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Interferon regulatory factor 5 in human autoimmunity and murine models of autoimmune disease

  • Hayley L. Eames
    Correspondence
    Reprint requests: Dr Hayley L. Eames and Prof Irina A. Udalova, Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7FY, United Kingdom
    Affiliations
    Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
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  • Alastair L. Corbin
    Affiliations
    Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
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  • Irina A. Udalova
    Correspondence
    Reprint requests: Dr Hayley L. Eames and Prof Irina A. Udalova, Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7FY, United Kingdom
    Affiliations
    Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
    Search for articles by this author
      Interferon regulatory factor 5 (IRF5) has been demonstrated as a key transcription factor of the immune system, playing important roles in modulating inflammatory immune responses in numerous cell types including dendritic cells, macrophages, and B cells. As well as driving the expression of type I interferon in antiviral responses, IRF5 is also crucial for driving macrophages toward a proinflammatory phenotype by regulating cytokine and chemokine expression and modulating B-cell maturity and antibody production. This review highlights the functional importance of IRF5 in a disease setting, by discussing polymorphic mutations at the human Irf5 locus that lead to susceptibility to systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel disease. In concordance with this, we also discuss lessons in IRF5 functionality learned from murine in vivo models of autoimmune disease and inflammation and hypothesize that modulation of IRF5 activity and expression could provide potential therapeutic benefits in the clinic.

      Abbreviations:

      GWAS (genome wide association study), IBD (inflammatory bowel disease), IFN (interferon), IRF (interferon regulatory factor), RA (rheumatoid arthritis), SLE (systemic lupus erythematosus), SNP (single nucleotide polymorphism)
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      References

        • Tamura T.
        • Yanai H.
        • Savitsky D.
        • et al.
        The IRF family transcription factors in immunity and oncogenesis.
        Annu Rev Immunol. 2008; 26: 535-584
        • Santini S.M.
        • Lapenta C.
        • Logozzi M.
        • et al.
        Type I interferon as a powerful adjuvant for monocyte-derived dendritic cell development and activity in vitro and in Hu-PBL-SCID mice.
        J Exp Med. 2000; 191: 1777-1788
        • Marrack P.
        • Kappler J.
        • Mitchell T.
        Type I interferons keep activated T cells alive.
        J Exp Med. 1999; 189: 521-530
        • Barnes B.
        • Lubyova B.
        • Pitha P.M.
        On the role of IRF in host defense.
        J Interferon Cytokine Res. 2002; 22: 59-71
        • Burysek L.
        • Yeow W.S.
        • Lubyova B.
        • et al.
        Functional analysis of human herpesvirus 8-encoded viral interferon regulatory factor 1 and its association with cellular interferon regulatory factors and p300.
        J Virol. 1999; 73: 7334-7342
        • Gao S.J.
        • Boshoff C.
        • Jayachandra S.
        • et al.
        KSHV ORF K9 (vIRF) is an oncogene which inhibits the interferon signaling pathway.
        Oncogene. 1997; 15: 1979-1985
        • Zimring J.C.
        • Goodbourn S.
        • Offermann M.K.
        Human herpesvirus 8 encodes an interferon regulatory factor (IRF) homolog that represses IRF-1-mediated transcription.
        J Virol. 1998; 72: 701-707
        • Tanaka N.
        • Kawakami T.
        • Taniguchi T.
        Recognition DNA sequences of interferon regulatory factor 1 (IRF-1) and IRF-2, regulators of cell growth and the interferon system.
        Mol Cell Biol. 1993; 13: 4531-4538
        • Merika M.
        • Thanos D.
        Enhanceosomes.
        Curr Opin Genet Dev. 2001; 11: 205-208
        • Panne D.
        • Maniatis T.
        • Harrison S.C.
        An atomic model of the interferon-beta enhanceosome.
        Cell. 2007; 129: 1111-1123
        • Escalante C.R.
        • Yie J.
        • Thanos D.
        • et al.
        Structure of IRF-1 with bound DNA reveals determinants of interferon regulation.
        Nature. 1998; 391: 103-106
        • Apostolou E.
        • Thanos D.
        Virus infection induces NF-kappaB-dependent interchromosomal associations mediating monoallelic IFN-beta gene expression.
        Cell. 2008; 134: 85-96
        • Juang Y.T.
        • Lowther W.
        • Kellum M.
        • et al.
        Primary activation of interferon A and interferon B gene transcription by interferon regulatory factor 3.
        Proc Natl Acad Sci U S A. 1998; 95: 9837-9842
        • Barnes B.J.
        • Moore P.A.
        • Pitha P.M.
        Virus-specific activation of a novel interferon regulatory factor, IRF-5, results in the induction of distinct interferon alpha genes.
        J Biol Chem. 2001; 276: 23382-23390
        • Yeow W.S.
        • Au W.C.
        • Juang Y.T.
        • et al.
        Reconstitution of virus-mediated expression of interferon alpha genes in human fibroblast cells by ectopic interferon regulatory factor-7.
        J Biol Chem. 2000; 275: 6313-6320
        • Heng T.S.
        • Painter M.W.
        • Immunological Genome Project C
        The Immunological Genome Project: networks of gene expression in immune cells.
        Nat Immunol. 2008; 9: 1091-1094
        • Mancl M.E.
        • Hu G.
        • Sangster-Guity N.
        • et al.
        Two discrete promoters regulate the alternatively spliced human interferon regulatory factor-5 isoforms. Multiple isoforms with distinct cell type-specific expression, localization, regulation, and function.
        J Biol Chem. 2005; 280: 21078-21090
        • Stone R.C.
        • Du P.
        • Feng D.
        • et al.
        RNA-Seq for enrichment and analysis of IRF5 transcript expression in SLE.
        PLoS One. 2013; 8: e54487
        • Ryzhakov G.
        • Eames H.L.
        • Udalova I.A.
        Activation and function of interferon regulatory factor 5.
        J Interferon Cytokine Res. 2015; 35: 71-78
        • Lazzari E.
        • Jefferies C.A.
        IRF5-mediated signaling and implications for SLE.
        Clin Immunol. 2014; 153: 343-352
        • Krausgruber T.
        • Saliba D.
        • Ryzhakov G.
        • et al.
        IRF5 is required for late-phase TNF secretion by human dendritic cells.
        Blood. 2010; 115: 4421-4430
        • Krausgruber T.
        • Blazek K.
        • Smallie T.
        • et al.
        IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses.
        Nat Immunol. 2011; 12: 231-238
        • Weiss M.
        • Blazek K.
        • Byrne A.J.
        • et al.
        IRF5 is a specific marker of inflammatory macrophages in vivo.
        Mediators Inflamm. 2013; 2013: 245804
        • Clark D.N.
        • Read R.D.
        • Mayhew V.
        • et al.
        Four promoters of IRF5 respond distinctly to stimuli and are affected by autoimmune-risk polymorphisms.
        Front Immunol. 2013; 4: 360
        • Kozyrev S.V.
        • Alarcon-Riquelme M.E.
        The genetics and biology of Irf5-mediated signaling in lupus.
        Autoimmunity. 2007; 40: 591-601
        • Butler J.E.
        • Kadonaga J.T.
        The RNA polymerase II core promoter: a key component in the regulation of gene expression.
        Genes Dev. 2002; 16: 2583-2592
        • Saxonov S.
        • Berg P.
        • Brutlag D.L.
        A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters.
        Proc Natl Acad Sci U S A. 2006; 103: 1412-1417
        • Zhu J.
        • He F.
        • Hu S.
        • et al.
        On the nature of human housekeeping genes.
        Trends Genet. 2008; 24: 481-484
        • Larsen F.
        • Gundersen G.
        • Lopez R.
        • et al.
        CpG islands as gene markers in the human genome.
        Genomics. 1992; 13: 1095-1107
        • Ramirez-Carrozzi V.R.
        • Braas D.
        • Bhatt D.M.
        • et al.
        A unifying model for the selective regulation of inducible transcription by CpG islands and nucleosome remodeling.
        Cell. 2009; 138: 114-128
        • Lu R.
        • Au W.C.
        • Yeow W.S.
        • et al.
        Regulation of the promoter activity of interferon regulatory factor-7 gene. Activation by interferon snd silencing by hypermethylation.
        J Biol Chem. 2000; 275: 31805-31812
        • Gestermann N.
        • Koutero M.
        • Belkhir R.
        • et al.
        Methylation profile of the promoter region of IRF5 in primary Sjogren's syndrome.
        Eur Cytokine Netw. 2012; 23: 166-172
        • Balasa A.
        • Gathungu G.
        • Kisfali P.
        • et al.
        Assessment of DNA methylation at the interferon regulatory factor 5 (IRF5) promoter region in inflammatory bowel diseases.
        Int J Colorectal Dis. 2010; 25: 553-556
        • Wen F.
        • Ellingson S.M.
        • Kyogoku C.
        • et al.
        Exon 6 variants carried on systemic lupus erythematosus (SLE) risk haplotypes modulate IRF5 function.
        Autoimmunity. 2011; 44: 82-89
        • Rechsteiner M.
        • Rogers S.W.
        PEST sequences and regulation by proteolysis.
        Trends Biochem Sci. 1996; 21: 267-271
        • Graham R.R.
        • Kyogoku C.
        • Sigurdsson S.
        • et al.
        Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus.
        Proc Natl Acad Sci U S A. 2007; 104: 6758-6763
        • Saliba D.G.
        • Heger A.
        • Eames H.L.
        • et al.
        IRF5:RelA interaction targets inflammatory genes in macrophages.
        Cell Rep. 2014; 8: 1308-1317
        • Feng D.
        • Sangster-Guity N.
        • Stone R.
        • et al.
        Differential requirement of histone acetylase and deacetylase activities for IRF5-mediated proinflammatory cytokine expression.
        J Immunol. 2010; 185: 6003-6012
        • Kim S.
        • Becker J.
        • Bechheim M.
        • et al.
        Characterizing the genetic basis of innate immune response in TLR4-activated human monocytes.
        Nat Commun. 2014; 5: 5236
        • Lee M.N.
        • Ye C.
        • Villani A.C.
        • et al.
        Common genetic variants modulate pathogen-sensing responses in human dendritic cells.
        Science. 2014; 343: 1246980
        • Kawasaki A.
        • Kyogoku C.
        • Ohashi J.
        • et al.
        Association of IRF5 polymorphisms with systemic lupus erythematosus in a Japanese population: support for a crucial role of intron 1 polymorphisms.
        Arthritis Rheum. 2008; 58: 826-834
        • Brogna S.
        • Wen J.
        Nonsense-mediated mRNA decay (NMD) mechanisms.
        Nat Struct Mol Biol. 2009; 16: 107-113
        • Feng D.
        • Stone R.C.
        • Eloranta M.L.
        • et al.
        Genetic variants and disease-associated factors contribute to enhanced interferon regulatory factor 5 expression in blood cells of patients with systemic lupus erythematosus.
        Arthritis Rheum. 2010; 62: 562-573
        • Niewold T.B.
        • Kelly J.A.
        • Flesch M.H.
        • et al.
        Association of the IRF5 risk haplotype with high serum interferon-alpha activity in systemic lupus erythematosus patients.
        Arthritis Rheum. 2008; 58: 2481-2487
        • Hedl M.
        • Abraham C.
        IRF5 risk polymorphisms contribute to interindividual variance in pattern recognition receptor-mediated cytokine secretion in human monocyte-derived cells.
        J Immunol. 2012; 188: 5348-5356
        • Sigurdsson S.
        • Goring H.H.
        • Kristjansdottir G.
        • et al.
        Comprehensive evaluation of the genetic variants of interferon regulatory factor 5 (IRF5) reveals a novel 5 bp length polymorphism as strong risk factor for systemic lupus erythematosus.
        Hum Mol Genet. 2008; 17: 872-881
        • Cunninghame Graham D.S.
        • Manku H.
        • Wagner S.
        • et al.
        Association of IRF5 in UK SLE families identifies a variant involved in polyadenylation.
        Hum Mol Genet. 2007; 16: 579-591
        • Kozyrev S.V.
        • Lewen S.
        • Reddy P.M.
        • et al.
        Structural insertion/deletion variation in IRF5 is associated with a risk haplotype and defines the precise IRF5 isoforms expressed in systemic lupus erythematosus.
        Arthritis Rheum. 2007; 56: 1234-1241
        • Ferreiro-Neira I.
        • Calaza M.
        • Alonso-Perez E.
        • et al.
        Opposed independent effects and epistasis in the complex association of IRF5 to SLE.
        Genes Immun. 2007; 8: 429-438
        • Demirci F.Y.
        • Manzi S.
        • Ramsey-Goldman R.
        • et al.
        Association of a common interferon regulatory factor 5 (IRF5) variant with increased risk of systemic lupus erythematosus (SLE).
        Ann Hum Genet. 2007; 71: 308-311
        • Graham R.R.
        • Kozyrev S.V.
        • Baechler E.C.
        • et al.
        A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus.
        Nat Genet. 2006; 38: 550-555
        • Shimane K.
        • Kochi Y.
        • Yamada R.
        • et al.
        A single nucleotide polymorphism in the IRF5 promoter region is associated with susceptibility to rheumatoid arthritis in the Japanese population.
        Ann Rheum Dis. 2009; 68: 377-383
        • Lofgren S.E.
        • Yin H.
        • Delgado-Vega A.M.
        • et al.
        Promoter insertion/deletion in the IRF5 gene is highly associated with susceptibility to systemic lupus erythematosus in distinct populations, but exerts a modest effect on gene expression in peripheral blood mononuclear cells.
        J Rheumatol. 2010; 37: 574-578
        • Armstrong D.L.
        • Zidovetzki R.
        • Alarcon-Riquelme M.E.
        • et al.
        GWAS identifies novel SLE susceptibility genes and explains the association of the HLA region.
        Genes Immun. 2014; 15: 347-354
        • Kaiser R.
        • Criswell L.A.
        Genetics research in systemic lupus erythematosus for clinicians: methodology, progress, and controversies.
        Curr Opin Rheumatol. 2010; 22: 119-125
        • Lyons R.
        • Narain S.
        • Nichols C.
        • et al.
        Effective use of autoantibody tests in the diagnosis of systemic autoimmune disease.
        Ann N Y Acad Sci. 2005; 1050: 217-228
        • Berden J.H.
        • Licht R.
        • van Bruggen M.C.
        • et al.
        Role of nucleosomes for induction and glomerular binding of autoantibodies in lupus nephritis.
        Curr Opin Nephrol Hypertens. 1999; 8: 299-306
        • Bengtsson A.A.
        • Sturfelt G.
        • Truedsson L.
        • et al.
        Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies.
        Lupus. 2000; 9: 664-671
        • Kanayama Y.
        • Kim T.
        • Inariba H.
        • et al.
        Possible involvement of interferon alfa in the pathogenesis of fever in systemic lupus erythematosus.
        Ann Rheum Dis. 1989; 48: 861-863
        • Baechler E.C.
        • Batliwalla F.M.
        • Reed A.M.
        • et al.
        Gene expression profiling in human autoimmunity.
        Immunol Rev. 2006; 210: 120-137
        • Kyogoku C.
        • Langefeld C.D.
        • Ortmann W.A.
        • et al.
        Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE.
        Am J Hum Genet. 2004; 75: 504-507
        • Shiina T.
        • Inoko H.
        • Kulski J.K.
        An update of the HLA genomic region, locus information and disease associations: 2004.
        Tissue Antigens. 2004; 64: 631-649
        • Remmers E.F.
        • Plenge R.M.
        • Lee A.T.
        • et al.
        STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus.
        N Engl J Med. 2007; 357: 977-986
        • Sigurdsson S.
        • Nordmark G.
        • Goring H.H.
        • et al.
        Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus.
        Am J Hum Genet. 2005; 76: 528-537
        • Siu H.O.
        • Yang W.
        • Lau C.S.
        • et al.
        Association of a haplotype of IRF5 gene with systemic lupus erythematosus in Chinese.
        J Rheumatol. 2008; 35: 360-362
        • Stone R.C.
        • Feng D.
        • Deng J.
        • et al.
        Interferon regulatory factor 5 activation in monocytes of systemic lupus erythematosus patients is triggered by circulating autoantigens independent of type I interferons.
        Arthritis Rheum. 2012; 64: 788-798
        • Xu Y.
        • Lee P.Y.
        • Li Y.
        • et al.
        Pleiotropic IFN-dependent and -independent effects of IRF5 on the pathogenesis of experimental lupus.
        J Immunol. 2012; 188: 4113-4121
        • Yang L.
        • Feng D.
        • Bi X.
        • et al.
        Monocytes from Irf5-/- mice have an intrinsic defect in their response to pristane-induced lupus.
        J Immunol. 2012; 189: 3741-3750
        • Richez C.
        • Yasuda K.
        • Bonegio R.G.
        • et al.
        IFN regulatory factor 5 is required for disease development in the FcgammaRIIB-/-Yaa and FcgammaRIIB-/- mouse models of systemic lupus erythematosus.
        J Immunol. 2010; 184: 796-806
        • Tada Y.
        • Kondo S.
        • Aoki S.
        • et al.
        Interferon regulatory factor 5 is critical for the development of lupus in MRL/lpr mice.
        Arthritis Rheum. 2011; 63: 738-748
        • Feng D.
        • Yang L.
        • Bi X.
        • et al.
        Irf5-deficient mice are protected from pristane-induced lupus via increased Th2 cytokines and altered IgG class switching.
        Eur J Immunol. 2012; 42: 1477-1487
        • Lien C.
        • Fang C.M.
        • Huso D.
        • et al.
        Critical role of IRF-5 in regulation of B-cell differentiation.
        Proc Natl Acad Sci U S A. 2010; 107: 4664-4668
        • Savitsky D.A.
        • Yanai H.
        • Tamura T.
        • et al.
        Contribution of IRF5 in B cells to the development of murine SLE-like disease through its transcriptional control of the IgG2a locus.
        Proc Natl Acad Sci U S A. 2010; 107: 10154-10159
        • Fang C.M.
        • Roy S.
        • Nielsen E.
        • et al.
        Unique contribution of IRF-5-Ikaros axis to the B-cell IgG2a response.
        Genes Immun. 2012; 13: 421-430
        • Paun A.
        • Reinert J.T.
        • Jiang Z.
        • et al.
        Functional characterization of murine interferon regulatory factor 5 (IRF-5) and its role in the innate antiviral response.
        J Biol Chem. 2008; 283: 14295-14308
        • Yanai H.
        • Chen H.M.
        • Inuzuka T.
        • et al.
        Role of IFN regulatory factor 5 transcription factor in antiviral immunity and tumor suppression.
        Proc Natl Acad Sci U S A. 2007; 104: 3402-3407
        • Feldmann M.
        • Maini R.N.
        Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned?.
        Annu Rev Immunol. 2001; 19: 163-196
        • Feldmann M.
        Development of anti-TNF therapy for rheumatoid arthritis.
        Nat Rev Immunol. 2002; 2: 364-371
        • Muller-Ladner U.
        • Pap T.
        • Gay R.E.
        • et al.
        Mechanisms of disease: the molecular and cellular basis of joint destruction in rheumatoid arthritis.
        Nat Clin Pract Rheumatol. 2005; 1: 102-110
        • Gregersen P.K.
        • Silver J.
        • Winchester R.J.
        The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis.
        Arthritis Rheum. 1987; 30: 1205-1213
        • Morgan A.W.
        • Haroon-Rashid L.
        • Martin S.G.
        • et al.
        The shared epitope hypothesis in rheumatoid arthritis: evaluation of alternative classification criteria in a large UK Caucasian cohort.
        Arthritis Rheum. 2008; 58: 1275-1283
        • Mewar D.
        • Wilson A.G.
        Autoantibodies in rheumatoid arthritis: a review.
        Biomed Pharmacother. 2006; 60: 648-655
        • van Venrooij W.J.
        • van Beers J.J.
        • Pruijn G.J.
        Anti-CCP antibodies: the past, the present and the future.
        Nat Rev Rheumatol. 2011; 7: 391-398
        • Szodoray P.
        • Szabo Z.
        • Kapitany A.
        • et al.
        Anti-citrullinated protein/peptide autoantibodies in association with genetic and environmental factors as indicators of disease outcome in rheumatoid arthritis.
        Autoimmun Rev. 2010; 9: 140-143
        • Dawidowicz K.
        • Allanore Y.
        • Guedj M.
        • et al.
        The interferon regulatory factor 5 gene confers susceptibility to rheumatoid arthritis and influences its erosive phenotype.
        Ann Rheum Dis. 2011; 70: 117-121
        • Dieguez-Gonzalez R.
        • Calaza M.
        • Perez-Pampin E.
        • et al.
        Association of interferon regulatory factor 5 haplotypes, similar to that found in systemic lupus erythematosus, in a large subgroup of patients with rheumatoid arthritis.
        Arthritis Rheum. 2008; 58: 1264-1274
        • Rueda B.
        • Reddy M.V.
        • Gonzalez-Gay M.A.
        • et al.
        Analysis of IRF5 gene functional polymorphisms in rheumatoid arthritis.
        Arthritis Rheum. 2006; 54: 3815-3819
        • Garnier S.
        • Dieude P.
        • Michou L.
        • et al.
        IRF5 rs2004640-T allele, the new genetic factor for systemic lupus erythematosus, is not associated with rheumatoid arthritis.
        Ann Rheum Dis. 2007; 66: 828-831
        • Maalej A.
        • Hamad M.B.
        • Rebai A.
        • et al.
        Association of IRF5 gene polymorphisms with rheumatoid arthritis in a Tunisian population.
        Scand J Rheumatol. 2008; 37: 414-418
        • Khandpur R.
        • Carmona-Rivera C.
        • Vivekanandan-Giri A.
        • et al.
        NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis.
        Sci Transl Med. 2013; 5: 178ra40
        • Brennan F.M.
        • McInnes I.B.
        Evidence that cytokines play a role in rheumatoid arthritis.
        J Clin Invest. 2008; 118: 3537-3545
        • Simmonds R.E.
        • Foxwell B.M.
        Signalling, inflammation and arthritis: NF-kappaB and its relevance to arthritis and inflammation.
        Rheumatology. 2008; 47: 584-590
        • Dayer J.M.
        • Beutler B.
        • Cerami A.
        Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts.
        J Exp Med. 1985; 162: 2163-2168
        • Bertolini D.R.
        • Nedwin G.E.
        • Bringman T.S.
        • et al.
        Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors.
        Nature. 1986; 319: 516-518
        • Brennan F.M.
        • Chantry D.
        • Jackson A.M.
        • et al.
        Cytokine production in culture by cells isolated from the synovial membrane.
        J Autoimmun. 1989; 2 Suppl: 177-186
        • Hirano T.
        • Matsuda T.
        • Turner M.
        • et al.
        Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis.
        Eur J Immunol. 1988; 18: 1797-1801
        • Brennan F.M.
        • Zachariae C.O.
        • Chantry D.
        • et al.
        Detection of interleukin 8 biological activity in synovial fluids from patients with rheumatoid arthritis and production of interleukin 8 mRNA by isolated synovial cells.
        Eur J Immunol. 1990; 20: 2141-2144
        • Haworth C.
        • Brennan F.M.
        • Chantry D.
        • et al.
        Expression of granulocyte-macrophage colony-stimulating factor in rheumatoid arthritis: regulation by tumor necrosis factor-alpha.
        Eur J Immunol. 1991; 21: 2575-2579
        • Brennan F.M.
        • Chantry D.
        • Jackson A.
        • et al.
        Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis.
        Lancet. 1989; 2: 244-247
        • Butler D.M.
        • Maini R.N.
        • Feldmann M.
        • et al.
        Modulation of proinflammatory cytokine release in rheumatoid synovial membrane cell cultures. Comparison of monoclonal anti TNF-alpha antibody with the interleukin-1 receptor antagonist.
        Eur Cytokine Netw. 1995; 6: 225-230
        • Takaoka A.
        • Yanai H.
        • Kondo S.
        • et al.
        Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors.
        Nature. 2005; 434: 243-249
        • van den Berg W.B.
        • Joosten L.A.
        • van Lent P.L.
        Murine antigen-induced arthritis.
        Methods Mol Med. 2007; 136: 243-253
        • Brand D.D.
        • Latham K.A.
        • Rosloniec E.F.
        Collagen-induced arthritis.
        Nat Protoc. 2007; 2: 1269-1275
        • Inglis J.J.
        • Criado G.
        • Medghalchi M.
        • et al.
        Collagen-induced arthritis in C57BL/6 mice is associated with a robust and sustained T-cell response to type II collagen.
        Arthritis Res Ther. 2007; 9: R113
        • Backlund J.
        • Li C.
        • Jansson E.
        • et al.
        C57BL/6 mice need MHC class II Aq to develop collagen-induced arthritis dependent on autoreactive T cells.
        Ann Rheum Dis. 2013; 72: 1225-1232
        • Paun A.
        • Bankoti R.
        • Joshi T.
        • et al.
        Critical role of IRF-5 in the development of T helper 1 responses to Leishmania donovani infection.
        PLoS Pathog. 2011; 7: e1001246
        • Honma K.
        • Udono H.
        • Kohno T.
        • et al.
        Interferon regulatory factor 4 negatively regulates the production of proinflammatory cytokines by macrophages in response to LPS.
        Proc Natl Acad Sci U S A. 2005; 102: 16001-16006
        • Zheng Y.
        • Chaudhry A.
        • Kas A.
        • et al.
        Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses.
        Nature. 2009; 458: 351-356
        • Lech M.
        • Weidenbusch M.
        • Kulkarni O.P.
        • et al.
        IRF4 deficiency abrogates lupus nephritis despite enhancing systemic cytokine production.
        J Am Soc Nephrol. 2011; 22: 1443-1452
        • Satoh T.
        • Takeuchi O.
        • Vandenbon A.
        • et al.
        The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection.
        Nat Immunol. 2010; 11: 936-944
        • Negishi H.
        • Ohba Y.
        • Yanai H.
        • et al.
        Negative regulation of Toll-like-receptor signaling by IRF-4.
        Proc Natl Acad Sci U S A. 2005; 102: 15989-15994
        • Garber M.
        • Yosef N.
        • Goren A.
        • et al.
        A high-throughput chromatin immunoprecipitation approach reveals principles of dynamic gene regulation in mammals.
        Mol Cell. 2012; 47: 810-822
        • Xu D.
        • Meyer F.
        • Ehlers E.
        • et al.
        Interferon regulatory factor 4 (IRF-4) targets IRF-5 to regulate Epstein-Barr virus transformation.
        J Biol Chem. 2011; 286: 18261-18267
        • Maloy K.J.
        • Powrie F.
        Intestinal homeostasis and its breakdown in inflammatory bowel disease.
        Nature. 2011; 474: 298-306
        • Philpott D.J.
        • Sorbara M.T.
        • Robertson S.J.
        • et al.
        NOD proteins: regulators of inflammation in health and disease.
        Nat Rev Immunol. 2014; 14: 9-23
        • Lesage S.
        • Zouali H.
        • Cezard J.-P.
        • et al.
        CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease.
        Am J Hum Genet. 2002; 70: 845-857
        • Thrasher A.J.
        • Burns S.O.
        WASP: a key immunological multitasker.
        Nat Rev Immunol. 2010; 10: 182-192
        • Cheng L.E.
        • Kanwar B.
        • Tcheurekdjian H.
        • et al.
        Persistent systemic inflammation and atypical enterocolitis in patients with NEMO syndrome.
        Clin Immunol. 2009; 132: 124-131
        • Marsh R.A.
        • Madden L.
        • Kitchen B.J.
        • et al.
        XIAP deficiency: a unique primary immunodeficiency best classified as X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked lymphoproliferative disease.
        Blood. 2010; 116: 1079-1082
        • Pachlopnik Schmid J.
        • Canioni D.
        • Moshous D.
        • et al.
        Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency).
        Blood. 2011; 117: 1522-1529
        • Moraes-Vasconcelos D.
        • Costa-Carvalho B.T.
        • Torgerson T.R.
        • et al.
        Primary immune deficiency disorders presenting as autoimmune diseases: IPEX and APECED.
        J Clin Immunol. 2008; 28: S11-S19
        • Marks D.J.
        • Miyagi K.
        • Rahman F.Z.
        • et al.
        Inflammatory bowel disease in CGD reproduces the clinicopathological features of Crohn's disease.
        Am J Gastroenterol. 2009; 104: 117-124
        • Glocker E.O.
        • Kotlarz D.
        • Boztug K.
        • et al.
        Inflammatory bowel disease and mutations affecting the interleukin-10 receptor.
        N Engl J Med. 2009; 361: 2033-2045
        • Begue B.
        • Verdier J.
        • Rieux-Laucat F.
        • et al.
        Defective IL10 signaling defining a subgroup of patients with inflammatory bowel disease.
        Am J Gastroenterol. 2011; 106: 1544-1555
        • Kotlarz D.
        • Beier R.
        • Murugan D.
        • et al.
        Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy.
        Gastroenterology. 2012; 143: 347-355
        • Gambineri E.
        • Torgerson T.R.
        • Ochs H.D.
        Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis.
        Curr Opin Rheumatol. 2003; 15: 430-435
        • Hadis U.
        • Wahl B.
        • Schulz O.
        • et al.
        Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria.
        Immunity. 2011; 34: 237-246
        • Franke A.
        • Balschun T.
        • Karlsen T.H.
        • et al.
        Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility.
        Nat Genet. 2008; 40: 1319-1323
        • Amre D.K.
        • Mack D.R.
        • Morgan K.
        • et al.
        Interleukin 10 (IL-10) gene variants and susceptibility for paediatric onset Crohn's disease.
        Aliment Pharmacol Ther. 2009; 29: 1025-1031
        • Annunziato F.
        • Cosmi L.
        • Santarlasci V.
        • et al.
        Phenotypic and functional features of human Th17 cells.
        J Exp Med. 2007; 204: 1849-1861
        • Aychek T.
        • Mildner A.
        • Yona S.
        • et al.
        IL-23-mediated mononuclear phagocyte crosstalk protects mice from Citrobacter rodentium-induced colon immunopathology.
        Nat Commun. 2015; 6: 6525
        • Hirota K.
        • Duarte J.
        • Veldhoen M.
        • et al.
        Fate mapping of IL-17 producing T cells in inflammatory responses.
        Nature Immunol. 2011; 12: 255-263
        • Galvez J.
        Role of Th17 cells in the pathogenesis of human IBD.
        ISRN Inflamm. 2014; 2014: 14
        • Hue S.
        • Ahern P.P.
        • Buonocore S.
        • et al.
        Interleukin-23 drives innate and T cell-mediated intestinal inflammation.
        J Exp Med. 2006; 203: 2473-2483
        • Tremelling M.
        • Cummings F.
        • Fisher S.A.
        • et al.
        IL23R variation determines susceptibility but not disease phenotype in inflammatory bowel disease.
        Gastroenterology. 2007; 132: 1657-1664
        • Hueber W.
        • Sands B.E.
        • Lewitzky S.
        • et al.
        Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial.
        Gut. 2012; 61: 1693-1700
        • McLean L.P.
        • Cross R.K.
        • Shea-Donohue T.
        Combined blockade of IL-17A and IL-17F may prevent the development of experimental colitis.
        Immunotherapy. 2013; 5: 923-925
        • Sandborn W.J.
        • Gasink C.
        • Gao L.L.
        • et al.
        Ustekinumab induction and maintenance therapy in refractory Crohn's disease.
        N Engl J Med. 2012; 367: 1519-1528
        • Cayatte C.
        • Joyce-Shaikh B.
        • Vega F.
        • et al.
        Biomarkers of therapeutic response in the IL-23 pathway in inflammatory bowel disease.
        Clin Trans Gastroenterol. 2012; 3: e10
        • Dideberg V.
        • Kristjansdottir G.
        • Milani L.
        • et al.
        An insertion-deletion polymorphism in the interferon regulatory factor 5 (IRF5) gene confers risk of inflammatory bowel diseases.
        Hum Mol Genet. 2007; 16: 3008-3016
        • Gathungu G.
        • Zhang C.
        • Zhang W.
        • et al.
        A two-marker haplotype in the IRF5 gene is associated with inflammatory bowel disease in a North American cohort.
        Genes Immun. 2012; 13: 351-355
        • Chua K.H.
        • Lian L.H.
        • Khor W.C.
        • et al.
        Association between genetic polymorphisms in interferon regulatory factor 5 (IRF5) gene and Malaysian patients with Crohn's disease.
        J Dig Dis. 2015; 16: 205-216
        • Li P.
        • Lv H.
        • Yang H.
        • et al.
        IRF5, but not TLR4, DEFEB1, or VDR, is associated with the risk of ulcerative colitis in a Han Chinese population.
        Scand J Gastroenterol. 2013; 48: 1145-1151
        • Globig A.M.
        • Hennecke N.
        • Martin B.
        • et al.
        Comprehensive intestinal T helper cell profiling reveals specific accumulation of IFN-gamma+IL-17+coproducing CD4+ T cells in active inflammatory bowel disease.
        Inflamm Bowel Dis. 2014; 20: 2321-2329
        • Ahern P.P.
        • Schiering C.
        • Buonocore S.
        • et al.
        Interleukin-23 drives intestinal inflammation through direct activity on T cells.
        Immunity. 2010; 33: 279-288
        • Chionh Y.T.
        • Ng G.Z.
        • Ong L.
        • et al.
        Protease-activated receptor 1 suppresses Helicobacter pylori gastritis via the inhibition of macrophage cytokine secretion and interferon regulatory factor 5.
        Mucosal Immunol. 2015; 8: 68-79
        • Yasuda K.
        • Nundel K.
        • Watkins A.A.
        • et al.
        Phenotype and function of B cells and dendritic cells from interferon regulatory factor 5-deficient mice with and without a mutation in DOCK2.
        Int Immunol. 2013; 25: 295-306
        • Fukui Y.
        • Hashimoto O.
        • Sanui T.
        • et al.
        Haematopoietic cell-specific CDM family protein DOCK2 is essential for lymphocyte migration.
        Nature. 2001; 412: 826-831
        • Nishikimi A.
        • Fukuhara H.
        • Su W.
        • et al.
        Sequential regulation of DOCK2 dynamics by two phospholipids during neutrophil chemotaxis.
        Science. 2009; 324: 384-387
        • Tanaka Y.
        • Hamano S.
        • Gotoh K.
        • et al.
        T helper type 2 differentiation and intracellular trafficking of the interleukin 4 receptor-alpha subunit controlled by the Rac activator Dock2.
        Nat Immunol. 2007; 8: 1067-1075
        • Purtha W.E.
        • Swiecki M.
        • Colonna M.
        • et al.
        Spontaneous mutation of the Dock2 gene in Irf5-/- mice complicates interpretation of type I interferon production and antibody responses.
        Proc Natl Acad Sci U S A. 2012; 109: E898-904
        • Yasuda K.
        • Watkins A.A.
        • Kochar G.S.
        • et al.
        Interferon regulatory factor-5 deficiency ameliorates disease severity in the MRL/lpr mouse model of lupus in the absence of a mutation in DOCK2.
        PLoS One. 2014; 9: e103478
        • Shen H.
        • Panchanathan R.
        • Rajavelu P.
        • et al.
        Gender-dependent expression of murine Irf5 gene: implications for sex bias in autoimmunity.
        J Mol Cell Biol. 2010; 2: 284-290
        • Dieude P.
        • Guedj M.
        • Wipff J.
        • et al.
        Association between the IRF5 rs2004640 functional polymorphism and systemic sclerosis: a new perspective for pulmonary fibrosis.
        Arthritis Rheum. 2009; 60: 225-233
        • Ito I.
        • Kawaguchi Y.
        • Kawasaki A.
        • et al.
        Association of a functional polymorphism in the IRF5 region with systemic sclerosis in a Japanese population.
        Arthritis Rheum. 2009; 60: 1845-1850
        • Miceli-Richard C.
        • Gestermann N.
        • Ittah M.
        • et al.
        The CGGGG insertion/deletion polymorphism of the IRF5 promoter is a strong risk factor for primary Sjogren's syndrome.
        Arthritis Rheum. 2009; 60: 1991-1997
        • Kristjansdottir G.
        • Sandling J.K.
        • Bonetti A.
        • et al.
        Interferon regulatory factor 5 (IRF5) gene variants are associated with multiple sclerosis in three distinct populations.
        J Med Genet. 2008; 45: 362-369
        • Masuda T.
        • Iwamoto S.
        • Yoshinaga R.
        • et al.
        Transcription factor IRF5 drives P2X4R+-reactive microglia gating neuropathic pain.
        Nat Commun. 2014; 5: 3771
        • Vosslamber S.
        • van der Voort L.F.
        • van den Elskamp I.J.
        • et al.
        Interferon regulatory factor 5 gene variants and pharmacological and clinical outcome of Interferonbeta therapy in multiple sclerosis.
        Genes Immun. 2011; 12: 466-472
        • Wang C.
        • Rose-Zerilli M.J.
        • Koppelman G.H.
        • et al.
        Evidence of association between interferon regulatory factor 5 gene polymorphisms and asthma.
        Gene. 2012; 504: 220-225
        • Nordang G.B.
        • Viken M.K.
        • Amundsen S.S.
        • et al.
        Interferon regulatory factor 5 gene polymorphism confers risk to several rheumatic diseases and correlates with expression of alternative thymic transcripts.
        Rheumatology. 2012; 51: 619-626
        • Sigurdsson S.
        • Padyukov L.
        • Kurreeman F.A.
        • et al.
        Association of a haplotype in the promoter region of the interferon regulatory factor 5 gene with rheumatoid arthritis.
        Arthritis Rheum. 2007; 56: 2202-2210
        • Stahl E.A.
        • Raychaudhuri S.
        • Remmers E.F.
        • et al.
        Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci.
        Nat Genet. 2010; 42: 508-514
        • Wang C.
        • Kokkonen H.
        • Sandling J.K.
        • et al.
        Preferential association of interferon regulatory factor 5 gene variants with seronegative rheumatoid arthritis in 2 Swedish case-control studies.
        J Rheumatol. 2011; 38: 2130-2132
        • Anderson C.A.
        • Boucher G.
        • Lees C.W.
        • et al.
        Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.
        Nat Genet. 2011; 43: 246-252