IRF5 GENETIC RISK VARIANTS DRIVE MYELOID-SPECIFIC IRF5 HYPER-ACTIVATION AND PRE-SYMPTOMATIC SLE
- Betsy J. Barnes, United States of America
Abstract
Background and Aims
Genetic variants within/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.
Methods
Healthy donors carrying the major IRF5-SLE risk haplotype in European Caucasians (rs2004640, rs10954213, rs10488631, and rs142738614 (CGGGG indel)) were identified from the Feinstein Genotype and Phenotype (GaP) Registry after genotyping on the Illumina Human Immunochip. Participants carried either the major IRF5 homozygous risk or non-risk haplotype and had no personal/family history of autoimmune/inflammatory diseases or cancer. Immuno-phenotypes were characterized by ELISA, flow cytometry, ex vivo co-culture and RNA-sequencing.
Results
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 hyper-activation in the myeloid compartment of risk donors that drives an SLE immune-phenotype. Risk donors were ANA positive with anti-Ro and -MPO specificity, had increased circulating plasma cells and plasmacytoid dendritic cells, and enhanced spontaneous NETosis. The IRF5-SLE immune-phenotype was conserved over time and probed mechanistically by ex vivo co-culture, indicating that risk neutrophils are drivers of the global immune-phenotype. RNAseq of risk neutrophils revealed increased IRF5 transcript expression, IFN pathway enrichment and decreased expression of ROS pathway genes.
Conclusions
Altogether, 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 autoimmune diseases, such as SLE.