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.

  • Review Article
  • Published:

Pathogenetic mechanisms in the initiation and perpetuation of Sjögren's syndrome

Nature Reviews Rheumatology volume 6, pages 529–537 (2010)Cite this article

Subjects

Abstract

Sjögren's syndrome (SS), a chronic autoimmune disorder, particularly compromises the function of exocrine glands. The involvement of these glands is characterized by focal, mononuclear cell infiltrates that surround the ducts and replace the secretory units. The pathogenetic mechanisms of this autoimmune exocrinopathy have not been fully elucidated. Immunologically-activated or apoptotic glandular epithelial cells that expose autoantigens in genetically predisposed individuals might drive autoimmune-mediated tissue injury. Alterations in several immune mediators, such as upregulation of type I interferon-regulated genes, abnormal expression of B-cell-activating factor and activation of the interleukin-23–type 17 T-helper cell pathway, have been reported. Extension of the pathological process that affects the exocrine glands into periepithelial and extraepithelial tissue can cause a considerable percentage of patients to exhibit systemic findings that involve the lungs, liver or kidneys. These manifestations develop as a result of lymphocytic invasion or an immune-complex-mediated process, or both, and present as skin vasculitis coupled with peripheral neuropathy or glomerulonephritis (or both). Patients with systemic extraepithelial manifestations display low serum levels of the complement component C4 and mixed type II cryoglobulins, and show an increased risk of developing non-Hodgkin lymphoma, thereby reflecting an overall worse prognosis with higher mortality rates than those without extraepithelial manifestations.

Key Points

  • At the molecular and cellular levels, epithelial cells have an important role in the initiation and perpetuation of autoimmune lesions in Sjögren's syndrome (SS)

  • Antigen presentation, apoptosis, chemokine production or germinal center formation lie at the center of SS pathogenesis; epithelial cells have a key role in all these processes

  • Alterations in a number of immune mediators contribute to chronic immune dysregulation

  • These changes include: upregulation of type I-interferon-regulated genes; abnormal expression of B-cell-activating factor; and activation of the interleukin-23–T-helper type 17 cell pathway

  • Among autoimmune diseases, SS displays the highest incidence of malignant lymphoproliferative disorders

  • Severe involvement of exocrine glands, vasculitis, low C4 levels and cryoglobulinemia at diagnosis identify specific SS patients with a high risk of lymphoma development and therefore high mortality rates

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: Lesions in the salivary glands of patients with Sjögren's syndrome.
Figure 2: Cellular and molecular pathways implicated in the pathogenesis of Sjögren's syndrome.
Figure 3: B-cell hyperactivity, monoclonality and lymphomagenesis.

Similar content being viewed by others

References

  1. Anaya, J. M. & Talal, N. In Arthritis and Allied Conditions: a Textbook of Rheumatology 13th edn (ed. Koopman, W. J.) 1561–1580 (Williams & Wilkins, Baltimore, 1997).

    Google Scholar 

  2. Alamanos, Y. et al. Epidemiology of primary Sjögren's syndrome in north-west Greece, 1982–2003. Rheumatology (Oxford) 45, 187–191 (2006).

    Article  CAS  Google Scholar 

  3. Trontzas, P. I. & Andrianakos, A. A. Sjogren's syndrome: a population based study of prevalence in Greece. The ESORDIG study. Ann. Rheum. Dis. 64, 1240–1241 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bowman, S. J., Ibrahim, G. H., Holmes, G., Hamburger, J. & Ainsworth, J. R. Estimating the prevalence among Caucasian women of primary Sjögren's syndrome in two general practices in Birmingham, UK. Scand. J. Rheumatol. 33, 39–43 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Delaleu, N., Jonsson, M. V., Appel, S. & Jonsson, R. New concepts in the pathogenesis of Sjögren's syndrome. Rheum. Dis. Clin. North Am. 34, 833–845 (2008).

    Article  PubMed  Google Scholar 

  6. Venables, P. J. Sjögren's syndrome. Best Pract. Res. Clin. Rheumatol. 18, 313–329 (2004).

    CAS  PubMed  Google Scholar 

  7. Ramos-Casals, M. et al. SS-HCV Study Group. Sjögren syndrome associated with hepatitis C virus: a multicenter analysis of 137 cases. Medicine (Baltimore) 84, 81–89 (2005).

    Article  Google Scholar 

  8. Moutsopoulos, H. M. Sjögren's syndrome: autoimmune epithelitis. Clin. Immunol. Immunopathol. 72, 162–165 (1994).

    Article  CAS  PubMed  Google Scholar 

  9. Papiris, S. A. et al. Lung involvement in primary Sjögren's syndrome is mainly related to the small airway disease. Ann. Rheum. Dis. 58, 61–64 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tu, W. H., Shearn, M. A., Lee, J. C. & Hopper, J. Jr. Interstitial nephritis in Sjögren's syndrome. Ann. Intern. Med. 69, 1163–1170 (1968).

    Article  CAS  PubMed  Google Scholar 

  11. Skopouli, F. N., Barbatis, C. & Moutsopoulos, H. M. Liver involvement in primary Sjögren's syndrome. Br. J. Rheumatol. 33, 745–748 (1994).

    Article  CAS  PubMed  Google Scholar 

  12. Ramos-Casals, M. et al. Cutaneous vasculitis in primary Sjögren syndrome: classification and clinical significance of 52 patients. Medicine (Baltimore) 83, 96–106 (2004).

    Article  Google Scholar 

  13. Talal, N., Zisman, E. & Schur, P. H. Renal tubular acidosis, glomerulonephritis and immunologic factors in Sjögren's syndrome. Arthritis Rheum. 11, 774–786 (1968).

    Article  CAS  PubMed  Google Scholar 

  14. Tsokos, M., Lazarou, S. A. & Moutsopoulos, H. M. Vasculitis in primary Sjögren's syndrome. Histologic classification and clinical presentation. Am. J. Clin. Pathol. 88, 26–31 (1987).

    Article  CAS  PubMed  Google Scholar 

  15. Skopouli, F. N., Dafni, U., Ioannidis, J. P. & Moutsopoulos, H. M. Clinical evolution, and morbidity and mortality of primary Sjogren's syndrome. Semin. Arthritis Rheum. 29, 296–304 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Voulgarelis, M., Dafni, U. G., Isenberg, D. A. & Moutsopoulos, H. M. Malignant lymphoma in primary Sjögren's syndrome: a multicenter, retrospective, clinical study by the European Concerted Action on Sjögren's Syndrome. Arthritis Rheum. 42, 1765–1772 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Tzioufas, A. G., Boumba, D. S., Skopouli, F. N. & Moutsopoulos, H. M. Mixed monoclonal cryoglobulinemia and monoclonal rheumatoid factor cross-reactive idiotypes as predictive factors for the development of lymphoma in primary Sjögren's syndrome. Arthritis Rheum. 39, 767–772 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. Ioannidis, J. P., Vassiliou, V. A. & Moutsopoulos, H. M. Long-term risk of mortality and lymphoproliferative disease and predictive classification of primary Sjogren's syndrome. Arthritis Rheum. 46, 741–747 (2002).

    Article  PubMed  Google Scholar 

  19. Katsifis, G. E., Moutsopoulos, N. M. & Wahl, S. M. T lymphocytes in Sjögren's syndrome: contributors to and regulators of pathophysiology. Clin. Rev. Allergy Immunol. 32, 252–264 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Manoussakis, M. N. et al. Rates of infiltration by macrophages and dendritic cells and expression of interleukin-18 and interleukin-12 in the chronic inflammatory lesions of Sjögren's syndrome: correlation with certain features of immune hyperactivity and factors associated with high risk of lymphoma development. Arthritis Rheum. 56, 3977–3988 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Bolstad, A. I. & Jonsson, R. Genetic aspects of Sjögren's syndrome. Arthritis Res. 4, 353–359 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Gottenberg, J. E. et al. In primary Sjögren's syndrome, HLA class II is associated exclusively with autoantibody production and spreading of the autoimmune response. Arthritis Rheum. 48, 2240–2245 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Miyagawa, S. et al. Polymorphisms of HLA class II genes and autoimmune responses to Ro/SS-A–La/SS-B among Japanese subjects. Arthritis Rheum. 41, 927–934 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Miceli-Richard, C. et al. Association of an IRF5 gene functional polymorphism with Sjögren's syndrome. Arthritis Rheum. 56, 3989–3994 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Nordmark, G. et al. Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjögren's syndrome. Genes Immun. 10, 68–76 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. Shim, G. J. et al. Aromatase-deficient mice spontaneously develop a lymphoproliferative autoimmune disease resembling Sjogren's syndrome. Proc. Natl Acad. Sci. USA 101, 12628–12633 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ishimaru, N. et al. Expression of the retinoblastoma protein RbAp48 in exocrine glands leads to Sjögren's syndrome-like autoimmune exocrinopathy. J. Exp. Med. 205, 2915–2927 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Takeda, K., Kaisho, T. & Akira, S. Toll-like receptors. Annu. Rev. Immunol. 21, 335–376 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Pflugfelder, S. C. et al. Epstein–Barr virus and the lacrimal gland pathology of Sjögren's syndrome. Am. J. Pathol. 143, 49–64 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Green, J. E., Hinrichs, S. H., Vogel, J. & Jay, G. Exocrinopathy resembling Sjögren's syndrome in HTLV-1 tax transgenic mice. Nature 341, 72–74 (1989).

    Article  CAS  PubMed  Google Scholar 

  31. Saito, I., Servenius, B., Compton, T. & Fox, R. I. Detection of Epstein–Barr virus DNA by polymerase chain reaction in blood and tissue biopsies from patients with Sjögren's syndrome. J. Exp. Med. 169, 2191–2198 (1989).

    Article  CAS  PubMed  Google Scholar 

  32. Mariette, X., Gozlan, J., Clerc, D., Bisson, M. & Morinet, F. Detection of Epstein–Barr virus DNA by in situ hybridization and polymerase chain reaction in salivary gland biopsy specimens from patients with Sjögren's syndrome. Am. J. Med. 90, 286–294 (1991).

    Article  CAS  PubMed  Google Scholar 

  33. Inoue, H. et al. Possible involvement of EBV-mediated alpha-fodrin cleavage for organ-specific autoantigen in Sjögren's syndrome. J. Immunol. 166, 5801–5809 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Nagata, Y. et al. Activation of Epstein–Barr virus by saliva from Sjögren's syndrome patients. Immunology 111, 223–229 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yamaoka, K., Miyasaka, N. & Yamamoto, K. Possible involvement of Epstein–Barr virus in polyclonal B cell activation in Sjögren's syndrome. Arthritis Rheum. 31, 1014–1021 (1988).

    Article  CAS  PubMed  Google Scholar 

  36. Triantafyllopoulou, A., Tapinos, N. & Moutsopoulos, H. M. Evidence for coxsackievirus infection in primary Sjögren's syndrome. Arthritis Rheum. 50, 2897–2902 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Spachidou, M. P. et al. Expression of functional Toll-like receptors by salivary gland epithelial cells: increased mRNA expression in cells derived from patients with primary Sjögren's syndrome. Clin. Exp. Immunol. 147, 497–503 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gottenberg, J. E. et al. Failure to confirm coxsackievirus infection in primary Sjögren's syndrome. Arthritis Rheum. 54, 2026–2028 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Cha, S., Peck, A. B. & Humphreys-Beher, M. G. Progress in understanding autoimmune exocrinopathy using the non-obese diabetic mouse: an update. Crit. Rev. Oral Biol. Med. 13, 5–16 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. McArthur, C. P., Daniels, P. J., Kragel, P., Howard, P. F. & Julian, L. Sjögren's syndrome salivary gland immunopathology: increased laminin expression precedes lymphocytic infiltration. J. Autoimmun. 10, 59–65 (1997).

    Article  CAS  PubMed  Google Scholar 

  41. Goicovich, E. et al. Enhanced degradation of proteins of the basal lamina and stroma by matrix metalloproteinases from the salivary glands of Sjögren's syndrome patients: correlation with reduced structural integrity of acini and ducts. Arthritis Rheum. 48, 2573–2584 (2003).

    Article  CAS  PubMed  Google Scholar 

  42. Molina, C. et al. Basal lamina disorganisation of the acini and ducts of labial salivary glands from patients with Sjögren's syndrome: association with mononuclear cell infiltration. Ann. Rheum. Dis. 65, 178–183 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Pérez, P. et al. Differential expression of matrix metalloproteinases in labial salivary glands of patients with primary Sjögren's syndrome. Arthritis Rheum. 43, 2807–2817 (2000).

    Article  PubMed  Google Scholar 

  44. Aziz, K. E., McCluskey, P. J., Montanaro, A. & Wakefield, D. Vascular endothelium and lymphocyte adhesion molecules in minor salivary glands of patients with Sjögren's syndrome. J. Clin. Lab. Immunol. 37, 39–49 (1992).

    CAS  PubMed  Google Scholar 

  45. Xanthou, G. et al. “Lymphoid” chemokine messenger RNA expression by epithelial cells in the chronic inflammatory lesion of the salivary glands of Sjögren's syndrome patients: possible participation in lymphoid structure formation. Arthritis Rheum. 44, 408–418 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Moutsopoulos, H. M. et al. HLA-DR expression by labial minor salivary gland tissues in Sjögren's syndrome. Ann. Rheum. Dis. 45, 677–683 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Manoussakis, M. N. et al. Expression of B7 costimulatory molecules by salivary gland epithelial cells in patients with Sjögren's syndrome. Arthritis Rheum. 42, 229–239 (1999).

    Article  CAS  PubMed  Google Scholar 

  48. Matsumura, R. et al. Glandular and extraglandular expression of costimulatory molecules in patients with Sjögren's syndrome. Ann. Rheum. Dis. 60, 473–482 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Manoussakis, M. N. & Kapsogeorgou, E. K. The role of epithelial cells in the pathogenesis of Sjögren's syndrome. Clin. Rev. Allergy Immunol. 32, 225–230 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Tsunawaki, S. et al. Possible function of salivary gland epithelial cells as nonprofessional antigen-presenting cells in the development of Sjögren's syndrome. J. Rheumatol. 29, 1884–1896 (2002).

    CAS  PubMed  Google Scholar 

  51. Dimitriou, I. D., Kapsogeorgou, E. K., Moutsopoulos, H. M. & Manoussakis, M. N. CD40 on salivary gland epithelial cells: high constitutive expression by cultured cells from Sjögren's syndrome patients indicating their intrinsic activation. Clin. Exp. Immunol. 127, 386–392 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lavie, F. et al. Expression of BAFF (BLyS) in T cells infiltrating labial salivary glands from patients with Sjögren's syndrome. J. Pathol. 202, 496–502 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Ohlsson, M., Szodoray, P., Loro, L. L., Johannessen, A. C. & Jonsson, R. CD40, CD154, Bax and Bcl-2 expression in Sjögren's syndrome salivary glands: a putative anti-apoptotic role during its effector phases. Scand. J. Immunol. 56, 561–571 (2002).

    Article  CAS  PubMed  Google Scholar 

  54. Mitsias, D. I., Kapsogeorgou, E. K. & Moutsopoulos, H. M. The role of epithelial cells in the initiation and perpetuation of autoimmune lesions: lessons from Sjögren's syndrome (autoimmune epithelitis). Lupus 15, 255–261 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Jonsson, R., Gordon, T. P. & Konttinen, Y. T. Recent advances in understanding molecular mechanisms in the pathogenesis and antibody profile of Sjögren's syndrome. Curr. Rheumatol. Rep. 5, 311–316 (2003).

    Article  PubMed  Google Scholar 

  56. Vogelsang, P., Jonsson, M. V., Dalvin, S. T. & Appel, S. Role of dendritic cells in Sjögren's syndrome. Scand. J. Immunol. 64, 219–226 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Kong, L. et al. Bcl-2 family expression in salivary glands from patients with primary Sjögren's syndrome: involvement of Bax in salivary gland destruction. Clin. Immunol. Immunopathol. 88, 133–141 (1998).

    Article  CAS  PubMed  Google Scholar 

  58. Kapsogeorgou, E. K., Abu-Helu, R. F., Moutsopoulos, H. M. & Manoussakis, M. N. Salivary gland epithelial cell exosomes: A source of autoantigenic ribonucleoproteins. Arthritis Rheum. 52, 1517–1521 (2005).

    Article  CAS  PubMed  Google Scholar 

  59. Ittah, M. et al. B-cell-activating factor of the tumor necrosis factor family (BAFF) is expressed under stimulation by interferon in salivary gland epithelial cells in primary Sjögren's syndrome. Arthritis Res. Ther. 8, R51 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Ittah, M. et al. B-cell-activating factor expressions in salivary epithelial cells after dsRNA virus infection depends on RNA-activated protein kinase activation. Eur. J. Immunol. 39, 1271–1279 (2009).

    Article  CAS  PubMed  Google Scholar 

  61. Båve, U. et al. Activation of the type I interferon system in primary Sjögren's syndrome: a possible etiopathogenic mechanism. Arthritis Rheum. 52, 1185–1195 (2005).

    Article  PubMed  CAS  Google Scholar 

  62. Gottenberg, J. E. et al. Activation of IFN pathways and plasmacytoid dendritic cell recruitment in target organs of primary Sjögren's syndrome. Proc. Natl Acad. Sci. USA 103, 2770–2775 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ma-Krupa, W. et al. Activation of arterial wall dendritic cells and breakdown of self-tolerance in giant cell arteritis. J. Exp. Med. 199, 173–183 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Deshmukh, U. S., Nandula, S. R., Thimmalapura, P. R., Scindia, Y. M. & Bagavant, H. Activation of innate immune responses through Toll-like receptor 3 causes a rapid loss of salivary gland function. J. Oral Pathol. Med. 38, 42–47 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Robinson, C. P. et al. Characterization of the changing lymphocyte populations and cytokine expression in the exocrine tissues of autoimmune NOD mice. Autoimmunity 27, 29–44 (1998).

    Article  CAS  PubMed  Google Scholar 

  66. Robinson, C. P. et al. Infiltrating lymphocyte populations and cytokine production in the salivary and lacrimal glands of autoimmune NOD mice. Adv. Exp. Med. Biol. 438, 493–497 (1998).

    Article  CAS  PubMed  Google Scholar 

  67. Kolkowski, E. C. et al. TH1 predominance and perforin expression in minor salivary glands from patients with primary Sjögren's syndrome. J. Autoimmun. 13, 155–162 (1999).

    Article  CAS  PubMed  Google Scholar 

  68. Mitsias, D. I. et al. The TH1/TH2 cytokine balance changes with the progress of the immunopathological lesion of Sjogren's syndrome. Clin. Exp. Immunol. 128, 562–568 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Nguyen, C. Q., Hu, M. H., Li, Y., Stewart, C. & Peck, A. B. Salivary gland tissue expression of interleukin-23 and interleukin-17 in Sjögren's syndrome: findings in humans and mice. Arthritis Rheum. 58, 734–743 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Bettelli, E., Korn, T., Oukka, M. & Kuchroo, V. K. Induction and effector functions of TH17 cells. Nature 453, 1051–1057 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Espinosa, A. et al. Loss of the lupus autoantigen Ro52/Trim21 induces tissue inflammation and systemic autoimmunity by disregulating the IL-23–TH17 pathway. J. Exp. Med. 206, 1661–1671 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Katsifis, G. E., Rekka, S., Moutsopoulos, N. M., Pillemer, S. & Wahl, S. M. Systemic and local interleukin 17 and linked cytokines associated with Sjögren's syndrome immunopathogenesis. Am. J. Pathol. 175, 1167–1177 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Christodoulou, M. I., Kapsogeorgou, E. K., Moutsopoulos, N. M. & Moutsopoulos, H. M. Foxp3+ T-regulatory cells in Sjögren's syndrome: correlation with the grade of the autoimmune lesion and certain adverse prognostic factors. Am. J. Pathol. 173, 1389–1396 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Christodoulou, M. I., Kapsogeorgou, E. K. & Moutsopoulos, H. M. Characteristics of the minor salivary gland infiltrates in Sjögren's syndrome. J. Autoimmun. 34, 400–407 (2010).

    Article  CAS  PubMed  Google Scholar 

  75. Zintzaras, E., Voulgarelis, M. & Moutsopoulos, H. M. The risk of lymphoma development in autoimmune diseases: a meta-analysis. Arch. Intern. Med. 165, 2337–2344 (2005).

    Article  PubMed  Google Scholar 

  76. Fox, R. I. Sjögren's syndrome. Lancet 366, 321–331 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Salomonsson, S. et al. Cellular basis of ectopic germinal center formation and autoantibody production in the target organ of patients with Sjögren's syndrome. Arthritis Rheum. 48, 3187–3201 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Hansen, A., Lipsky, P. E. & Dörner, T. B cells in Sjögren's syndrome: indications for disturbed selection and differentiation in ectopic lymphoid tissue. Arthritis Res. Ther. 9, 218 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Jonsson, M. V., Skarstein, K., Jonsson, R. & Brun, J. G. Serological implications of germinal center-like structures in primary Sjögren's syndrome. J. Rheumatol. 34, 2044–2049 (2007).

    PubMed  Google Scholar 

  80. Le Pottier, L. et al. Ectopic germinal centers are rare in Sjögren's syndrome salivary glands and do not exclude autoreactive B cells. J. Immunol. 182, 3540–3547 (2009).

    Article  CAS  PubMed  Google Scholar 

  81. Szodoray, P. et al. Distinct profiles of Sjögren's syndrome patients with ectopic salivary gland germinal centers revealed by serum cytokines and BAFF. Clin. Immunol. 117, 168–176 (2005).

    Article  CAS  PubMed  Google Scholar 

  82. Daridon, C. et al. Aberrant expression of BAFF by B lymphocytes infiltrating the salivary glands of patients with primary Sjögren's syndrome. Arthritis Rheum. 56, 1134–1144 (2007).

    Article  CAS  PubMed  Google Scholar 

  83. Sutherland, A. P., Mackay, F. & Mackay, C. R. Targeting BAFF: immunomodulation for autoimmune diseases and lymphomas. Pharmacol. Ther. 112, 774–786 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Mariette, X. et al. The level of BLyS (BAFF) correlates with the titre of autoantibodies in human Sjögren's syndrome. Ann. Rheum. Dis. 62, 168–171 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Groom, J. et al. Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjögren's syndrome. J. Clin. Invest. 109, 59–68 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Cheema, G. S., Roschke, V., Hilbert, D. M. & Stohl, W. Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases. Arthritis Rheum. 44, 1313–1319 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Sellam, J. et al. Decreased B cell activating factor receptor expression on peripheral lymphocytes associated with increased disease activity in primary Sjögren's syndrome and systemic lupus erythematosus. Ann. Rheum. Dis. 66, 790–797 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Jacobi, A. M. et al. Correlation between circulating CD27high plasma cells and disease activity in patients with systemic lupus erythematosus. Arthritis Rheum. 48, 1332–1342 (2003).

    Article  PubMed  Google Scholar 

  89. Hansen, A. et al. Diminished peripheral blood memory B cells and accumulation of memory B cells in the salivary glands of patients with Sjögren's syndrome. Arthritis Rheum. 46, 2160–2171 (2002).

    Article  CAS  PubMed  Google Scholar 

  90. DiGiuseppe, J. A., Corio, R. L. & Westra, W. H. Lymphoid infiltrates of the salivary glands: pathology, biology and clinical significance. Curr. Opin. Oncol. 8, 232–237 (1996).

    Article  CAS  PubMed  Google Scholar 

  91. Hansen, A., Lipsky, P. E. & Dörner, T. B-cell lymphoproliferation in chronic inflammatory rheumatic diseases. Nat. Clin. Pract. Rheumatol. 3, 561–569 (2007).

    Article  CAS  PubMed  Google Scholar 

  92. Tapinos, N. I., Polihronis, M. & Moutsopoulos, H. M. Lymphoma development in Sjögren's syndrome: novel p53 mutations. Arthritis Rheum. 42, 1466–1472 (1999).

    Article  CAS  PubMed  Google Scholar 

  93. Kassan, S. S. et al. Increased risk of lymphoma in sicca syndrome. Ann. Inter. Med. 89, 888–892 (1978).

    Article  CAS  Google Scholar 

  94. Baimpa, E., Dahabreh, I. J., Voulgarelis, M. & Moutsopoulos, H. M. Hematologic manifestations and predictors of lymphoma development in primary Sjögren syndrome: clinical and pathophysiologic aspects. Medicine (Baltimore) 88, 284–293 (2009).

    Article  Google Scholar 

  95. Mariette, X. Lymphomas complicating Sjögren's syndrome and hepatitis C virus infection may share a common pathogenesis: chronic stimulation of rheumatoid factor B cells. Ann. Rheum. Dis. 60, 1007–1010 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Anderson, L. G. & Talal, N. The spectrum of benign to malignant lymphoproliferation in Sjogren's syndrome. Clin. Exp. Immunol. 10, 199–221 (1972).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Anaya, J. M., McGuff, H. S., Banks, P. M. & Talal, N. Clinicopathological factors relating malignant lymphoma with Sjogren's syndrome. Semin. Arthritis Rheum. 25, 337–346 (1996).

    Article  CAS  PubMed  Google Scholar 

  98. Valesini, G. et al. Differential risk of non-Hodgkin's lymphoma in Italian patients with primary Sjogren's syndrome. J. Rheumatol. 24, 2376–2380 (1997).

    CAS  PubMed  Google Scholar 

  99. Theander, E. et al. Lymphoma and other malignancies in primary Sjogren's syndrome: A cohort study on cancer incidence and lymphoma predictors. Ann. Rheum. Dis. 65, 796–803 (2006).

    Article  CAS  PubMed  Google Scholar 

  100. Voulgarelis, M., Tzioufas, A. G. & Moutsopoulos, H. M. Mortality in Sjögren's syndrome. Clin. Exp. Rheumatol. 26 (5 Suppl. 51), S66–S71 (2008).

    CAS  PubMed  Google Scholar 

  101. Theander, E., Manthorpe, R. & Jacobsson, L. T. Mortality and causes of death in primary Sjögren's syndrome: a prospective cohort study. Arthritis Rheum. 50, 1262–1269 (2004).

    Article  PubMed  Google Scholar 

  102. Alamanos, Y. et al. Epidemiology of primary Sjögren's syndrome in north-west Greece, 1982–2003. Rheumatology (Oxford) 45, 187–191 (2006).

    Article  CAS  Google Scholar 

  103. Brito-Zerón, P., Ramos-Casals, M., Bove, A., Sentis, J. & Font, J. Predicting adverse outcomes in primary Sjogren's syndrome: identification of prognostic factors. Rheumatology (Oxford) 46, 1359–1362 (2007).

    Article  Google Scholar 

  104. Ramos-Casals, M. et al. Hypocomplementaemia as an immunological marker of morbidity and mortality in patients with primary Sjogren's syndrome. Rheumatology (Oxford) 44, 89–94 (2005).

    Article  CAS  Google Scholar 

  105. Martens, P. B., Pillemer, S. R., Jacobsson, L. T., O'Fallon, W. M. & Matteson, E. L. Survivorship in a population based cohort of patients with Sjögren's syndrome, 1976–1992. J. Rheumatol. 26, 1296–1300 (1999).

    CAS  PubMed  Google Scholar 

  106. Pertovaara, M., Pukkala, E., Laippala, P., Miettinen, A. & Pasternack, A. A longitudinal cohort study of Finnish patients with primary Sjögren's syndrome: clinical, immunological, and epidemiological aspects. Ann. Rheum. Dis. 60, 467–472 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Scalzi, L. V., Ballou, S. P., Park, J. Y., Redline, S. & Kirchner, H. L. Cardiovascular disease risk awareness in systemic lupus erythematosus patients. Arthritis Rheum. 58, 1458–1464 (2008).

    Article  PubMed  Google Scholar 

  108. Vaudo, G. et al. Precocious intima–media thickening in patients with primary Sjögren's syndrome. Arthritis Rheum. 52, 3890–3897 (2005).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Professor H. M. Moutsopoulos for his inspiration and guidance.

Author information

Authors and Affiliations

  1. Department of Pathophysiology, Medical School, National University of Athens, 75 Mikras Asias Street, Athens, 11527, Greece

    Michael Voulgarelis & Athanasios G. Tzioufas

Authors
  1. Michael Voulgarelis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Athanasios G. Tzioufas
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M. Voulgarelis researched the data for the article, provided a substantial contribution to the discussion of content and wrote the article. A. G. Tzioufas reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Michael Voulgarelis.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Voulgarelis, M., Tzioufas, A. Pathogenetic mechanisms in the initiation and perpetuation of Sjögren's syndrome. Nat Rev Rheumatol 6, 529–537 (2010). https://doi.org/10.1038/nrrheum.2010.118

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrrheum.2010.118

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing