Tu135 - Immune Cell Heterogeneity in Lupus Nephritis Kidneys and Its Relation to Histopathological Features: Lessons from the Accelerating Medicines Partnership (AMP) in SLE Consortium

Jennifer Anolik; William Apruzzese; Jennifer Barnas; Michael Belmont; Celine Berthier; Michael Brenner; Jill Buyon; Robert Clancy; Maria Dall'Era; Anne Davidson; Betty Diamond; Thomas Eisenhaure; Andrea Fava; Derek Fine; Richard Furie; Jennifer Grossman; Siddarth Gurajala; Joel Guthridge; Nir Hacohen; David Hildeman; Jeffrey Hodgin; Paul Hoover; Mariko Ishimori; Peter Izmirly; Judith James; Kenneth Kalunian; Diane Kamen; Matthias Kretzler; James Lederer; Maureen McMahon; Joseph Mears; Fernanda Payan-Schober; Michelle Petri; Chaim Putterman; Deepak Rao; Soumya Raychaudhuri; Saori Sakaue; Thomas Tuschl; Michael Weisman; David Wofsy; Steve Woodle; Qian Xiao

Abstract Text: 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. Droplet-based single-cell RNA-sequencing was applied to the analysis of dissociated kidney samples, collected from 155 LN patients with active LN and 30 healthy controls. 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 disease-related activation and differentiation. Principal component analysis (PCA) was used to characterize the variability in cell subset frequencies across the LN patients, and its relation to histopathological features. We found that the main source of variability in leukocyte composition (PC1) reflected the balance between lymphocytes and monocytes/macrophages, and was significantly correlated with the Chronicity index, such that patients with a higher lymphocytes-to-monocytes/macrophages ratio had a higher Chronicity score (rho = -0.439, p-value < 0.001). The second source of variability (PC2) represented the degree of macrophage differentiation to an alternatively activated phagocytic profile, and was positively correlated with the Activity index (rho = 0.495, p-value < 0.001). Furthermore, a higher degree of macrophage differentiation was associated with proliferative or mixed histology class, compared to pure membranous nephritis (p-value = 0.001, Kruskal–Wallis test). Network analysis revealed a complex structure of interactions associated with different modes of immune responses. These results provide important insights into the immune mechanisms underlying LN.