title: IFN-α production by plasmacytoid dendritic cell associations with polymorphisms in gene loci related to autoimmune and inflammatory diseases.
abstract: The type I interferon (IFN) system is persistently activated in systemic lupus erythematosus (SLE) and many other systemic autoimmune diseases. Studies have shown an association between SLE and several gene variants within the type I IFN system. We investigated whether single-nucleotide polymorphisms (SNPs) associated with SLE and other autoimmune diseases affect the IFN-α production in healthy individuals. Plasmacytoid dendritic cells (pDCs), B cells and NK cells were isolated from peripheral blood of healthy individuals and stimulated with RNA-containing immune complexes (ICs), herpes simplex virus (HSV) or the oligonucleotide ODN2216. IFN-α production by pDCs alone or in cocultures with B or NK cells was measured by an immunoassay. All donors were genotyped with the 200K ImmunoChip, and a 5 bp CGGGG length polymorphism in the IFN regulatory factor 5 gene (IRF5) was genotyped by PCR. We found associations between IFN-α production and 18-86 SNPs (P ≤ 0.001), depending on the combination of the stimulated cell types. However, only three of these associated SNPs were shared between the cell-type combinations. Several SNPs showed novel associations to the type I IFN system among all the associated SNPs, whereas some loci have been described earlier for their association with SLE. Furthermore, we found that the SLE-risk variant of the IRF5 CGGGG-indel was associated with lower IFN-α production. We conclude that the genetic variants affecting the IFN-α production highlight the intricate regulation of the type I IFN system and the importance of understanding the mechanisms behind the dysregulated type I IFN system in SLE.
authors.affiliation: Department of Medical Sciences, Rheumatology, Science for Life Laboratory, Uppsala University, Uppsala 75185, Sweden, olof.berggren@medsci.uu.se.
authors.forename: Olof
authors.initials: O
authors.lastname: Berggren
authors.affiliation: Department of Medical Sciences, Rheumatology, Science for Life Laboratory, Uppsala University, Uppsala 75185, Sweden.
authors.forename: Andrei
authors.initials: A
authors.lastname: Alexsson
authors.affiliation: Department of Medical & Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London W12 0NN, UK and.
authors.forename: David L
authors.initials: DL
authors.lastname: Morris
authors.affiliation: Department of Medical Sciences, Rheumatology, Science for Life Laboratory, Uppsala University, Uppsala 75185, Sweden.
authors.forename: Karolina
authors.initials: K
authors.lastname: Tandre
authors.affiliation: Free University of Berlin, Berlin 14195, Germany.
authors.forename: Gert
authors.initials: G
authors.lastname: Weber
authors.affiliation: Department of Medical & Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London W12 0NN, UK and.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Vyse
authors.affiliation: Department of Medical Sciences, Molecular Medicine, Science for Life Laboratory, Uppsala University, Uppsala 75185, Sweden.
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Syvänen
authors.affiliation: Department of Medical Sciences, Rheumatology, Science for Life Laboratory, Uppsala University, Uppsala 75185, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Rönnblom
authors.affiliation: Department of Medical Sciences, Rheumatology, Science for Life Laboratory, Uppsala University, Uppsala 75185, Sweden.
authors.forename: Maija-Leena
authors.initials: ML
authors.lastname: Eloranta
mesh_terms: D000328:Adult; D000368:Aged; D001327:Autoimmune Diseases / Q000209:etiology* / Q000378:metabolism*; D016022:Case-Control Studies; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D053263:Gene Regulatory Networks; D056426:Genetic Loci; D005838:Genotype; D006801:Humans; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism*; D050835:Interferon Regulatory Factors / Q000235:genetics; D016898:Interferon-alpha / Q000096:biosynthesis*; D008180:Lupus Erythematosus, Systemic / Q000209:etiology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D016898:Interferon-alpha