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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 3

The IRF5-SLE risk haplotype has no effect on IRF5 expression but drives IRF5 hyperactivation in myeloid cells.

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The IRF5-SLE risk haplotype has no effect on IRF5 expression but drives ...
(A and B) IRF5 expression was determined in B cell subsets from n = 11 homozygous risk and nonrisk donors as mean fluorescence intensity (MFI) by flow cytometry. Naive, transitional (trans), nonswitched memory (NSM), switched memory (SM), and PBs were examined. (C–F) Monocyte subsets from n = 9 homozygous risk and n = 12 nonrisk donors (C and D), pDCs from n = 10 homozygous risk and n = 12 nonrisk donors (E), and neutrophils from n = 12 homozygous risk and nonrisk donors (F) were examined (unpaired 2-tailed t test between NR and R for each group). (G–L) IRF5 activation was determined in same cell subsets as A–F by imaging flow cytometry. Percentage of IRF5+ cells within a given subset that contain nuclear-localized IRF5 is shown (unpaired 2-tailed t test). (M) A further increase in IRF5 activation was seen after stimulation of PBMCs from nonrisk and risk donors with 500 ng/mL R848 for 2 hours. Fold change in percentage of IRF5 nuclear localization is shown after gating on IRF5+CD14+ monocytes in unstimulated (basal) and stimulated cells (unpaired 2-tailed t test between NR and R for each group). (N) Same as M except fold change in IRF5 activation is shown in pDCs after R848 stimulation (unpaired 2-tailed t test). (O) Percentage of pDCs from N that are positive for intracellular IFN-α is shown between nonrisk and risk donors after stimulation of PBMCs with R848 (unpaired 2-tailed t test). Experiments were repeated 4 or more times (A, C, E, G, and I), were repeated 3 times (B, D, J, K, M, and N), or were repeated twice (F, H, L, and O). Single data points represent individual donors. Data are presented as mean ± SEM. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001.

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