Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
Host B Cell Gene Expression Responses Following Epstein-Barr Virus Exposure Differ Based Upon IRF5 Genetic Risk Haplotype
Templeton1, Amanda, Poole2, Brian, Dominguez1, Nicolas, Lu1, Rufei, Vidal1, Gabriel S., Levin3, Jeremy, Sestak1, Andrea L.
Systemic Lupus Erythematosus (SLE) is a complex, systemic autoimmune disease. Both gene and environment interactions are thought to play a role in SLE development. Epstein-Barr virus (EBV) exposure is one environmental factor that has been shown to influence the development of SLE. EBV binds to cell surface receptors such as CR2/CD21 on B cells and EBV remains latent after infection in B cells. B cells also play key roles in SLE development. Some previously described genetic associations with SLE, such as the interferon regulatory factor 5 gene (IRF5), regulate the interferon responses of cells, a pathway previously linked with SLE pathogenesis. In this study, we examined the effect of carrying the IRF5 lupus risk haplotype upon the host's B cell gene expression response to binding or infection with EBV.
Whole genome microarray expression profile data was collected from peripheral blood B cells from lupus cases and healthy controls selected based upon their IRF5 risk and protective haplotypes based on genotypes at SNPs rs2004640 and rs10954213. B cells isolated by negative selection using magnetic beads were exposed to EBV for 16 hours after which total cellular RNA was isolated. Whole genome gene expression was performed using Illumina whole genome human gene expression chips. Gene set enrichment analysis (GSEA) was utilized to analyze differential gene expression between SLE patients and controls.
IRF5 haplotypes appear to differentially regulate genes that are part of three biologically relevant pathways in EBV stimulated B cells: 1.) B cell receptor pathway genes, 2.) Interferon pathway genes and 3.) Toll-receptor pathway genes. The haplotype specific regulation by EBV stimulation was seen in both lupus cases and controls with the respective haplotypes. The main SLE specific differences in gene expression among individuals carrying the IRF5 risk and non-risk haplotype, was in a subset of the interferon response gene signatures. Patients with the IRF5 risk haplotype have a heightened interferon signature under all experimental conditions; whereas, the patients with the IRF5 protective haplotype have a B cell interferon signature similar to that of unrelated, matched controls.
Over expression of interferon pathway genes in B cells from individuals carrying the IRF5 risk haplotype following viral exposure suggests that the IRF5 risk alleles alone can modulate ones biological response to the environmental insult. Patients carrying either the IRF5 risk or non-risk alleles appear to already be predisposed to having a higher interferon signature even without exposure to virus, suggesting the other genetic factors are also influencing the interferon response, independent of virus.
To cite this abstract, please use the following information:
Templeton, Amanda, Poole, Brian, Dominguez, Nicolas, Lu, Rufei, Vidal, Gabriel S., Levin, Jeremy, et al; Host B Cell Gene Expression Responses Following Epstein-Barr Virus Exposure Differ Based Upon IRF5 Genetic Risk Haplotype [abstract]. Arthritis Rheum 2009;60 Suppl 10 :735