Pathogenetic Aspects of Primary Sjögren’s Syndrome

  • Athanasios G. Tzioufas
  • Efstathia K. Kapsogeorgou
  • Menelaos N. Manoussakis
  • Haralampos M. Moutsopoulos


Sjögren’s syndrome (SjS) is an ideal model for dissecting the pathogenetic aspects of autoimmune disorders because the affected organs, the labial minor salivary glands, are easily accessible with minimal morbidity to the patient, and patient’s sera are rich with autoantibodies directed against organ-specific and non-organ specific antigens. Two major biologic phenomena underlie the autoimmune nature of SjS: (1) the peri-epithelial lymphocytic infiltration of the affected tissues; and (2) B lymphocyte hyperreactivity. Several studies in the past several years have pointed to the central role of the epithelial cell in the pathogenesis of the disease, suggesting that the condition, in effect, is an “autoimmune epithelitis” [1]. The importance of B cell hyperreactivity is demonstrated by the presence of hypergammaglobulinemia and the large array of autoantibodies associated with SjS.


Salivary Gland Lacrimal Gland Minor Salivary Gland Exocrine Gland Salivary Gland Epithelial Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Moutsopoulos HM. Sjogren’s syndrome: autoimmune epithelitis. Clin Immunol Immunopathol. 1994;72:162–5.PubMedGoogle Scholar
  2. 2.
    Tarpley Jr TM, Anderson LG, White CL. Minor salivary gland involvement in Sjogren’s ­syndrome. Oral Surg Oral Med Oral Pathol. 1974;37:64–74.PubMedGoogle Scholar
  3. 3.
    Hansen A, Lipsky PE, Dorner T. B cells in Sjogren’s syndrome: indications for disturbed selection and differentiation in ectopic lymphoid tissue. Arthritis Res Ther. 2007;9:218.PubMedGoogle Scholar
  4. 4.
    Christodoulou MI, Kapsogeorgou EK, Moutsopoulos HM. Characteristics of the minor ­salivary gland infiltrates in Sjogren’s syndrome. J Autoimmun. 2010;34:400–7.PubMedGoogle Scholar
  5. 5.
    Bluestone JA, Tang Q. How do CD4+CD25+ regulatory T cells control autoimmunity? Curr Opin Immunol. 2005;17:638–42.PubMedGoogle Scholar
  6. 6.
    Christodoulou MI, Kapsogeorgou EK, Moutsopoulos NM, Moutsopoulos HM. Foxp3+ T-regulatory cells in Sjogren’s syndrome: correlation with the grade of the autoimmune lesion and certain adverse prognostic factors. Am J Pathol. 2008;173:1389–96.PubMedGoogle Scholar
  7. 7.
    Skopouli FN, Fox PC, Galanopoulou V, Atkinson JC, Jaffe ES, Moutsopoulos HM. T cell subpopulations in the labial minor salivary gland histopathologic lesion of Sjogren’s syndrome. J Rheumatol. 1991;18:210–4.PubMedGoogle Scholar
  8. 8.
    Ohyama Y, Nakamura S, Matsuzaki G, Shinohara M, Hiroki A, Oka M, et al. T-cell receptor V alpha and V beta gene use by infiltrating T cells in labial glands of patients with Sjogren’s syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1995;79:730–7.PubMedGoogle Scholar
  9. 9.
    Matsumoto I, Tsubota K, Satake Y, Kita Y, Matsumura R, Murata H, et al. Common T cell receptor clonotype in lacrimal glands and labial salivary glands from patients with Sjogren’s syndrome. J Clin Invest. 1996;97:1969–77.PubMedGoogle Scholar
  10. 10.
    Sumida T, Yonaha F, Maeda T, Tanabe E, Koike T, Tomioka H, et al. T cell receptor repertoire of infiltrating T cells in lips of Sjogren’s syndrome patients. J Clin Invest. 1992;89:681–5.PubMedGoogle Scholar
  11. 11.
    Sumida T, Kita Y, Yonaha F, Maeda T, Iwamoto I, Yoshida S. T cell receptor V alpha repertoire of infiltrating T cells in labial salivary glands from patients with Sjogren’s syndrome. J Rheumatol. 1994;21:1655–61.PubMedGoogle Scholar
  12. 12.
    Namekawa T, Kuroda K, Kato T, Yamamoto K, Murata H, Sakamaki T, et al. Identification of Ro(SjSA) 52 kDa reactive T cells in labial salivary glands from patients with Sjogren’s syndrome. J Rheumatol. 1995;22:2092–9.PubMedGoogle Scholar
  13. 13.
    Hansen A, Odendahl M, Reiter K, Jacobi AM, Feist E, Scholze J, et al. Diminished peripheral blood memory B cells and accumulation of memory B cells in the salivary glands of patients with Sjogren’s syndrome. Arthritis Rheum. 2002;46:2160–71.PubMedGoogle Scholar
  14. 14.
    Dorner T, Lipsky PE. Abnormalities of B cell phenotype, immunoglobulin gene expression and the emergence of autoimmunity in Sjogren’s syndrome. Arthritis Res. 2002;4:360–71.PubMedGoogle Scholar
  15. 15.
    Matthews JB, Deacon EM, Wilson C, Potts AJ, Hamburger J. Plasma cell populations in labial ­salivary glands from patients with and without Sjogren’s syndrome. Histopathology. 1993;23:399–407.PubMedGoogle Scholar
  16. 16.
    Salomonsson S, Rozell BL, Heimburger M, Wahren-Herlenius M. Minor salivary gland ­immunohistology in the diagnosis of primary Sjogren’s syndrome. J Oral Pathol Med. 2009;38:282–8.PubMedGoogle Scholar
  17. 17.
    Speight PM, Cruchley A, Williams DM. Quantification of plasma cells in labial salivary glands: increased expression of IgM in Sjogren’s syndrome. J Oral Pathol Med. 1990;19:126–30.PubMedGoogle Scholar
  18. 18.
    Halse A, Harley JB, Kroneld U, Jonsson R. Ro/SjS-A-reactive B lymphocytes in salivary glands and peripheral blood of patients with Sjogren’s syndrome. Clin Exp Immunol. 1999;115:203–7.PubMedGoogle Scholar
  19. 19.
    Deacon EM, Matthews JB, Potts AJ, Hamburger J, Mageed RA, Jefferis R. Expression of rheumatoid factor associated cross-reactive idiotopes by glandular B cells in Sjogren’s syndrome. Clin Exp Immunol. 1991;83:280–5.PubMedGoogle Scholar
  20. 20.
    Fox RI, Chen P, Carson DA, Fong S. Expression of a cross-reactive idiotype on rheumatoid factor in patients with Sjogren’s syndrome. J Immunol. 1986;136:477–83.PubMedGoogle Scholar
  21. 21.
    Salomonsson S, Jonsson MV, Skarstein K, Brokstad KA, Hjelmstrom P, Wahren-Herlenius M, et al. Cellular basis of ectopic germinal center formation and autoantibody production in the target organ of patients with Sjogren’s syndrome. Arthritis Rheum. 2003;48:3187–201.PubMedGoogle Scholar
  22. 22.
    Gellrich S, Rutz S, Borkowski A, Golembowski S, Gromnica-Ihle E, Sterry W, et al. Analysis of V(H)-D-J(H) gene transcripts in B cells infiltrating the salivary glands and lymph node tissues of patients with Sjogren’s syndrome. Arthritis Rheum. 1999;42:240–7.PubMedGoogle Scholar
  23. 23.
    Stott DI, Hiepe F, Hummel M, Steinhauser G, Berek C. Antigen-driven clonal proliferation of B cells within the target tissue of an autoimmune disease. The salivary glands of patients with Sjogren’s syndrome. J Clin Invest. 1998;102:938–46.PubMedGoogle Scholar
  24. 24.
    Jordan R, Diss TC, Lench NJ, Isaacson PG, Speight PM. Immunoglobulin gene rearrangements in lymphoplasmacytic infiltrates of labial salivary glands in Sjogren’s syndrome. A possible predictor of lymphoma development. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1995;79:723–9.PubMedGoogle Scholar
  25. 25.
    Schmid U, Helbron D, Lennert K. Development of malignant lymphoma in myoepithelial sialadenitis (Sjogren’s syndrome). Virchows Arch A Pathol Anat Histol. 1982;395:11–43.PubMedGoogle Scholar
  26. 26.
    Groom J, Kalled SL, Cutler AH, Olson C, Woodcock SA, Schneider P, et al. Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjogren’s syndrome. J Clin Invest. 2002;109:59–68.PubMedGoogle Scholar
  27. 27.
    Daridon C, Guerrier T, Devauchelle V, Saraux A, Pers JO, Youinou P. Polarization of B effector cells in Sjogren’s syndrome. Autoimmun Rev. 2007;6:427–31.PubMedGoogle Scholar
  28. 28.
    Jonsson R, Nginamau E, Szyszko E, Brokstad KA. Role of B cells in Sjogren’s syndrome – from benign lymphoproliferation to overt malignancy. Front Biosci. 2007;12:2159–70.PubMedGoogle Scholar
  29. 29.
    Manoussakis MN, Boiu S, Korkolopoulou P, Kapsogeorgou EK, Kavantzas N, Ziakas P, et al. Rates of infiltration by macrophages and dendritic cells and expression of interleukin-18 and interleukin-12 in the chronic inflammatory lesions of Sjogren’s syndrome: correlation with certain features of immune hyperactivity and factors associated with high risk of lymphoma development. Arthritis Rheum. 2007;56:3977–88.PubMedGoogle Scholar
  30. 30.
    Skopouli FN, Dafni U, Ioannidis JP, Moutsopoulos HM. Clinical evolution, and morbidity and mortality of primary Sjogren’s syndrome. Semin Arthritis Rheum. 2000;29:296–304.PubMedGoogle Scholar
  31. 31.
    Ioannidis JP, Vassiliou VA, Moutsopoulos HM. Long-term risk of mortality and lymphoproliferative disease and predictive classification of primary Sjogren’s syndrome. Arthritis Rheum. 2002;46:741–7.PubMedGoogle Scholar
  32. 32.
    Ramos-Casals M, Brito-Zeron P, Yague J, Akasbi M, Bautista R, Ruano M, et al. Hypocomplementaemia as an immunological marker of morbidity and mortality in patients with primary Sjogren’s syndrome. Rheumatology (Oxford). 2005;44:89–94.Google Scholar
  33. 33.
    Sutcliffe N, Inanc M, Speight P, Isenberg D. Predictors of lymphoma development in primary Sjogren’s syndrome. Semin Arthritis Rheum. 1998;28:80–7.PubMedGoogle Scholar
  34. 34.
    Voulgarelis M, Dafni UG, Isenberg DA, Moutsopoulos HM. Malignant lymphoma in primary Sjogren’s syndrome: a multicenter, retrospective, clinical study by the European Concerted Action on Sjogren’s syndrome. Arthritis Rheum. 1999;42:1765–72.PubMedGoogle Scholar
  35. 35.
    Gerli R, Muscat C, Giansanti M, Danieli MG, Sciuto M, Gabrielli A, et al. Quantitative assessment of salivary gland inflammatory infiltration in primary Sjogren’s syndrome: its relationship to different demographic, clinical and serological features of the disorder. Br J Rheumatol. 1997;36:969–75.PubMedGoogle Scholar
  36. 36.
    Ohlsson M, Jonsson R, Brokstad KA. Subcellular redistribution and surface exposure of the Ro52, Ro60 and La48 autoantigens during apoptosis in human ductal epithelial cells: a possible mechanism in the pathogenesis of Sjogren’s syndrome. Scand J Immunol. 2002;56:456–69.PubMedGoogle Scholar
  37. 37.
    Yannopoulos DI, Roncin S, Lamour A, Pennec YL, Moutsopoulos HM, Youinou P. Conjunctival epithelial cells from patients with Sjogren’s syndrome inappropriately express major histocompatibility complex molecules, La(SjSB) antigen, and heat-shock proteins. J Clin Immunol. 1992;12:259–65.PubMedGoogle Scholar
  38. 38.
    Skopouli FN, Kousvelari EE, Mertz P, Jaffe ES, Fox PC, Moutsopoulos HM. c-myc mRNA expression in minor salivary glands of patients with Sjogren’s syndrome. J Rheumatol. 1992;19:693–9.PubMedGoogle Scholar
  39. 39.
    Amft N, Bowman SJ. Chemokines and cell trafficking in Sjogren’s syndrome. Scand J Immunol. 2001;54:62–9.PubMedGoogle Scholar
  40. 40.
    Barone F, Bombardieri M, Rosado MM, Morgan PR, Challacombe SJ, De Vita S, et al. CXCL13, CCL21, and CXCL12 expression in salivary glands of patients with Sjogren’s ­syndrome and MALT lymphoma: association with reactive and malignant areas of lymphoid organization. J Immunol. 2008;180:5130–40.PubMedGoogle Scholar
  41. 41.
    Cuello C, Palladinetti P, Tedla N, Di Girolamo N, Lloyd AR, McCluskey PJ, et al. Chemokine expression and leucocyte infiltration in Sjogren’s syndrome. Br J Rheumatol. 1998;37:779–83.PubMedGoogle Scholar
  42. 42.
    Sfriso P, Oliviero F, Calabrese F, Miorin M, Facco M, Contri A, et al. Epithelial CXCR3-B regulates chemokines bioavailability in normal, but not in Sjogren’s syndrome, salivary glands. J Immunol. 2006;176:2581–9.PubMedGoogle Scholar
  43. 43.
    Xanthou G, Polihronis M, Tzioufas AG, Paikos S, Sideras P, Moutsopoulos HM. “Lymphoid” chemokine messenger RNA expression by epithelial cells in the chronic inflammatory lesion of the salivary glands of Sjogren’s syndrome patients: possible participation in lymphoid structure formation. Arthritis Rheum. 2001;44:408–18.PubMedGoogle Scholar
  44. 44.
    Bombardieri M, Barone F, Pittoni V, Alessandri C, Conigliaro P, Blades MC, et al. Increased circulating levels and salivary gland expression of interleukin-18 in patients with Sjogren’s syndrome: relationship with autoantibody production and lymphoid organization of the periductal inflammatory infiltrate. Arthritis Res Ther. 2004;6:R447–56.PubMedGoogle Scholar
  45. 45.
    Boumba D, Skopouli FN, Moutsopoulos HM. Cytokine mRNA expression in the labial salivary gland tissues from patients with primary Sjogren’s syndrome. Br J Rheumatol. 1995;34:326–33.PubMedGoogle Scholar
  46. 46.
    Daridon C, Devauchelle V, Hutin P, Le Berre R, Martins-Carvalho C, Bendaoud B, et al. Aberrant expression of BAFF by B lymphocytes infiltrating the salivary glands of patients with primary Sjogren’s syndrome. Arthritis Rheum. 2007;56:1134–44.PubMedGoogle Scholar
  47. 47.
    Fox RI, Kang HI, Ando D, Abrams J, Pisa E. Cytokine mRNA expression in salivary gland biopsies of Sjogren’s syndrome. J Immunol. 1994;152:5532–9.PubMedGoogle Scholar
  48. 48.
    Katsiougiannis S, Kapsogeorgou EK, Manoussakis MN, Skopouli FN. Salivary gland epithelial cells: a new source of the immunoregulatory hormone adiponectin. Arthritis Rheum. 2006;54:2295–9.PubMedGoogle Scholar
  49. 49.
    Moutsopoulos HM, Hooks JJ, Chan CC, Dalavanga YA, Skopouli FN, Detrick B. HLA-DR expression by labial minor salivary gland tissues in Sjogren’s syndrome. Ann Rheum Dis. 1986;45:677–83.PubMedGoogle Scholar
  50. 50.
    Thrane PS, Halstensen TS, Haanaes HR, Brandtzaeg P. Increased epithelial expression of HLA-DQ and HLA-DP molecules in salivary glands from patients with Sjogren’s syndrome compared with obstructive sialadenitis. Clin Exp Immunol. 1993;92:256–62.PubMedGoogle Scholar
  51. 51.
    Tsunawaki S, Nakamura S, Ohyama Y, Sasaki M, Ikebe-Hiroki A, Hiraki A, et al. Possible function of salivary gland epithelial cells as nonprofessional antigen-presenting cells in the development of Sjogren’s syndrome. J Rheumatol. 2002;29:1884–96.PubMedGoogle Scholar
  52. 52.
    Dimitriou ID, Kapsogeorgou EK, Moutsopoulos HM, Manoussakis MN. CD40 on salivary gland epithelial cells: high constitutive expression by cultured cells from Sjogren’s syndrome patients indicating their intrinsic activation. Clin Exp Immunol. 2002;127:386–92.PubMedGoogle Scholar
  53. 53.
    Kobayashi M, Kawano S, Hatachi S, Kurimoto C, Okazaki T, Iwai Y, et al. Enhanced expression of programmed death-1 (PD-1)/PD-L1 in salivary glands of patients with Sjogren’s ­syndrome. J Rheumatol. 2005;32:2156–63.PubMedGoogle Scholar
  54. 54.
    Manoussakis MN, Dimitriou ID, Kapsogeorgou EK, Xanthou G, Paikos S, Polihronis M, et al. Expression of B7 costimulatory molecules by salivary gland epithelial cells in patients with Sjogren’s syndrome. Arthritis Rheum. 1999;42:229–39.PubMedGoogle Scholar
  55. 55.
    Kapsogeorgou EK, Dimitriou ID, Abu-Helu RF, Moutsopoulos HM, Manoussakis MN. Activation of epithelial and myoepithelial cells in the salivary glands of patients with Sjogren’s syndrome: high expression of intercellular adhesion molecule-1 (ICAM.1) in biopsy specimens and cultured cells. Clin Exp Immunol. 2001;124:126–33.PubMedGoogle Scholar
  56. 56.
    St Clair EW, Angellilo JC, Singer KH. Expression of cell-adhesion molecules in the salivary gland microenvironment of Sjogren’s syndrome. Arthritis Rheum. 1992;35:62–6.PubMedGoogle Scholar
  57. 57.
    Polihronis M, Tapinos NI, Theocharis SE, Economou A, Kittas C, Moutsopoulos HM. Modes of epithelial cell death and repair in Sjogren’s syndrome (SjS). Clin Exp Immunol. 1998;114:485–90.PubMedGoogle Scholar
  58. 58.
    Dimitriou ID, Kapsogeorgou EK, Abu-Helu RF, Moutsopoulos HM, Manoussakis MN. Establishment of a convenient system for the long-term culture and study of non-neoplastic human salivary gland epithelial cells. Eur J Oral Sci. 2002;110:21–30.PubMedGoogle Scholar
  59. 59.
    Abu-Helu RF, Dimitriou ID, Kapsogeorgou EK, Moutsopoulos HM, Manoussakis MN. Induction of salivary gland epithelial cell injury in Sjogren’s syndrome: in vitro assessment of T cell-derived cytokines and Fas protein expression. J Autoimmun. 2001;17:141–53.PubMedGoogle Scholar
  60. 60.
    Kapsogeorgou EK, Moutsopoulos HM, Manoussakis MN. Functional expression of a costimulatory B7.2 (CD86) protein on human salivary gland epithelial cells that interacts with the CD28 receptor, but has reduced binding to CTLA4. J Immunol. 2001;166:3107–13.PubMedGoogle Scholar
  61. 61.
    Kapsogeorgou EK, Moutsopoulos HM, Manoussakis MN. A novel B7-2 (CD86) splice variant with a putative negative regulatory role. J Immunol. 2008;180:3815–23.PubMedGoogle Scholar
  62. 62.
    Ping L, Ogawa N, Sugai S. Novel role of CD40 in Fas-dependent apoptosis of cultured salivary epithelial cells from patients with Sjogren’s syndrome. Arthritis Rheum. 2005;52:573–81.PubMedGoogle Scholar
  63. 63.
    Bourazopoulou E, Kapsogeorgou EK, Routsias JG, Manoussakis MN, Moutsopoulos HM, Tzioufas AG. Functional expression of the alpha 2-macroglobulin receptor CD91 in salivary gland epithelial cells. J Autoimmun. 2009;33:141–6.PubMedGoogle Scholar
  64. 64.
    Spachidou MP, Bourazopoulou E, Maratheftis CI, Kapsogeorgou EK, Moutsopoulos HM, Tzioufas AG, et al. Expression of functional Toll-like receptors by salivary gland epithelial cells: increased mRNA expression in cells derived from patients with primary Sjogren’s syndrome. Clin Exp Immunol. 2007;147:497–503.PubMedGoogle Scholar
  65. 65.
    Ittah M, Miceli-Richard C, Eric Gottenberg J, Lavie F, Lazure T, Ba N, 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 Sjogren’s syndrome. Arthritis Res Ther. 2006;8:R51.PubMedGoogle Scholar
  66. 66.
    Ittah M, Miceli-Richard C, Gottenberg JE, Sellam J, Eid P, Lebon P, et al. Viruses induce high expression of BAFF by salivary gland epithelial cells through TLR- and type-I IFN-dependent and -independent pathways. Eur J Immunol. 2008;38:1058–64.PubMedGoogle Scholar
  67. 67.
    Jonsson MV, Szodoray P, Jellestad S, Jonsson R, Skarstein K. Association between circulating levels of the novel TNF family members APRIL and BAFF and lymphoid organization in primary Sjogren’s syndrome. J Clin Immunol. 2005;25:189–201.PubMedGoogle Scholar
  68. 68.
    Thery C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002;2:569–79.PubMedGoogle Scholar
  69. 69.
    Kapsogeorgou EK, Abu-Helu RF, Moutsopoulos HM, Manoussakis MN. Salivary gland epithelial cell exosomes: a source of autoantigenic ribonucleoproteins. Arthritis Rheum. 2005;52:1517–21.PubMedGoogle Scholar
  70. 70.
    Tzioufas AG, Tsonis J, Moutsopoulos HM. Neuroendocrine dysfunction in Sjogren’s ­syndrome. Neuroimmunomodulation. 2008;15:37–45.PubMedGoogle Scholar
  71. 71.
    Zoukhri D, Kublin CL. Impaired neurotransmitter release from lacrimal and salivary gland nerves of a murine model of Sjogren’s syndrome. Invest Ophthalmol Vis Sci. 2001;42:925–32.PubMedGoogle Scholar
  72. 72.
    Tornwall J, Uusitalo H, Hukkanen M, Sorsa T, Konttinen YT. Distribution of vasoactive intestinal peptide (VIP) and its binding sites in labial salivary glands in Sjogren’s syndrome and in normal controls. Clin Exp Rheumatol. 1994;12:287–92.PubMedGoogle Scholar
  73. 73.
    Deshmukh US, Ohyama Y, Bagavant H, Guo X, Gaskin F, Fu SM. Inflammatory stimuli ­accelerate Sjogren’s syndrome-like disease in (NZB x NZW)F1 mice. Arthritis Rheum. 2008;58:1318–23.PubMedGoogle Scholar
  74. 74.
    Deshmukh US, Nandula SR, Thimmalapura PR, Scindia YM, Bagavant H. Activation of innate immune responses through Toll-like receptor 3 causes a rapid loss of salivary gland function. J Oral Pathol Med. 2009;38:42–7.PubMedGoogle Scholar
  75. 75.
    Beroukas D, Goodfellow R, Hiscock J, Jonsson R, Gordon TP, Waterman SA. Up-regulation of M3-muscarinic receptors in labial salivary gland acini in primary Sjogren’s syndrome. Lab Invest. 2002;82:203–10.PubMedGoogle Scholar
  76. 76.
    Casciola-Rosen L, Nagaraju K, Plotz P, Wang K, Levine S, Gabrielson E, et al. Enhanced autoantigen expression in regenerating muscle cells in idiopathic inflammatory myopathy. J Exp Med. 2005;201:591–601.PubMedGoogle Scholar
  77. 77.
    Li J, Ha YM, Ku NY, Choi SY, Lee SJ, Oh SB, et al. Inhibitory effects of autoantibodies on the muscarinic receptors in Sjogren’s syndrome. Lab Invest. 2004;84:1430–8.PubMedGoogle Scholar
  78. 78.
    Dawson L, Tobin A, Smith P, Gordon T. Antimuscarinic antibodies in Sjogren’s syndrome: where are we, and where are we going? Arthritis Rheum. 2005;52:2984–95.PubMedGoogle Scholar
  79. 79.
    Manoussakis MN, Moutsopoulos HM. Sjogren’s syndrome: current concepts. Adv Intern Med. 2001;47:191–217.PubMedGoogle Scholar
  80. 80.
    Bolstad AI, Eiken HG, Rosenlund B, Alarcon-Riquelme ME, Jonsson R. Increased salivary gland tissue expression of Fas, Fas ligand, cytotoxic T lymphocyte-associated antigen 4, and programmed cell death 1 in primary Sjogren’s syndrome. Arthritis Rheum. 2003;48:174–85.PubMedGoogle Scholar
  81. 81.
    Espinosa A, Zhou W, Ek M, Hedlund M, Brauner S, Popovic K, et al. The Sjogren’s syndrome-associated autoantigen Ro52 is an E3 ligase that regulates proliferation and cell death. J Immunol. 2006;176:6277–85.PubMedGoogle Scholar
  82. 82.
    Stepp MA, Zhu L, Sheppard D, Cranfill RL. Localized distribution of alpha 9 integrin in the cornea and changes in expression during corneal epithelial cell differentiation. J Histochem Cytochem. 1995;43:353–62.PubMedGoogle Scholar
  83. 83.
    Laurie GW, Glass JD, Ogle RA, Stone CM, Sluss JR, Chen L. “BM180”: a novel basement membrane protein with a role in stimulus-secretion coupling by lacrimal acinar cells. Am J Physiol. 1996;270:C1743–50.PubMedGoogle Scholar
  84. 84.
    Patel VN, Rebustini IT, Hoffman MP. Salivary gland branching morphogenesis. Differentiation. 2006;74:349–64.PubMedGoogle Scholar
  85. 85.
    Martel-Pelletier J, Welsch DJ, Pelletier JP. Metalloproteases and inhibitors in arthritic ­diseases. Best Pract Res Clin Rheumatol. 2001;15:805–29.PubMedGoogle Scholar
  86. 86.
    Garcia-Carrasco M, Fuentes-Alexandro S, Escarcega RO, Salgado G, Riebeling C, Cervera R. Pathophysiology of Sjogren’s syndrome. Arch Med Res. 2006;37:921–32.PubMedGoogle Scholar
  87. 87.
    Fox RI, Stern M. Sjogren’s syndrome: mechanisms of pathogenesis involve interaction of immune and neurosecretory systems. Scand J Rheumatol Suppl. 2002;116:3–13.PubMedGoogle Scholar
  88. 88.
    Konttinen YT, Kangaspunta P, Lindy O, Takagi M, Sorsa T, Segerberg M, et al. Collagenase in Sjogren’s syndrome. Ann Rheum Dis. 1994;53:836–9.PubMedGoogle Scholar
  89. 89.
    Jones DT, Monroy D, Ji Z, Atherton SS, Pflugfelder SC. Sjogren’s syndrome: cytokine and Epstein-Barr viral gene expression within the conjunctival epithelium. Invest Ophthalmol Vis Sci. 1994;35:3493–504.PubMedGoogle Scholar
  90. 90.
    Schenke-Layland K, Xie J, Magnusson M, Angelis E, Li X, Wu K, et al. Lymphocytic infiltration leads to degradation of lacrimal gland extracellular matrix structures in NOD mice exhibiting a Sjogren’s syndrome-like exocrinopathy. Exp Eye Res. 2010;90:223–37.PubMedGoogle Scholar
  91. 91.
    Fye KH, Terasaki PI, Michalski JP, Daniels TE, Opelz G, Talal N. Relationship of HLA-Dw3 and HLA-B8 to Sjogren’s syndrome. Arthritis Rheum. 1978;21:337–42.PubMedGoogle Scholar
  92. 92.
    Mann DL, Moutsopoulos HM. HLA DR alloantigens in different subsets of patients with Sjogren’s syndrome and in family members. Ann Rheum Dis. 1983;42:533–6.PubMedGoogle Scholar
  93. 93.
    Reveille JD, Macleod MJ, Whittington K, Arnett FC. Specific amino acid residues in the second hypervariable region of HLA-DQA1 and DQB1 chain genes promote the Ro (SjS-A)/La (SjS-B) autoantibody responses. J Immunol. 1991;146:3871–6.PubMedGoogle Scholar
  94. 94.
    Scofield RH. Genetics of systemic lupus erythematosus and Sjogren’s syndrome. Curr Opin Rheumatol. 2009;21:448–53.PubMedGoogle Scholar
  95. 95.
    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;56:3989–94.PubMedGoogle Scholar
  96. 96.
    Nordmark G, Kristjansdottir G, Theander E, Eriksson P, Brun JG, Wang C, et al. Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjogren’s syndrome. Genes Immun. 2009;10:68–76.PubMedGoogle Scholar
  97. 97.
    Manoussakis MN, Kapsogeorgou EK. The role of epithelial cells in the pathogenesis of Sjogren’s syndrome. Clin Rev Allergy Immunol. 2007;32:225–30.PubMedGoogle Scholar
  98. 98.
    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;52:1534–44.PubMedGoogle Scholar
  99. 99.
    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;103:2770–5.PubMedGoogle Scholar
  100. 100.
    Bave U, Nordmark G, Lovgren T, Ronnelid J, Cajander S, Eloranta ML, et al. Activation of the type I interferon system in primary Sjogren’s syndrome: a possible etiopathogenic mechanism. Arthritis Rheum. 2005;52:1185–95.PubMedGoogle Scholar
  101. 101.
    Leimola-Virtanen R, Salo T, Toikkanen S, Pulkkinen J, Syrjanen S. Expression of estrogen receptor (ER) in oral mucosa and salivary glands. Maturitas. 2000;36:131–7.PubMedGoogle Scholar
  102. 102.
    Tsinti M, Kassi E, Korkolopoulou P, Kapsogeorgou E, Moutsatsou P, Patsouris E, et al. Functional estrogen receptors alpha and beta are expressed in normal human salivary gland epithelium and apparently mediate immunomodulatory effects. Eur J Oral Sci. 2009;117:498–505.PubMedGoogle Scholar
  103. 103.
    Kassi E, Moutsatsou P, Sekeris CE, Moutsopoulos HM, Manoussakis MN. Oestrogen receptors in cultured epithelial cells from salivary glands of Sjogren’s syndrome patients. Rheumatology (Oxford). 2003;42:1120–2.Google Scholar
  104. 104.
    Ishimaru N, Arakaki R, Watanabe M, Kobayashi M, Miyazaki K, Hayashi Y. Development of autoimmune exocrinopathy resembling Sjogren’s syndrome in estrogen-deficient mice of healthy background. Am J Pathol. 2003;163:1481–90.PubMedGoogle Scholar
  105. 105.
    Carlsten H, Nilsson N, Jonsson R, Backman K, Holmdahl R, Tarkowski A. Estrogen accelerates immune complex glomerulonephritis but ameliorates T cell-mediated vasculitis and sialadenitis in autoimmune MRL lpr/lpr mice. Cell Immunol. 1992;144:190–202.PubMedGoogle Scholar
  106. 106.
    Ishimaru N, Saegusa K, Yanagi K, Haneji N, Saito I, Hayashi Y. Estrogen deficiency accelerates autoimmune exocrinopathy in murine Sjogren’s syndrome through fas-mediated apoptosis. Am J Pathol. 1999;155:173–81.PubMedGoogle Scholar
  107. 107.
    Shim GJ, Warner M, Kim HJ, Andersson S, Liu L, Ekman J, et al. Aromatase-deficient mice spontaneously develop a lymphoproliferative autoimmune disease resembling Sjogren’s syndrome. Proc Natl Acad Sci U S A. 2004;101:12628–33.PubMedGoogle Scholar

Copyright information

© Springer-Verlag London Limited 2011

Authors and Affiliations

  • Athanasios G. Tzioufas
    • 1
  • Efstathia K. Kapsogeorgou
    • 1
  • Menelaos N. Manoussakis
    • 1
  • Haralampos M. Moutsopoulos
    • 1
  1. 1.Department of Pathophysiology, School of MedicineNational University of AthensAthensGreece

Personalised recommendations