol-Myers Squibb, Scipher Medicine, HiFiBio, Inc., AstraZeneca, Pfizer; C. Berthier, None; A. Fava, Sanofi; S. Gurajala, None; M. Peters, None; T. Jones, None; W. Apruzzese, None; J. Barnas, None; R. Furie, AstraZeneca, Biogen; A. Davidson, None; D. Hildeman, None; J. James, Bristol-Myers Squibb(BMS), AstraZeneca, Novartis, Progentec Biosciences; J. Guthridge, None; M. Dall'Era, GlaxoSmithKline (GSK), AstraZeneca, Aurinia, BMS, Amgen; D. Wofsy, None; P. Izmirly, Momenta/Janssen; H. Belmont, None; R. Clancy, None; D. Kamen, None; C. Putterman, Equillium, Progentec, Kidneycure; T. Tuschl, None; M. McMahon, None; J. Grossman, None; K. Kalunian, AbbVie/Abbott, Amgen, AstraZeneca, Aurinia, Biogen, Bristol Myers Squibb (BMS), Eli Lilly, Equillium, Genentech, Gilead, Janssen, Roche, Lupus Research Alliance, Pfizer, Sanford Consortium, Viela, Nektar; M. Weisman, None; M. Kretzler, AstraZeneca, NovoNordisc, Eli Lilly, Gilead, Janssen, Boehringer Ingelheim, Moderna, Certa, Chinook, Angion, Travere, Regeneron, Ionis; M. Brenner, GSK, 4FO Ventures, Mestag Therapeutics; J. Anolik, None; M. Petri, Exagen, AstraZeneca, Alexion, Amgen, AnaptysBio, Argenx, Aurinia, Biogen, Caribou Biosciences, CVS Health, EMD Serono, Eli Lilly, Emergent Biosolutions, GlaxoSmithKline (GSK), IQVIA, Janssen, Kira Pharmaceuticals, MedShr, Sanofi, SinoMab, Thermofisher, BPR Scientific Advisory Committee; J. Buyon, None; S. Raychaudhuri, Mestag, Inc, Rheos Medicines, Janssen, Pfizer, Biogen; N. Hacohen, DangerBio/Related Sciences; B. Diamond, None; t. RA/SLE Network, None.

To cite this abstract in AMA style:

Arazi A, Mears J, Eisenhaure T, Xiao Q, Hoover P, Rao D, Berthier C, Fava A, Gurajala S, Peters M, Jones T, Apruzzese W, Barnas J, Furie R, Davidson A, Hildeman D, James J, Guthridge J, Dall'Era M, Wofsy D, Izmirly P, Belmont H, Clancy R, Kamen D, Putterman C, Tuschl T, McMahon M, Grossman J, Kalunian K, Weisman M, Kretzler M, Brenner M, Anolik J, Petri M, Buyon J, Raychaudhuri S, Hacohen N, Diamond B, RA/SLE Network t. Immune Cell Heterogeneity in Lupus Nephritis Kidneys and Its Relation to Histopathological Features [abstract]. Arthritis Rheumatol. 2022; 74 (suppl 9). https://acrabstracts.org/abstract/immune-cell-heterogeneity-in-lupus-nephritis-kidneys-and-its-relation-to-histopathological-features/. Accessed .

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