A common lupus haplotype in IRF7 increases interferon responses in monocytes

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B641
Abstract ID: 4367

Presenting Author:
Samuel J Virolainen , Graduate Research Assistant at Cincinnati Children’s Hosp. Med. Ctr., Univ. of Cincinnati Col. of Med.

Abstract:

Systemic Lupus Erythematosus (SLE) is an autoimmune disease with a polygenic basis characterized by widespread inflammation and chronic immune activation. More than 200 genetic risk loci are implicated in the etiology of SLE, yet the mechanisms connecting these loci to disease risk are not well understood. We focus on a lupus-associated haplotype containing two coding variants in perfect (R² =1) linkage disequilibrium (rs1131665 and rs1061502) at the IRF7 locus. IRF7 is a transcription factor and critical regulator of type I Interferon (IFN-I) responses. A majority of SLE patients exhibit elevated levels of IFN-I in a disease-activity specific manner. We hypothesize that this IRF7 haplotype leads to increased IRF7 activity and downstream IFN-I responses. Using IRF7-null THP-1 monocytes, we generated cells expressing physiologically relevant levels of either the risk or non-risk haplotypes of IRF7. In this experimental system, monocytes expressing the risk haplotype express two-fold more IFN-α RNA and protein following stimulation of endosomal Toll-like receptors (TLR). Similar results were observed for TLR-mediated induction of IFNλ-2, a Type III IFN that is implicated in SLE and whose expression is also IRF7-dependent. We propose a model in which the IRF7 risk haplotype increases SLE risk by increasing Type I and Type III interferons following TLR stimulation.