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Interferon regulatory factor 5 and autoimmune lupus

  • Wang-Dong Xu (a1), Hai-Feng Pan (a1), Yuekang Xu (a1) (a2) and Dong-Qing Ye (a1)
Abstract

Systemic lupus erythematosus (SLE) is a severe multi-system autoimmune disease, whereas interferon regulatory factor (IRF) 5 belongs to the family of transcription factors that modulate immune system activities. Recently, many lines of investigations suggested that IRF5 gene polymorphisms are closely associated with the disease onset of SLE. Indeed, expressed in B cells, dendritic cells (DCs), monocytes and macrophages, IRF5 could significantly affect these immune cells participating in the pathogenesis of SLE, and numerous studies implied that this transcription factor is mechanistically linked to the disease progression. Here, we comprehensively review the updated evidence indicating the roles of IRF5 in autoimmune lupus. Hopefully, the information obtained will lead to a better understanding of the pathogenesis and development of novel therapeutic strategies for the systemic autoimmune disease.

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Corresponding author
*Corresponding author: Dong-Qing Ye, Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, 230032, PR China. E-mail: ydq@ahmu.edu.cn
References
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1Xu, W.D. et al. (2012) IRF7, a functional factor associates with systemic lupus erythematosus. Cytokine 58, 317-320
2Tamura, T. et al. (2008) The IRF family transcription factors in immunity and oncogenesis. Annual Review of Immunology 26, 535-584
3Savitsky, D.A. et al. (2010) Contribution of IRF5 in B cells to the development of murine SLE-like disease through its transcriptional control of the IgG2a locus. Proceedings of the National Academy of Sciences of the United States of America 107, 10154-10159
4Fang, C.M. et al. (2012) Unique contribution of IRF-5-Ikaros axis to the B-cell IgG2a response. Genes and Immunity 13, 421-430
5Shen, H. et al. (2010) Gender-dependent expression of murine Irf5 gene: implications for sex bias in autoimmunity. Journal of Molecular Cell Biology 2, 284-290
6Paun, A. et al. (2008) Functional characterization of murine interferon regulatory factor 5 (IRF-5) and its role in the innate antiviral response. Journal of Biological Chemistry 283, 14295-14308
7Yanai, H. et al. (2007) Role of IFN regulatory factor 5 transcription factor in antiviral immunity and tumor suppression. Proceedings of the National Academy of Sciences of the United States of America 104, 3402-3407
8Takaoka, A. et al. (2005) Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 434, 243-249
9Kozyrev, S.V. and Alarcon-Riquelme, M.E. (2007) The genetics and biology of Irf5-mediated signaling in lupus. Autoimmunity 40, 591-601
10Li, Q. and Tainsky, M.A. (2011) Epigenetic silencing of IRF7 and/or IRF5 in lung cancer cells leads to increased sensitivity to oncolytic viruses. PLoS ONE 6, e28683
11Kondo, Y. and Issa, J.P. (2010) DNA methylation profiling in cancer. Expert Reviews in Molecular Medicine 12, e23
12Kyogoku, C. et al. (2006) Functional characterization of the systemic lupus erythematosus risk gene IRF-5. In American College of Rheumatology Annual Meeting, http://www.rheumatologyorg/
13Cunninghame et al. (2007) Association of IRF5 in UK SLE families identifies a variant involved in polyadenylation. Human Molecular Genetics 16, 579-591
14Kozyrev, S.V. et al. (2007) Structural insertion/deletion variation in IRF5 is associated with a risk haplotype and defines the precise IRF5 isoforms expressed in systemic lupus erythematosus. Arthritis Rheumatism 56, 1234-1241
15Khabar, K.S. (2005) The AU-rich transcriptome: more than interferons and cytokines, and its role in disease. Journal of Interferon and Cytokine Research 25, 1-10
16Barnes, B.J. et al. (2004) Global and distinct targets of IRF-5 and IRF-7 during innate response to viral infection. Journal of Biological Chemistry 279, 45194-45207
17Mancl, M.E. et al. (2005) 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. Journal of Biological Chemistry 280, 21078-21090
18Barnes, B.J. et al. (2002) Multiple regulatory domains of IRF-5 control activation, cellular localization, and induction of chemokines that mediate recruitment of T lymphocytes. Molecular and Cellular Biology 22, 5721-5740
19Feng, D. et al. (2010) Genetic variants and disease-associated factors contribute to enhanced IRF-5 expression in blood cells of systemic lupus erythematosus patients. Arthritis Rheumatism 62, 562-573
20Niewold, T.B. et al. (2008) Association of the IRF5 risk haplotype with high serum interferon-alpha activity in systemic lupus erythematosus patients. Arthritis Rheumatism 58, 2481-2487
21Hooks, J.J. et al. (1979) Immune interferon in the circulation of patients with autoimmune disease. New England Journal of Medicine 301, 5-8
22Baechler, E.C. et al. (2003) Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proceedings of the National Academy of Sciences of the United States of America 100, 2610-2615
23Kirou, K.A. et al. (2005) Activation of the interferon-alpha pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease. Arthritis Rheumatism 52, 1491-1503
24Barnes, B.J. et al. (2003) IRF-5, a novel mediator of cell-cycle arrest and cell death. Cancer Research 63, 6424-6431
25Blanco, P. et al. (2001) Induction of dendritic cell differentiation by IFN-α in systemic lupus erythematosus. Science 294, 1540-1543
26Weckerle, C.E. et al. (2011) Network analysis of associations between serum interferon-α activity, autoantibodies, and clinical features in systemic lupus erythematosus. Arthritis Rheumatism 63, 1044-1053
27Rönnblom, L.E., Alm, G.V. and Oberg, K.E. (1990) Possible induction of systemic lupus erythematosus by interferon-alpha treatment in a patient with a malignant carcinoid tumour. Journal of Internal Medicine 227, 207-210
28Niewold, T.B. and Swedler, W.I. (2005) Systemic lupus erythematosus arising during interferon-alpha therapy for cryoglobulinemic vasculitis associated with hepatitis C. Clinical Rheumatology 24, 178-181
29Lövgren, T. et al. (2004) Induction of interferon-alpha production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG. Arthritis Rheumatism 50, 1861-1872
30Niewold, T.B. et al. (2012) IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus. Annals of the Rheumatic Diseases 71, 463-468
31Graham, R.R. et al. (2007) Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus. Proceedings of the National Academy of Sciences of the United States of America 104, 6758-6763
32Kelly, J.A. et al. (2008) Interferon regulatory factor-5 is genetically associated with systemic lupus erythematosus in African Americans. Genes and Immunity 9, 187-194
33Kawasaki, A. et al. (2008) Association of IRF5 polymorphisms with systemic lupus erythematosus in a Japanese population: support for a crucial role of intron 1 polymorphisms. Arthritis Rheumatism 58, 826-834
34Guthridge, J.M. et al. (2012) Effects of IRF5 lupus risk haplotype on pathways predicted to influence B cell functions. Journal of Biomedicine and Biotechnology 2012, 594056
35Cherian, T.S. et al. (2012) Brief Report: IRF5 systemic lupus erythematosus risk haplotype is associated with asymptomatic serologic autoimmunity and progression to clinical autoimmunity in mothers of children with neonatal lupus. Arthritis Rheumatism 64, 3383-3387
36Sigurdsson, S. et al. (2005) Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. American Journal of Human Genetics 76, 528-537
37Graham, R.R. et al. (2006) A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nature Genetics 38, 550-555
38Yasuda, K. et al. (2007) Murine dendritic cell type I IFN production induced by human IgG-RNA immune complexes is IFN regulatory factor (IRF)5 and IRF7 dependent and is required for IL-6 production. Journal of Immunology 178, 6876-6885
39Chen, H. et al. (2005) Regulation of expression of the Epstein-Barr virus BamHI-A rightward transcripts. Journal of Virology 79, 1724-1733
40Ning, S., Huye, L.E. and Pagano, J.S. (2005) Interferon regulatory factor 5 represses expression of the Epstein-Barr virus oncoprotein LMP1: braking of the IRF7/LMP1 regulatory circuit. Journal of Virology 79, 11671-11676
41Martin, H.J. et al. (2007) Manipulation of the toll-like receptor 7 signaling pathway by Epstein-Barr virus. Journal of Virology 81, 9748-9758
42James, J.A., Harley, J.B. and Scofield, R.H. (2006) Epstein-Barr virus and systemic lupus erythematosus. Current Opinion in Rheumatology 18, 462-467
43James, J.A. et al. (1997) An increased prevalence of Epstein-Barr virus infection in young patients suggests a possible etiology for systemic lupus erythematosus. Journal of Clinical Investigation 100, 3019-3026
44James, J.A. et al. (2001) Systemic lupus erythematosus in adults is associated with previous Epstein-Barr virus exposure. Arthritis Rheumatism 44, 1122-1126
45Lu, J.J. et al. (2007) Association of Epstein-Barr virus infection with systemic lupus erythematosus in Taiwan. Lupus 16, 168-175
46Jacob, C.O., Lee, S.K. and Strassmann, G. (1996) Mutational analysis of TNF-α gene reveals a regulatory role for the 3′-untranslated region in the genetic predisposition to lupus-like autoimmune disease. Journal of Immunology 156, 3043-3050
47Kontoyiannis, D. et al. (1999) Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity 10, 387-398
48Lerner, M.K. and Steitz, J.A. (1979) Antibodies to small nuclear RNAs complexed with proteins are produced by patients with systemic lupus erythematosus. Proceedings of the National Academy of Sciences of the United States of America 76, 5495-5499
49Neugebauer, K.M. et al. (2000) SR proteins are autoantigens in patients with systemic lupus erythematosus. Arthritis Rheumatism 43, 1768-1778
50Wen, F. et al. (2011) Exon 6 variants carried on systemic lupus erythematosus (SLE) risk haplotypes modulate IRF5 function. Autoimmunity 44, 82-89
51Panchanathan, R. et al. (2012) Distinct regulation of murine lupus susceptibility genes by the IRF5/Blimp-1 axis. Journal of Immunology 188, 270-278
52Panchanathan, R. et al. (2010) Aim2 deficiency stimulates the expression of IFN-inducible Ifi202, a lupus susceptibility murine gene within the Nba2 autoimmune susceptibility locus. Journal of Immunology 185, 7385-7393
53Panchanathan, R. et al. (2011) Cell type and gender-dependent differential regulation of the p202 and Aim2 proteins: implications for the regulation of innate immune responses in SLE. Molecular Immunology 49, 273-280
54Xu, W.D. et al. (2012) Targeting IRF4 in autoimmune diseases. Autoimmunity Reviews 11, 918-924
55Lien, C. et al. (2010) Critical role of IRF-5 in regulation of B-cell differentiation. Proceedings of the National Academy of Sciences of the United States of America 107, 4664-4668
56Stavnezer, J. (2000) Molecular processes that regulate class switching. Current Topics in Microbiology and Immunology 245, 127-168
57Kim, J. et al. (1999) Ikaros DNA-binding proteins direct formation of chromatin remodeling complexes in lymphocytes. Immunity 10, 345-355
58Wang, J.H. K. et al. (1996) Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation. Immunity 5, 537-549
59Kirstetter, P. et al. (2002) Ikaros is critical for B cell differentiation and function. European Journal of Immunology 32, 720-730
60Sellars, M. et al. (2009) Ikaros controls isotype selection during immunoglobulin class switch recombination. Journal of Experimental Medicine 206, 1073-1087
61Xu, Y. et al. (2012) Pleiotropic IFN-dependent and -independent effects of IRF5 on the pathogenesis of experimental lupus. Journal of Immunology 188, 4113-4121
62Feng, D. et al. (2012) Irf5-deficient mice a re protected from pristane-induced lupus via increased Th2 cytokines and altered IgG class switching. European Journal of Immunology 42, 1477-1487
63Richez, C. et al. (2010) IFN regulatory factor 5 is required for disease development in the FcgammaRIIB −/− Yaa and FcgammaRIIB −/− mouse models of systemic lupus erythematosus. Journal of Immunology 184, 796-806
64Tada, Y. et al. (2011) Interferon regulatory factor 5 is critical for the development of lupus in MRL/lpr mice. Arthritis Rheumatism 63, 738-748
65Richards, H.B. et al. (1998) Interleukin 6 dependence of anti-DNA antibody production: evidence for two pathways of autoantibody formation in pristane-induced lupus. Journal of Experimental Medicine 188, 985-990
66Bolland, S. and Ravetch, J.V. (2000) Spontaneous autoimmune disease in Fc(gamma)RIIB-deficient mice results from strain-specific epistasis. Immunity 13, 277-285
67Bolland, S. et al. (2002) Genetic modifiers of systemic lupus erythematosus in FcgammaRIIB(−/−) mice. Journal of Experimental Medicine 195, 1167-1174
68Hunter, C.A. (2005) New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions. Nature Reviews of Immunology 5, 521-531
69Takahashi, S. et al. (1996) Imbalance towards Th1 predominance is associated with acceleration of lupus-like autoimmune syndrome in MRL mice. Journal of Clinical Investigation 97, 1597-1604
70Oritani, K. et al. (2001) Type I interferons and limitin: a comparison of structures, receptors, and functions. Cytokine Growth Factor Reviews 12, 337-348
71Fenner, J.E. et al. (2006) Suppressor of cytokine signaling 1 regulates the immune response to infection by a unique inhibition of type I interferon activity. Nature Immunology 7, 33-39
72Uzé, G. et al. (2007) The receptor of the type I interferon family. Current Topics in Microbiology Immunology 316, 71-95
73Illei, G.G. et al. (2004) Biomarkers in systemic lupus erythematosus: II. Markers of disease activity. Arthritis Rheumatism 50, 2048-2065
74Seth, S. et al. (2011) CCR7 essentially contributes to the homing of plasmacytoid dendritic cells to lymph nodes under steady-state as well as inflammatory conditions. Journal of Immunology 186, 3364-3372
75Boulé, M.W. et al. (2004) Toll-like receptor 9-dependent and -independent dendritic cell activation by chromatin-immunoglobulin G complexes. Journal of Experimental Medicine 199, 1631-1640
76Means, T.K. et al. (2005) Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. Journal of Clinical Investigation 115, 407-417
77Savarese, E. et al. (2006) U1 small nuclear ribonucleroprotein immune complexes induce type I interferon in plasmacytoid dendritic cells through TLR7. Blood 107, 3229-3234
78Leadbetter, E.A. et al. (2002) Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416, 603-607
79Richez, C. et al. (2009) TLR4 ligands induce IFN-alpha production by mouse conventional dendritic cells and human monocytes after IFN-beta priming. Journal of Immunology 182, 820-828
80Theofilopoulos, A.N. et al. (2005) Type I interferons (α/β) in immunity and autoimmunity. Annual Review of Immunology 23, 307-336
81Purtha, W.E. et al. (2012) Spontaneous mutation of the Dock2 gene in Irf5 −/− mice complicates interpretation of type I interferon production and antibody responses. Proceedings of the National Academy of Sciences of the United States of America 109, E898-E904
82Yasuda, K. et al. (2013) Phenotype and function of B cells and dendritic cells from interferon regulatory factor 5-deficient mice with and without a mutation in DOCK2. International Immunology 25, 295-306
83Salloum, R. and Niewold, T.B. (2011) Interferon regulatory factors in human lupus pathogenesis. Translation Research 157, 326-331

  • Niewold, T.B. et al. (2008) Association of the IRF5 risk haplotype with high serum interferon-alpha activity in systemic lupus erythematosus patients. Arthritis Rheumatism 58, 2481-2487.

  • This article shows the biologic relevance of the SLE risk haplotype of IRF5 at the protein level.

  • Niewold, T.B. et al. (2012) IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus. Annals of the Rheumatic Diseases 71, 463-468.

  • This study indicates the association between IRF5 haplotypes, IFNα and SLE-specific auto-antibodies in the pathogenesis of SLE.

  • Lien, C. et al. (2010) Critical role of IRF-5 in regulation of B-cell differentiation. Proceedings of the National Academy of Sciences of the United States of America 107, 4664-4668.

  • This study demonstrates that IRF-5 is involved in B-cell maturation and the stimulation of Blimp-1 expression.

  • Savitsky, D.A. et al. (2010) Contribution of IRF5 in B cells to the development of murine SLE-like disease through its transcriptional control of the IgG2a locus. Proceedings of the National Academy of Sciences of the United States of America 107, 10154-10159.

  • This article demonstrates a requirement for IRF5 in development of murine SLE via its role in B lymphocytes.

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