Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Peripheral blood gene expression profiling in Sjögren's syndrome

Genes & Immunity volume 10, pages 285–296 (2009)Cite this article

Abstract

Sjögren's syndrome (SS) is a common chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands. The affected cases commonly present with oral and ocular dryness, which is thought to be the result of inflammatory cell-mediated gland dysfunction. To identify important molecular pathways involved in SS, we used high-density microarrays to define global gene expression profiles in the peripheral blood. We first analyzed 21 SS cases and 23 controls, and identified a prominent pattern of overexpressed genes that are inducible by interferons (IFNs). These results were confirmed by evaluation of a second independent data set of 17 SS cases and 22 controls. Additional inflammatory and immune-related pathways with altered expression patterns in SS cases included B- and T-cell receptor, insulin-like growth factor-1, granulocyte macrophage-colony stimulating factor, peroxisome proliferator-activated receptor-α/retinoid X receptor-α and PI3/AKT signaling. Exploration of these data for relationships to clinical features of disease showed that expression levels for most interferon-inducible genes were positively correlated with titers of anti-Ro/SSA (P<0.001) and anti-La/SSB (P<0.001) autoantibodies. Diagnostic and therapeutic approaches targeting interferon-signaling pathway may prove most effective in the subset of SS cases that produce anti-Ro/SSA and anti-La/SSB autoantibodies. Our results strongly support innate and adaptive immune processes in the pathogenesis of SS, and provide numerous candidate disease markers for further study.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Lahita RG . Sjögren's Syndrome: Textbook of the Autoimmune Diseases. Lippincott Williams & Wilkins: Philadelphia, 2000: 569–572pp.

    Google Scholar 

  2. Rhodus NL . An update on the management for the dental patient with Sjögren's syndrome and xerostomia. Northwest Dent 1999; 78: 27–34.

    CAS  PubMed  Google Scholar 

  3. Masaki Y, Sugai S . Lymphoproliferative disorders in Sjogren's syndrome. Autoimmun Rev 2004; 3: 175–182.

    Article  Google Scholar 

  4. Kassan SS, Thomas TL, Moutsopoulos HM, Hoover R, Kimberly RP, Budman DR et al. Increased risk of lymphoma in sicca syndrome. Ann intern med 1978; 89: 888–892.

    Article  CAS  Google Scholar 

  5. Fox PC, Speight PM . Current concepts of autoimmune exocrinopathy: immunologic mechanisms in the salivary pathology of Sjogren's syndrome. Crit Rev Oral Biol Med 1996; 7: 144–158.

    Article  CAS  Google Scholar 

  6. Delaleu N, Jonsson R, Koller MM . Sjogren's syndrome. Eur J Oral Sci 2005; 113: 101–113.

    Article  CAS  Google Scholar 

  7. Fox RI . Sjogren's syndrome. Lancet 2005; 366: 321–331.

    Article  CAS  Google Scholar 

  8. Ogawa N, Dang H, Talal N . Apoptosis and autoimmunity. J Autoimmun 1995; 8: 1–19.

    Article  CAS  Google Scholar 

  9. James JA, Harley JB, Scofield RH . Role of viruses in systemic lupus erythematosus and Sjogren syndrome. Curr Opin Rheumatol 2001; 13: 370–376.

    Article  CAS  Google Scholar 

  10. Triantafyllopoulou A, Tapinos N, Moutsopoulos HM . Evidence for coxsackievirus infection in primary Sjogren's syndrome. Arthritis Rheum 2004; 50: 2897–2902.

    Article  CAS  Google Scholar 

  11. Bolstad A, Jonsson R . Genetic aspects of Sjogren's syndrome. Arthritis Res 2002; 4: 353–359.

    Article  Google Scholar 

  12. Miceli-Richard C, Comets E, Loiseau P, Puechal X, Hachulla E, Mariette X . Association of an IRF5 gene functional polymorphism with Sjogren's syndrome. Arthritis Rheum 2007; 56: 3989–3994.

    Article  CAS  Google Scholar 

  13. Imanishi T, Morinobu A, Hayashi N, Kanagawa S, Koshiba M, Kondo S et al. A novel polymorphism of the SSA1 gene is associated with anti-SS-A/Ro52 autoantibody in Japanese patients with primary Sjogren's syndrome. Clin Exp Rheumatol 2005; 23: 521–524.

    CAS  PubMed  Google Scholar 

  14. Pertovaara M, Hurme M, Antonen J, Pasternack A, Pandey JP . Immunoglobulin KM and GM gene polymorphisms modify the clinical presentation of primary Sjogren's syndrome. J Rheumatol 2004; 31: 2175–2180.

    CAS  PubMed  Google Scholar 

  15. Pertovaara M, Lehtimaki T, Rontu R, Antonen J, Pasternack A, Hurme M . Presence of apolipoprotein E epsilon4 allele predisposes to early onset of primary Sjogren's syndrome. Rheumatology (Oxford) 2004; 43: 1484–1487.

    Article  CAS  Google Scholar 

  16. Hjelmervik TO, Petersen K, Jonassen I, Jonsson R, Bolstad AI . Gene expression profiling of minor salivary glands clearly distinguishes primary Sjogren's syndrome patients from healthy control subjects. Arthritis rheum 2005; 52: 1534–1544.

    Article  CAS  Google Scholar 

  17. Gottenberg JE, Cagnard N, Lucchesi C, Letourneur F, Mistou S, Lazure T et al. Activation of IFN pathways and plasmacytoid dendritic cell recruitment in target organs of primary Sjogren's syndrome. Proc Natl Acad Sci USA 2006; 103: 2770–2775.

    Article  CAS  Google Scholar 

  18. Baechler EC, Batliwalla FM, Reed AM, Peterson EJ, Gaffney PM, Moser KL et al. Gene expression profiling in human autoimmunity. Immunol Rev 2006; 210: 120–137.

    Article  CAS  Google Scholar 

  19. Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE et al. Classification criteria for Sjogren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 2002; 61: 554–558.

    Article  CAS  Google Scholar 

  20. Hu S, Wang J, Meijer J, Ieong S, Xie Y, Yu T et al. Salivary proteomic and genomic biomarkers for primary Sjogren's syndrome. Arthritis Rheum 2007; 56: 3588–3600.

    Article  CAS  Google Scholar 

  21. Wakamatsu E, Nakamura Y, Matsumoto I, Goto D, Ito S, Tsutsumi A et al. DNA microarray analysis of labial salivary glands of patients with Sjogren's syndrome. Ann Rheum Dis 2007; 66: 844–845.

    Article  CAS  Google Scholar 

  22. Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci USA 2003; 100: 2610–2615.

    Article  CAS  Google Scholar 

  23. Harada H, Takahashi E, Itoh S, Harada K, Hori TA, Taniguchi T . Structure and regulation of the human interferon regulatory factor 1 (IRF-1) and IRF-2 genes: implications for a gene network in the interferon system. Mol Cell Biol 1994; 14: 1500–1509.

    Article  CAS  Google Scholar 

  24. Taniguchi T, Ogasawara K, Takaoka A, Tanaka N . IRF family of transcription factors as regulators of host defense. Annu Rev Immunol 2001; 19: 623–655.

    Article  CAS  Google Scholar 

  25. Zhang L, Pagano JS . Structure and function of IRF-7. J Interferon Cytokine Res 2002; 22: 95–101.

    Article  Google Scholar 

  26. Ning S, Huye LE, Pagano JS . Regulation of the transcriptional activity of the IRF7 promoter by a pathway independent of interferon signaling. J Biol Chem 2005; 280: 12262–12270.

    Article  CAS  Google Scholar 

  27. Harley JB, Alarcon-Riquelme ME, Criswell LA, Jacob CO, Kimberly RP, Moser KL et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet 2008; 40: 204–210.

    Article  CAS  Google Scholar 

  28. Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl j Med 2007; 357: 977–986.

    Article  CAS  Google Scholar 

  29. 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 USA 2007; 104: 6758–6763.

    Article  CAS  Google Scholar 

  30. Korman BD, Alba MI, Le JM, Alevizos I, Smith JA, Nikolov NP et al. Variant form of STAT4 is associated with primary Sjogren's syndrome. Genes immun 2008; 9: 267–270.

    Article  CAS  Google Scholar 

  31. Nordmark G, Alm GV, Ronnblom L . Mechanisms of disease: primary Sjogren's syndrome and the type I interferon system. Nat Clin Pract Rheumatol 2006; 2: 262–269.

    Article  CAS  Google Scholar 

  32. Samuel CE . Antiviral actions of interferons. Clin Microbiol Rev 2001; 14: 778–809, table of contents.

    Article  CAS  Google Scholar 

  33. Irie-Sasaki J, Sasaki T, Matsumoto W, Opavsky A, Cheng M, Welstead G et al. CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling. Nature 2001; 409: 349–354.

    Article  CAS  Google Scholar 

  34. Jacobsen M, Schweer D, Ziegler A, Gaber R, Schock S, Schwinzer R et al. A point mutation in PTPRC is associated with the development of multiple sclerosis. Nat Genet 2000; 26: 495–499.

    Article  CAS  Google Scholar 

  35. Katz J, Stavropoulos F, Cohen D, Robledo J, Stewart C, Heft M . IGF-1 and insulin receptor expression in the minor salivary gland tissues of Sjogren's syndrome and mucoceles—immunohistochemical study. Oral Dis 2003; 9: 7–13.

    Article  CAS  Google Scholar 

  36. Mustafa W, Mustafa A, Elbakri N, Link H, Adem A . Reduced levels of insulin-like growth factor-1 receptor (IGF-1R) suppress cellular signaling in experimental autoimmune sialadenitis (EAS). J Recept Signal Transduct Res 2001; 21: 47–54.

    Article  CAS  Google Scholar 

  37. Tan NS, Michalik L, Desvergne B, Wahli W . Multiple expression control mechanisms of peroxisome proliferator-activated receptors and their target genes. J Steroid Biochem Mol Biol 2005; 93: 99–105.

    Article  CAS  Google Scholar 

  38. Daynes RA, Jones DC . Emerging roles of PPARs in inflammation and immunity. Nat Rev Immunol 2002; 2: 748–759.

    Article  CAS  Google Scholar 

  39. Delerive P, De Bosscher K, Besnard S, Vanden Berghe W, Peters JM, Gonzalez FJ et al. Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1. J Biol Chem 1999; 274: 32048–32054.

    Article  CAS  Google Scholar 

  40. Dunn SE, Ousman SS, Sobel RA, Zuniga L, Baranzini SE, Youssef S et al. Peroxisome proliferator-activated receptor (PPAR)alpha expression in T cells mediates gender differences in development of T cell-mediated autoimmunity. J Exp Med 2007; 204: 321–330.

    Article  CAS  Google Scholar 

  41. Sertznig P, Seifert M, Tilgen W, Reichrath J . Peroxisome proliferator-activated receptors (PPARs) and the human skin: importance of PPARs in skin physiology and dermatologic diseases. Am J Clin Dermatol 2008; 9: 15–31.

    Article  Google Scholar 

  42. Beauregard C, Brandt PC . Peroxisome proliferator-activated receptor agonists inhibit interleukin-1beta-mediated nitric oxide production in cultured lacrimal gland acinar cells. J Ocul Pharmacol Ther 2003; 19: 579–587.

    Article  CAS  Google Scholar 

  43. Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Moser K, Ortmann WA et al. Expression levels for many genes in human peripheral blood cells are highly sensitive to ex vivo incubation. Genes immun 2004; 5: 347–353.

    Article  CAS  Google Scholar 

  44. Eisen MB, Spellman PT, Brown PO, Botstein D . Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA 1998; 95: 14863–14868.

    Article  CAS  Google Scholar 

  45. Whitney AR, Diehn M, Popper SJ, Alizadeh AA, Boldrick JC, Relman DA et al. Individuality and variation in gene expression patterns in human blood. Proc Natl Acad Sci USA 2003; 100: 1896–1901.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was funded by NIH NIAMS RO1 AR050782 and the Phileona Foundation (KLM). The authors are grateful for resources provided by the University of Minnesota Supercomputing Institute and the Affymetrix core. We also thank Carolyn M Meyer, Amber N Leiran, Liliana Tobon, Daniella Machado and Julie Ermer for their technical assistance, and Jennifer Lessard for assistance with graphics. Finally, we thank the study participants without whom this study would not be possible.

Author information

Authors and Affiliations

  1. Department of Diagnostic and Biological Sciences, University of Minnesota, Minneapolis, MN, USA

    E S Emamian & N L Rhodus

  2. Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA

    J M Leon

  3. Arthritis and Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA

    J M Leon, C J Lessard, P M Gaffney & K L Moser

  4. Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    C J Lessard & K L Moser

  5. Allina Medical Clinic, St Paul, MN, USA

    M Grandits

  6. Department of Medicine, University of Minnesota, Minneapolis, MN, USA

    E C Baechler & B Segal

Authors
  1. E S Emamian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J M Leon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C J Lessard
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Grandits
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E C Baechler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P M Gaffney
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B Segal
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. N L Rhodus
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. K L Moser
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K L Moser.

Additional information

Supplementary Information accompanies the paper on Genes and Immunity website (http://www.nature.com/gene)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Emamian, E., Leon, J., Lessard, C. et al. Peripheral blood gene expression profiling in Sjögren's syndrome. Genes Immun 10, 285–296 (2009). https://doi.org/10.1038/gene.2009.20

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gene.2009.20

Keywords

This article is cited by

Search

Advanced search

Quick links