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.
Highlights
Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease characterized by breakdown of tolerance to nuclear antigens, immune complex deposition, and multi-organ involvement
By anti-nuclear antibody (ANA)-HEp2, we found that healthy donors who are homozygous for the interferon regulatory factor 5 (IRF5) risk haplotype were ANA positive; sera from SLE patients with clinically high and low dsDNA titers were used as positive controls (Figure 1, B and C)
This is distinct from findings in patients with SLE where others and we reported an association of elevated IRF5 transcript and protein expression with patients carrying IRF5 risk variants [14,15,16,17,18,19,20,21,22]
Summary
Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease characterized by breakdown of tolerance to nuclear antigens, immune complex deposition, and multi-organ involvement. Circulating anti-dsDNA antibodies and antibodies against small nuclear RNA–binding proteins (anti-Ro, anti-LA, antiSM, and anti-RNP) are hallmarks of SLE [1,2,3]. Higher numbers and frequency of circulating antibody-secreting cells (ASCs, plasma cells) associate with SLE disease activity and anti-dsDNA titer [4, 5]. Patients with SLE display both innate and adaptive immune alterations, as well as granulocyte alterations that affect blood cell composition. Peripheral blood gene expression profiling identified an interferon (IFN) gene signature, a neutrophil-specific signature, and a plasma cell signature as biomarkers for SLE that correlate with disease activity [6,7,8,9]
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