Abstract Session
Systemic lupus erythematosus (SLE)
Jasmine Shwetar, -None-
New York School of Medicine
Ann Arbor, Michigan, United States
No financial relationships with ineligible companies to disclose
Lupus nephritis (LN) is a pathologically diverse autoimmune disease that can lead to end-stage kidney disease and mortality. Although Class II LN is considered as a milder form of LN which often requires no or minimal treatment, a growing body of clinical evidence suggests Class II LN may be more severe than previously thought. Urine proteomics previously demonstrated monocyte/neutrophil degranulation, macrophage activation, and wound healing/matrix degradation were enriched in class III and IV LN. We hypothesized that urine proteomics on Class II LN will capture the extent of kidney inflammation, revealing both similarities with more advanced stages of disease as well as proteomic signatures specific Class II.
Methods: We quantified 1200 biomarkers (Kiloplex, RayBiotech) in urine samples collected before a clinically indicated kidney biopsy that showed ISN Class II LN as part of the Accelerating Medicines Partnership in RA/SLE (AMP). Single-cell RNA sequencing (scRNAseq) of 16 Class II renal biopsies was utilized to corroborate urinary signatures with renal tissue. Over 35 thousand cells were captured across tubular, stromal and immune compartments. Leveraging the AMP scRNA-seq dataset, we included 30 control, 46 membranous, 51 mixed and 58 proliferative samples with over 600 thousand cells captured in total.
Results:
Urine proteomic profiles were compared in 16 Class II LN patients and 10 healthy controls, revealing an inflammatory and profibrotic signature in Class II. For example, patients with class II LN demonstrated an elevation of MMP-13, M-CSF receptor, CD163, ALCAM, and FOLR2 (Figure 1A). Pathway analysis showed enrichment of neutrophil degranulation, collagen containing extracellular matrix and tissue remodeling pathways (Figure 1B).
Kidney scRNA-seq confirmed an anti-inflammatory macrophage population expanded in Class II LN with high expression of FOLR2 and LYVE1 (Figure 2A). In addition, there was an expansion of fibroblasts in Class II with an activated phenotype (Figure 2B), possibly contributing to the enrichment of pathways involving tissue remodeling and collagen containing extracellular matrix in Figure 1B.
Conclusion:
Although Class II LN is generally considered mild, proteomic and kidney transcriptional analyses demonstrated immune activation and tissue remodeling signatures. These signatures are similar to those previously identified in the more aggressive proliferative LN suggesting that Class II LN, or at least a subset, exists on a spectrum with class III and IV LN.
Figure 1: A) Urine proteomic profiles (1200 proteins) were compared between baseline samples from class II (n=16) and healthy donors (n=10) using a Wilcoxon test. Proteins with nominal p < 0.05 are in pink. B) Pathway enrichment analysis (overlap < 50%) using the proteins significantly (nominal p<0.05) more abundant in Class II. FDR: false discovery rate; OR: odds ratio.
Figure 2: A) Proportion of LYVE1+ Resident Macrophage population (n=1956 cells) over all myeloid cells per sample and split by LN Class on the x-axis B) Proportion of fibroblasts (n=3899 cells) over all stromal cell types per sample and split by LN Class on the y-axis.
J. Shwetar: None; J. Buyon: Artiva Biotherapeutics, 1, Bristol-Myers Squibb(BMS), 1, 2, Equillium, 1, GlaxoSmithKlein(GSK), 1, 2, Otsuka Pharmaceuticals, 1, Related Sciences, 1, 2; M. Petri: Amgen, 2, AnaptysBio, 2, Annexon Bio, 2, Arthros-FocusMedEd, 6, AstraZeneca, 2, 5, Atara Biosciences, 2, Aurinia, 5, 6, Autolus, 2, Avoro Ventures, 2, Biocryst, 2, Boxer Capital, 2, Cabaletto Bio, 2, Caribou Biosciences, 2, CTI, 1, CVS Health, 1, Eli Lilly, 2, 5, Emergent Biosolutions, 1, Ermiium, 2, Escient Pharmaceuticals, 2, Exagen, 5, Exo Therapeutics, 2, Gentibio, 2, GlaxoSmithKlein(GSK), 2, 5, iCell Gene Therapeutics, 2, Innovaderm Research, 2, IQVIA, 1, Janssen, 5, Kira Pharmaceuticals, 2, Merck/EMD Serono, 1, Nexstone Immunology, 2, Nimbus Lakshmi, 2, Novartis, 2, PPD Development, 2, Precision Biosciences, 2, Proviant, 2, Regeneron Pharmaceuticals, 2, Sanofi, 2, Seismic Therapeutic, 2, Senti Bioscienes, 2, Sinomab Biosciences, 2, Takeda, 2, Tenet Medicines Inc, 2, TG Therapeutics, 2, UCB, 2, Vertex Pharmaceuticals, 2, Worldwide Clinical Trials, 1, Zydus, 2; K. Ruggles: None; A. Fava: Annexionbio, 2, Arctiva, 2, AstraZeneca, 2, Exagen, 5, Novartis, 6, UCB, 2.