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Genetic Versus Non-genetic Drivers of SLE: Implications of IRF5 Dysregulation in Both Roads Leading to SLE

  • Betsy J. BarnesEmail author
Systemic Lupus Erythematosus (G Tsokos, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Systemic Lupus Erythematosus

Abstract

Purpose of Review

Systemic lupus erythematosus (SLE) is characterized by a breakdown of immune tolerance, resulting in inflammation and tissue destruction. While the primary causes of SLE are still obscure, the disorder is highly heritable. Genetic risk variants, on their own, are rarely causal or fully explain disease pathogenesis. We discuss the possibility that IRF5, a SLE susceptibility gene, has both genetic and non-genetic contributions to disease pathogenesis.

Recent Findings

Genetic variants within and around IRF5 robustly associate with SLE risk. In SLE blood cells, IRF5 risk variants associate with elevated IRF5 expression and IFN production. Whether the observed increase in expression is due to risk variants or other disease-associated factors is not clear. Data from Irf5−/− mice backcrossed to multiple models of murine lupus support that IRF5’s role in disease pathogenesis is non-genetic.

Summary

Studies of IRF5 expression and function in genotyped healthy donors will address the question of whether IRF5 dysregulation in SLE is driven by genetic or non-genetic factors.

Keywords

Interferon regulatory factor Lupus Genotype Interferon 

Notes

Funding

This work was supported in part by grants from the Lupus Research Alliance and DoD CDMRP Lupus Research Program to BJB.

Compliance with Ethical Standards

Conflict of Interest

Dr. Barnes reports grants from Lupus Research Alliance and grants from DoD CDMRP Lupus Research Program, during the conduct of the study. In addition, Dr. Barnes has a patent WO2017/044855A2 issued.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    • Matta B, Song S, Li D, Barnes BJ. Interferon regulatory factor signaling in autoimmune disease. Cytokine. 2017;98:15–26 This review highlights the critical role of IRF5 in both human and mouse autoimmune disease pathogenesis.CrossRefGoogle Scholar
  2. 2.
    • Negishi H, Taniguchi T, Yanai H. The interferon (IFN) class of cytokines and the IFN regulatory factor (IRF) transcription factor family. Cold Spring Harb Perspect Biol. 2017;10.  https://doi.org/10.1101/cshperspect.a028423. This is the most recent, up-to-date review on the IRF family of transcription factors.
  3. 3.
    Sigurdsson S, Nordmark G, Goring HH, Lindroos K, Wilman AC, Sturfelt G, 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;76:528–37.CrossRefGoogle Scholar
  4. 4.
    Graham RR, Kozrev SV, Baechler EC, Reddy MV, Plenge RM, Bauer JW, 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;38:550–5.CrossRefGoogle Scholar
  5. 5.
    Graham RR, Kyogoku C, Sigurdsson S, Vlasova IA, Davies LR, Baechler EC, 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;104:6758–63.CrossRefGoogle Scholar
  6. 6.
    Sigurdsson S, Goring HH, Kristjansdottir G, Milani L, Nordmark G, Sandling JK, 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 erythematsosu. Hum Mol Genet. 2008;17:872–81.CrossRefGoogle Scholar
  7. 7.
    Lofgren SE, Yin H, Delgado-Vega AM, Sanchez E, Lewen S, Pons-Estel BA, 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;37:574–8.CrossRefGoogle Scholar
  8. 8.
    Kottyan LC, Zoller EE, Bene J, Lu X, Kelly JA, Rupert AM, et al. The IRF5-TNPO3 assocation with systemic lupus erythematosus has two components that other autoimmune disorders variably share. Hum Mol Gen. 2015;24:582–96.CrossRefGoogle Scholar
  9. 9.
    Feng D, Stone RC, Eloranta ML, Sangster-Guity N, Normark G, Sigurdsson S, 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;62:562–73.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Niewold TB, Kelly JA, Flesch MH, Espinoza LR, Harley JB, Crow MK. Association of the IRF5 risk haplotype with high serum interferon-alpha activity in systemic lupus erythematosus patients. Arthritis Rheum. 2008;58:2481–7.CrossRefGoogle Scholar
  11. 11.
    Niewold TB, Kelly JA, Kariuki SN, Franek BS, Kumar AA, Kaufman KM, et al. IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus. Ann Rheum Dis. 2012;71:463–8.CrossRefGoogle Scholar
  12. 12.
    Kozyrev SV, Lewén S, Reddy PM, Pons-Estel B; Argentine Collaborative Group, Witte T; German Collaborative Group, Junker P, Laustrup H, Gutiérrez C, Suárez A, Francisca González-Escribano M, Martín J; Spanish Collaborative Group, Alarcón-Riquelme ME. 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.Google Scholar
  13. 13.
    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;188:5348–56.CrossRefGoogle Scholar
  14. 14.
    Hedl M, Yan J, Abraham C. IRF5 and IRF5 disease-risk variants increase glycolysis and human M1 macrophage polarization by regulating proximal signaling and Akt2 activation. Cell Rep. 2016;16:2442–55.CrossRefGoogle Scholar
  15. 15.
    Mancl ME, Hu G, Sangster-Guity N, Olshalsky SL, Hoops K, Fitzgerald-Bocarsly P, 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;280:21078–90.CrossRefGoogle Scholar
  16. 16.
    Stone RC, Feng D, Deng J, Singh S, Yang L, Fitzgerald-Bocarsly P, 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;64:788–98.CrossRefGoogle Scholar
  17. 17.
    Schoenemeyer A, Barnes BJ, Mancl ME, Latz E, Goutagny N, Pitha PM, et al. The interferon regulatory factor, IRF-5, is a central mediator of toll-like receptor 7 signaling. J Biol Chem. 2005;280:17005–12.CrossRefGoogle Scholar
  18. 18.
    Barnes BJ, Moore PA, Pitha PM. Virus-specific activation of a novel interferon regulatory factor, IRF-5, results in the induction of distinct interferon alpha genes. J Biol Chem. 2001;276:23382–90.CrossRefGoogle Scholar
  19. 19.
    Barnes BJ, Kellum MJ, Field AE, Pitha PM. Multiple regulatory domains of IRF-5 control activation, cellular localization and induction of chemokines that mediate T-lymphocyte recruitment. Mol Cell Biol. 2002;22:5721–40.CrossRefGoogle Scholar
  20. 20.
    Barnes BJ, Kellum MJ, Pinder KE, Frisancho JA, Pitha PM. Interferon regulatory factor 5, a novel mediator of cell cycle arrest and cell death. Cancer Res. 2003;63:6424–31.Google Scholar
  21. 21.
    Hu G, Mancl M, Barnes BJ. Signaling through IFN regulatory factor-5 sensitizes p53-deficient tumors to DNA damage-induced apoptosis and cell death. Cancer Res. 2005;65:7403–12.CrossRefGoogle Scholar
  22. 22.
    Hu G, Barnes BJ. IRF-5 is a critical mediator of the death receptor-induced apoptotic signaling pathway. J Biol Chem. 2009;284:2767–77.CrossRefGoogle Scholar
  23. 23.
    Couzinet A, Tamura K, Chen HM, Nishimura K, Wang ZC, Morishita T, et al. A cell-type-specific requirement for IFN regulatory factor 5 (IRF5) in Fas-induced apoptosis. Proc Natl Acad Sci U S A. 2008;105:2556–61.CrossRefGoogle Scholar
  24. 24.
    Stone RC, Du P, Feng D, Dhawan K, Ronnblom L, Eloranta ML, et al. RNA-Seq for enrichment and analysis of IRF5 transcript expression in SLE. PLoS One. 2013;8:e54487.CrossRefGoogle Scholar
  25. 25.
    • Calise J, Marquez Renteria S, Gregersen PK, Diamond B. Lineage-specific functionality of an interferon regulatory factor 5 lupus risk haplotype: lack of B cell intrinsic effects. Front Immunol. 2018;9:996 This is the first study to document no effect of an IRF5 risk haplotype on IRF5 mRNA expression in genotyped healthy donors.CrossRefGoogle Scholar
  26. 26.
    Griesbeck M, Ziegler S, Laffont S, Smith N, Chauveau L, Tomezsko P, et al. Sex differences in plasmacytoid dendritic cell levels of IRF5 drive higher IFN-α production in women. J Immunol. 2015;195:5327–36.CrossRefGoogle Scholar
  27. 27.
    Berggren O, Alexsson A, Morris DL, Tandre K, Weber G, Vyse TJ, et al. IFN-α production by plasmacytoid dendritic cell associations with polymorphisms in gene loci related to autoimmune and inflammatory diseases. Hum Mol Genet. 2015;24:3571–81.CrossRefGoogle Scholar
  28. 28.
    Takaoka A, Yanai H, Kondo S, Duncan G, Negishi H, Mizutani T, et al. Integral role of IRF-5 in the gene induction programme activated by toll-like receptors. Nature. 2005;434:243–9.CrossRefGoogle Scholar
  29. 29.
    Yanai H, Chen HM, Inuzuka T, Kondo S, Mak TW, Takaoka A, et al. Role of IFN regulatory factor 5 transcription factor in antiviral immunity and tumor suppression. Proc Natl Acad Sci U S A. 2007;104:3402–7.CrossRefGoogle Scholar
  30. 30.
    Krausgruber T, Blazek K, Smallie T, Alzabin S, Lockstone H, Sahgal N, et al. IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses. Nat Immunol. 2011;12:231–8.CrossRefGoogle Scholar
  31. 31.
    Richez C, Yasuda K, Bonegio RG, Watkins AA, Aprahamian T, Busto P, 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.CrossRefGoogle Scholar
  32. 32.
    Tada Y, Kondo S, Aoki S, Koarada S, Inoue H, Suematsu R, et al. Interferon regulatory factor 5 is critical for the development of lupus in MRL/lpr mice. Arthritis Rheum. 2011;63:738–48.CrossRefGoogle Scholar
  33. 33.
    Feng D, Yang L, Bi X, Stone RC, Patel P, Barnes BJ. Irf5-deficient mice are protected from pristane-induced lupus via increased Th2 cytokines and altered IgG class switching. Eur J Immunol. 2012;42:1477–87.CrossRefGoogle Scholar
  34. 34.
    Xu Y, Lee PY, Li Y, Liu C, Zhuang H, Han S, et al. Pleiotropic IFN-dependent and -independent effects of IRF5 on the pathogenesis of experimental lupus. J Immunol. 2012;188:4113–21.CrossRefGoogle Scholar
  35. 35.
    Yasuda K, Watkins AA, Kochar GS, Wilson GE, Laskow B, Richez C, 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.CrossRefGoogle Scholar
  36. 36.
    Watkins AA, Yasuda K, Wilson GE, Aprahamian T, Xie Y, Maganto-Garcia E, et al. IRF5 deficiency ameliorates lupus but promotes atherosclerosis and metabolic dysfunction in a mouse model of lupus-associated atherosclerosis. J Immunol. 2015;194:1467–79.CrossRefGoogle Scholar
  37. 37.
    Savitsky DA, Yanai H, Tamura T, Taniguchi T, Honda K. 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;107:10154–9.CrossRefGoogle Scholar
  38. 38.
    Yang L, Feng D, Bi X, Stone RC, Barnes BJ. Monocytes from Irf5−/− mice have an intrinsic defect in their response to pristane-induced lupus. J Immunol. 2012;189:3741–50.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, Northwell Health, Feinstein Institute for Medical ResearchHofstra-Northwell School of MedicineHempsteadUSA

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