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IRF5 genetic risk variants drive myeloid-specific IRF5 hyperactivation and presymptomatic SLE
Dan Li, … , Peter Linsley, Betsy J. Barnes
Dan Li, … , Peter Linsley, Betsy J. Barnes
Published December 26, 2019
Citation Information: JCI Insight. 2020;5(2):e124020. https://doi.org/10.1172/jci.insight.124020.
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Research Article Genetics Immunology

IRF5 genetic risk variants drive myeloid-specific IRF5 hyperactivation and presymptomatic SLE

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Abstract

Genetic variants within or near the interferon regulatory factor 5 (IRF5) locus associate with systemic lupus erythematosus (SLE) across ancestral groups. The major IRF5-SLE risk haplotype is common across populations, yet immune functions for the risk haplotype are undefined. We characterized the global immune phenotype of healthy donors homozygous for the major risk and nonrisk haplotypes and identified cell lineage–specific alterations that mimic presymptomatic SLE. Contrary to previous studies in B lymphoblastoid cell lines and SLE immune cells, IRF5 genetic variants had little effect on IRF5 protein levels in healthy donors. Instead, we detected basal IRF5 hyperactivation in the myeloid compartment of risk donors that drives the SLE immune phenotype. Risk donors were anti-nuclear antibody positive with anti-Ro and -MPO specificity, had increased circulating plasma cells and plasmacytoid dendritic cells, and had enhanced spontaneous NETosis. The IRF5-SLE immune phenotype was conserved over time and probed mechanistically by ex vivo coculture, indicating that risk neutrophils are drivers of the global immune phenotype. RNA-Seq of risk neutrophils revealed increased IRF5 transcript expression, IFN pathway enrichment, and decreased expression of ROS pathway genes. Altogether, the data support that individuals carrying the IRF5-SLE risk haplotype are more susceptible to environmental/stochastic influences that trigger chronic immune activation, predisposing to the development of clinical SLE.

Authors

Dan Li, Bharati Matta, Su Song, Victoria Nelson, Kirsten Diggins, Kim R. Simpfendorfer, Peter K. Gregersen, Peter Linsley, Betsy J. Barnes

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Figure 1

Healthy donors carrying the homozygous IRF5-SLE risk haplotype are ANA and anti-Ro positive.

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Healthy donors carrying the homozygous IRF5-SLE risk haplotype are ANA a...
(A) Candidate causal SNPs associated with SLE are shown relative to the human IRF5 gene. IRF5 haplotypes were built in Caucasian subjects from the 1000 Genomes Project (74). Variants selected for inclusion in the haplotypes were candidate causal or associated with SLE in GWAS and thus proxies for the candidate causal variants. Genotype and Phenotype (GaP) Registry subjects were selected based on the indicated immunochip SNPs as homozygous for the nonrisk haplotype (B/B), homozygous for the risk haplotype (E/E), or other combinations of the IRF5 haplotypes. (B) ANA immunofluorescence scoring for C, including positive (dsDNAhi) and negative (dsDNAlo) control SLE serum (n = 4; 1:500 dilution); sera from n = 11 risk and nonrisk donors. Zero represents a negative signal; 4 represents the strongest signal (Mann-Whitney U test; comparisons are between risk and nonrisk healthy donors). (C) Representative ANA images from homozygous nonrisk (n = 5) and risk donors (n = 5) are shown with a serum dilution of 1:2 at original magnification ×200. (D) Anti-dsDNA Ig concentrations were determined by ELISA with a 1:5 dilution of GaP serum from nonrisk (NR) and risk (R) donors and 1:20 dilution of SLE serum (unpaired 2-tailed t test between nonrisk and risk donors). (E–H) Anti-Ro/SS-A (TROVE2) (E), anti–U1-snRNP-A (SNRPA) (F), anti-La/SS-B (SSB) (G), and anti–U1-snRNP-C (SNRNPC) (H) concentrations were determined by Luminex assay with a 1:5 serum dilution for GaP Registry donors and 1:20 for SLE donors (unpaired 2-tailed t test between nonrisk and risk donors). Single data points represent individual donors; sera from n = 11 risk and nonrisk donors. Plotted data are after background subtraction. Data are presented as mean or mean ± SEM. *P ≤ 0.05; **P ≤ 0.01. Experiments in B–H were done twice.

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