An amino acid change in IRF7 increases SLE risk through transcriptional regulation of type I interferons

Abstract

Systemic Lupus Erythematosus (SLE) is an incurable, debilitating autoimmune disease characterized by widespread inflammation and rampant production of autoantibodies. The most prominent and highly replicated set of genes up-regulated in the immune cells of patients with SLE are the type I interferons (IFN-I) and IFN-responsive genes. IFN-I are predominantly made by plasmacytoid dendritic cells (pDCs), and their expression is directly regulated by the transcription factor interferon regulatory factor 7 (IRF7). While IRF7 is an established SLE risk locus, the variants responsible for disease pathology remain unknown. We hypothesize that an amino-acid changing SLE risk variant in IRF7 (rs1131665) alters expression of disease-relevant IFN-I in clinically-relevant cells to increase SLE risk. The functional genomic consequences of the SLE-associated variant were assessed in human cell lines and in genome-edited mice with an introduced SLE-risk variant at Irf7. Our data demonstrate greater than 2-fold genotype-dependence in IFN-stimulated response element-driven luciferase activity and inflammatory cytokine secretion detected in supernatant after toll-like receptor-7 stimulation. Gene expression differences in cells with IRF7/Irf7 risk variants are consistent with those dysregulated in SLE patients. In the present study, we demonstrate the functional consequences of an amino acid substitution in a critical type I interferon regulator. Understanding these mechanisms will enhance development of more effective clinical practices for autoimmune patients expressing the risk variant for IRF7.