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
This file is in Adobe Acrobat (PDF) format. If you have not installed and configured the Adobe Acrobat Reader on your system.
Having trouble reading a PDF?
PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.
Having trouble saving a PDF?
Many versions of the free Acrobat Reader do not allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users: Right-click on the Download link and choose the option that says something like "Save Link As...". Mac users should hold the mouse button down on the link to get these same options.
Having trouble printing a PDF?
- Try printing one page at a time or to a newer printer.
- Try saving the file to disk before printing rather than opening it "on the fly." This requires that you configure your browser to "Save" rather than "Launch Application" for the file type "application/pdf", and can usually be done in the "Helper Applications" options.
- Make sure you are using the latest version of Adobe's Acrobat Reader.
