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Sjögren’s syndrome: An old tale with a new twist

  • Byung Ha Lee
  • Mauro A. Tudares
  • Cuong Q. Nguyen
Review

Abstract

Sjögren’s syndrome (SjS) is chronic autoimmune disease manifested by the loss of saliva and/or tear secretion by salivary and/or lacrimal glands, respectively. The pathogenesis of the disease remains elusive, perhaps due to the multiple triggers of the disease. However, substantial advances have been made in attempting to resolve the complexity of SjS using both animal models and human subjects. The primary objectives of this review are to provide a better understanding of the disease processes with major emphasis on the use of mouse models, how genetic predisposition plays a role in the natural history of the disease, as well as a presentation of new findings pertaining to the role of TH1, TH2, and TH17 cells in the pathogenesis of SjS.

Keywords

Sjögren’s syndrome animal models genetics TH1 cells TH2 cells TH17 cells 

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References

  1. Abdul Ajees A, Gunasekaran K, Volanakis JE et al(2006) The structure of complement C3b provides insights into complement activation and regulation. Nature 444: 221-25CrossRefPubMedGoogle Scholar
  2. Ambrosetti A, Zanotti R, Pattaro C et al(2004) Most cases of primary salivary mucosa-associated lymphoid tissue lymphoma are associated either with Sjoegren syndrome or hepatitis C virus infection. Br J Haematol 126: 43-9CrossRefPubMedGoogle Scholar
  3. Andrews BS, Eisenberg RA, Theofilopoulos AN et al(1978) Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains. J Exp Med 148: 1198-215CrossRefPubMedGoogle Scholar
  4. Argueso P, Balaram M, Spurr-Michaud S et al(2002) Decreased levels of the goblet cell mucin MUC5AC in tears of patients with Sjogren syndrome. Invest Ophthalmol Vis Sci 43: 1004-011PubMedGoogle Scholar
  5. Batten M, Fletcher C, Ng LG et al(2004) TNF deficiency fails to protect BAFF transgenic mice against autoimmunity and reveals a predisposition to B cell lymphoma. J Immunol 172: 812-22PubMedGoogle Scholar
  6. Baum PR, Gayle RB 3rd, Ramsdell F et al(1994) Molecular characterization of murine and human OX40/OX40 ligand systems: identification of a human OX40 ligand as the HTLV-1-regulated protein gp34. EMBO J 13: 3992-001PubMedGoogle Scholar
  7. Berditchevski F (2001) Complexes of tetraspanins with integrins: more than meets the eye. J Cell Sci 114: 4143-151PubMedGoogle Scholar
  8. Bettelli E, Carrier Y, Gao W et al(2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441: 235-38CrossRefPubMedGoogle Scholar
  9. Bettelli E, Korn T, Oukka M et al(2008) Induction and effector functions of T(H)17 cells. Nature 453: 1051-057CrossRefPubMedGoogle Scholar
  10. Bolstad AI, Jonsson R (2002) Genetic aspects of Sjogren’s syndrome. Arthritis Res 4: 353-59CrossRefPubMedGoogle Scholar
  11. Bolstad AI, Wargelius A, Nakken B et al(2000) Fas and Fas ligand gene polymorphisms in primary Sjogren’s syndrome. J Rheumatol 27: 2397-405PubMedGoogle Scholar
  12. Bombardieri M, Barone F, Pittoni V et al(2004) 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 6: R447-56CrossRefPubMedGoogle Scholar
  13. Brayer JB, Cha S, Nagashima H et al(2001) IL-4-dependent effector phase in autoimmune exocrinopathy as defined by the NOD. IL- 4(gene knockout mouse model of Sjogren’s syndrome. Scand J Immunol 54): 133-40Google Scholar
  14. Brayer J, Lowry J, Cha S et al(2000) Alleles from chromosomes 1 and 3 of NOD mice combine to influence Sjogren’s syndrome-like autoimmune exocrinopathy. J Rheumatol 27: 1896-904PubMedGoogle Scholar
  15. Carroll MC (1998) The role of complement and complement receptors in induction and regulation of immunity. Annu Rev Immunol 16: 545-68CrossRefPubMedGoogle Scholar
  16. Cha S, Brayer J, Gao J et al(2004) A dual role for interferongamma in the pathogenesis of Sjogren’s syndrome-like autoimmune exocrinopathy in the nonobese diabetic mouse. Scand J Immunol 60: 552-65CrossRefPubMedGoogle Scholar
  17. Crouse CA, Pflugfelder SC, Cleary T et al(1990) Detection of Epstein-Barr virus genomes in normal human lacrimal glands. J Clin Microbiol 28: 1026-032PubMedGoogle Scholar
  18. Cua DJ, Sherlock J, Chen Y et al(2003) Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421: 744-48CrossRefPubMedGoogle Scholar
  19. De Vita S, Boiocchi M, Sorrentino D et al(1997) Characterization of prelymphomatous stages of B cell lymphoproliferation in Sjogren’s syndrome. Arthritis Rheum 40: 318-31CrossRefPubMedGoogle Scholar
  20. Delaleu N, Immervoll H, Cornelius J et al(2008) Biomarker profiles in serum and saliva of experimental Sjogren’s syndrome: associations with specific autoimmune manifestations. Arthritis Res Ther 10: R22CrossRefPubMedGoogle Scholar
  21. Duerr RH, Taylor KD, Brant SR et al(2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314: 1461-463CrossRefPubMedGoogle Scholar
  22. Fox RI, Kang HI (1992) Pathogenesis of Sjogren’s syndrome. Rheum Dis Clin North Am 18: 517-38PubMedGoogle Scholar
  23. Fox RI, Luppi M, Pisa P et al(1992) Potential role of Epstein-Barr virus in Sjogren’s syndrome and rheumatoid arthritis. J Rheumatol Suppl 32: 18-4PubMedGoogle Scholar
  24. Fox RI, Michelson P (2000) Approaches to the treatment of Sjogren’s syndrome. J Rheumatol Suppl 61: 15-1PubMedGoogle Scholar
  25. Gao J (2004) Biological functions and molecular mechanisms of the interleukin 4 signaling pathways in autoimmune exocrinopathy using the NOD.B10.H2b mouse model of Sjögren’s syndrome. Department of Pathology, Immunology and Laboratory Medicine, University of Florida, GainesvilleGoogle Scholar
  26. Gao J, Killedar S, Cornelius JG et al(2006) Sjogren’s syndrome in the NOD mouse model is an interleukin-4 time-dependent, antibody isotype-specific autoimmune disease. J Autoimmun 26: 90-03CrossRefPubMedGoogle Scholar
  27. Gottenberg JE, Busson M, Loiseau P et al(2003) In primary Sjogren’s syndrome, HLA class II is associated exclusively with autoantibody production and spreading of the autoimmune response. Arthritis Rheum 48: 2240-245CrossRefPubMedGoogle Scholar
  28. Gottenberg JE, Busson M, Loiseau P et al(2004) Association of transforming growth factor beta1 and tumor necrosis factor alpha polymorphisms with anti-SSB/La antibody secretion in patients with primary Sjogren’s syndrome. Arthritis Rheum 50: 570-80CrossRefPubMedGoogle Scholar
  29. Hansen A, Lipsky PE, Dorner T (2003) New concepts in the pathogenesis of Sjogren syndrome: many questions, fewer answers. Curr Opin Rheumatol 15: 563-70CrossRefPubMedGoogle Scholar
  30. Harley JB, Alexander EL, Bias WB et al(1986) Anti-Ro (SS-A) and anti-La (SS-B) in patients with Sjogren’s syndrome. Arthritis Rheum 29: 196-06CrossRefPubMedGoogle Scholar
  31. Harrington LE, Hatton RD, Mangan PR et al(2005) Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6: 1123-132CrossRefPubMedGoogle Scholar
  32. Helmick CG, Felson DT, Lawrence RC et al(2008) Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum 58: 15-5CrossRefGoogle Scholar
  33. Hoffman RW, Alspaugh MA, Waggie KS et al(1984) Sjogren’s syndrome in MRL/l and MRL/n mice. Arthritis Rheum 27: 157-65CrossRefPubMedGoogle Scholar
  34. Hu S, Wang J, Meijer J et al(2007) Salivary proteomic and genomic biomarkers for primary Sjogren’s syndrome. Arthritis Rheum 56: 3588-600CrossRefPubMedGoogle Scholar
  35. Hu Y, Nakagawa Y, Purushotham KR et al(1992) Functional changes in salivary glands of autoimmune disease-prone NOD mice. Am J Physiol 263: E607-14PubMedGoogle Scholar
  36. Hue S, Ahern P, Buonocore S et al(2006) Interleukin-23 drives innate and T cell-mediated intestinal inflammation. J Exp Med 203: 2473-483CrossRefPubMedGoogle Scholar
  37. Humphreys-Beher MG, Brinkley L, Purushotham KR et al(1993) Characterization of antinuclear autoantibodies present in the serum from nonobese diabetic (NOD) mice. Clin Immunol Immunopathol 68: 350-56CrossRefPubMedGoogle Scholar
  38. Humphreys-Beher MG, Hu Y, Nakagawa Y et al(1994) Utilization of the non-obese diabetic (NOD) mouse as an animal model for the study of secondary Sjogren’s syndrome. Adv Exp Med Biol 350: 631-36PubMedGoogle Scholar
  39. Ito T, Wang YH, Duramad O et al(2006) OX40 ligand shuts down IL-10-producing regulatory T cells. Proc Natl Acad Sci USA 103: 13138-3143CrossRefPubMedGoogle Scholar
  40. Ivanov II, McKenzie BS, Zhou L et al(2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126: 1121-133CrossRefPubMedGoogle Scholar
  41. Jabs DA, Lee B, Whittum-Hudson JA et al(2000) Th1 versus Th2 immune responses in autoimmune lacrimal gland disease in MRL/Mp mice. Invest Ophthalmol Vis Sci 41: 826-31PubMedGoogle Scholar
  42. Jabs DA, Prendergast RA, Campbell AL et al(2007) Autoimmune Th2-mediated dacryoadenitis in MRL/MpJ mice becomes Th1-mediated in IL-4 deficient MRL/MpJ mice. Invest Ophthalmol Vis Sci, 48: 5624-629CrossRefGoogle Scholar
  43. Jonsson R, Tarkowski A, Backman K et al(1987) Sialadenitis in the MRL-l mouse: morphological and immunohistochemical characterization of resident and infiltrating cells. Immunology 60: 611-16PubMedGoogle Scholar
  44. Kastelein RA, Hunter CA, Cua DJ (2007) Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu Rev Immunol 25: 221-42CrossRefPubMedGoogle Scholar
  45. Kong L, Robinson CP, Peck AB et al(1998) Inappropriate apoptosis of salivary and lacrimal gland epithelium of immunodeficient NOD-scid mice. Clin Exp Rheumatol 16: 675-81PubMedGoogle Scholar
  46. Kumagai S, Kanagawa S, Morinobu A (1997) Association of a new allele of the TAP2 gene, TAP2*Bky2 (Val577), with susceptibility to Sjogren’s syndrome. Arthritis Rheum 40: 1685-692CrossRefPubMedGoogle Scholar
  47. Makino S, Kunimoto K, Muraoka Y et al(1980) Breeding of a non-obese, diabetic strain of mice. Jikken Dobutsu 29: 1-3PubMedGoogle Scholar
  48. Mangan PR, Harrington LE, O’Quinn DB et al(2006) Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441: 231-34CrossRefPubMedGoogle Scholar
  49. Manoussakis MN, Boiu S, Korkolopoulou P et al(2007) 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 56: 3977-988CrossRefPubMedGoogle Scholar
  50. Morinobu A, Kanagawa S, Koshiba M et al(1999) Association of the glutathione S-transferase M1 homozygous null genotype with susceptibility to Sjogren’s syndrome in Japanese individuals. Arthritis Rheum 42: 2612-615CrossRefPubMedGoogle Scholar
  51. Mustafa W, Zhu J, Deng G et al(1998) Augmented levels of macrophage and Th1 cell-related cytokine mRNA in submandibular glands of MRL/lpr mice with autoimmune sialoadenitis. Clin Exp Immunol 112: 389-96CrossRefPubMedGoogle Scholar
  52. Nguyen CQ, Cha SR, Peck AB (2007) Sjögren’s syndrome (SjS)-like disease of mice: the importance of B lymphocytes and autoantibodies. Front Biosci 12: 1767-789CrossRefPubMedGoogle Scholar
  53. Nguyen CQ, Cornelius JG, Cooper L et al(2008) Identification of possible candidate genes regulating Sjögren’s syndrome-associated autoimmunity: a potential role for Tnfsf4 in autoimmune exocrinopathy. Arthritis Res Ther 10: R137CrossRefPubMedGoogle Scholar
  54. Nguyen CQ, Gao JH, Kim H et al(2007) IL-4-STAT6 signal transduction-dependent induction of the clinical phase of Sjogren’s syndrome-like disease of the nonobese diabetic mouse. J Immunol 179: 382-90PubMedGoogle Scholar
  55. Nguyen CQ, Hu MN, Li Y et al(2008) Salivary gland tissue expression of interleukin-23 and interleukin-17 in Sjögren’s syndrome: findings in humans and mice. Arthritis Rheum 58: 734-43CrossRefPubMedGoogle Scholar
  56. Nguyen C, Singson E, Kim JY et al(2006) Sjogren’s syndrome-like disease of C57BL/6.NOD-Aec1 Aec2 mice: gender differences in keratoconjunctivitis sicca defined by a cross-over in the chromosome 3 Aec1 locus. Scand J Immunol 64: 295-07CrossRefPubMedGoogle Scholar
  57. Nguyen CQ, Sharma SA, She JX et al(2009) differential gene expressions in the lacrimal gland during development and onset of keratoconjunctivitis sicca in Sjogren’s Syndrome (SjS)-like disease of the C57BL/6.NOD-Aec1Aec2 mouse. Exp Eye Res (in press)Google Scholar
  58. Nguyen KH, Brayer J, Cha S et al(2000) Evidence for antimuscarinic acetylcholine receptor antibody-mediated secretory dysfunction in nod mice. Arthritis Rheum 43: 2297-306CrossRefPubMedGoogle Scholar
  59. Park H, Li Z, Yang XO et al(2005) A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6: 1133-141CrossRefPubMedGoogle Scholar
  60. Pertovaara M, Lehtimaki T, Rontu R et al(2004) Presence of apolipoprotein E epsilon4 allele predisposes to early onset of primary Sjogren’s syndrome. Rheumatology 43: 1484-487CrossRefPubMedGoogle Scholar
  61. Pflugfelder SC, Tseng SC, Pepose JS et al(1990) Epstein-Barr virus infection and immunologic dysfunction in patients with aqueous tear deficiency. Ophthalmology 97: 313-23PubMedGoogle Scholar
  62. Ramos-Casals M, Trejo O, Garcia-Carrasco M et al(2004) Triple association between hepatitis C virus infection, systemic autoimmune diseases, and B cell lymphoma. J Rheumatol 31: 495-99PubMedGoogle Scholar
  63. Ricchiuti V, Isenberg D, Muller S (1994) HLA association of anti-Ro60 and anti-Ro52 antibodies in Sjogren’s syndrome. J Autoimmun 7: 611-21CrossRefPubMedGoogle Scholar
  64. Robinson CP, Yamamoto H, Peck AB et al(1996) Genetically programmed development of salivary gland abnormalities in the NOD (nonobese diabetic)-scid mouse in the absence of detectable lymphocytic infiltration: a potential trigger for sialoadenitis of NOD mice. Clin Immunol Immunopathol 79: 50-9CrossRefPubMedGoogle Scholar
  65. Sakai A, Sugawara Y, Kuroishi T et al(2008) Identification of IL-18 and Th17 cells in salivary glands of patients with Sjogren’s syndrome, and amplification of IL-17-mediated secretion of inflammatory cytokines from salivary gland cells by IL-18. J Immunol 181: 2898-906PubMedGoogle Scholar
  66. Shimazaki J, Goto E, Ono M et al(1998) Meibomian gland dysfunction in patients with Sjogren syndrome. Ophthalmology 105: 1485-488CrossRefPubMedGoogle Scholar
  67. Singer GG, Abbas AK (1994) The fas antigen is involved in peripheral but not thymic deletion of T lymphocytes in T cell receptor transgenic mice. Immunity 1: 365-71CrossRefPubMedGoogle Scholar
  68. Sullivan DA (1997) Sex hormones and Sjogren’s syndrome. J Rheumatol Suppl 50: 17-2PubMedGoogle Scholar
  69. Sullivan DA (2004) Androgen deficiency and dry eye syndromes. Arch Soc Esp Oftalmol 79: 49-0PubMedCrossRefGoogle Scholar
  70. Sullivan DA, Krenzer KL, Sullivan BD et al(1999) Does androgen insufficiency cause lacrimal gland inflammation and aqueous tear deficiency. Invest Ophthalmol Vis Sci 40: 1261-265PubMedGoogle Scholar
  71. Sullivan DA, Sullivan BD, Evans JE et al(2002) Androgen deficiency, Meibomian gland dysfunction, and evaporative dry eye. Ann N Y Acad Sci 966: 211-22CrossRefPubMedGoogle Scholar
  72. Sullivan DA, Wickham LA, Rocha EM et al(1999) Androgens and dry eye in Sjogren’s syndrome. Ann N Y Acad Sci 876: 312-24CrossRefPubMedGoogle Scholar
  73. Takahashi S, Fossati L, Iwamoto M et al(1996) Imbalance towards Th1 predominance is associated with acceleration of lupus-like autoimmune syndrome in MRL mice. J Clin Invest 97: 1597-604CrossRefPubMedGoogle Scholar
  74. Teutsch SM, Booth DR, Bennetts BH et al(2003) Identification of 11 novel and common single nucleotide polymorphisms in the interleukin-7 receptor-alpha gene and their associations with multiple sclerosis. Eur J Hum Genet 11: 509-15CrossRefPubMedGoogle Scholar
  75. Theofilopoulos AN, Dixon FJ (1985) Murine models of systemic lupus erythematosus. Adv Immunol 37: 269-39CrossRefPubMedGoogle Scholar
  76. Toda I, Wickham LA, Sullivan DA (1998) Gender and androgen treatment influence the expression of proto-oncogenes and apoptotic factors in lacrimal and salivary tissues of MRL/lpr mice. Clin Immunol Immunopathol 86: 59-1CrossRefPubMedGoogle Scholar
  77. Tsubota K, Mishima K, Obara K et al(2007) Reactive oxygen species can be controlled by the secretory glycoprotein, clusterin, from side population cells in the lacrimal gland: a new intervention for age-related dry eye disorders. In: Tear Film and Ocular Surface 2007, Taormina, ItalyGoogle Scholar
  78. Veldhoen M, Hocking RJ, Atkins CJ et al(2006) TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24: 179-89CrossRefPubMedGoogle Scholar
  79. Voulgarelis M, Moutsopoulos HM (2003) Lymphoproliferation in autoimmunity and Sjogren’s syndrome. Curr Rheumatol Rep 5: 317-23CrossRefPubMedGoogle Scholar
  80. Wahren M, Skarstein K, Blange I et al(1994) MRL/lpr mice produce anti-Ro 52,000 MW antibodies: detection, analysis of specificity and site of production. Immunology 83: 9-5PubMedGoogle Scholar
  81. Wang H, Nakamura K, Inoue T et al(2004) Mannose-binding lectin polymorphisms in patients with Behcet’s disease. J Dermatol Sci 36: 115-17CrossRefPubMedGoogle Scholar
  82. Watson ML, Rao JK, Gilkeson GS et al(1992) Genetic analysis of MRL-lpr mice: relationship of the Fas apoptosis gene to disease manifestations and renal disease-modifying loci. J Exp Med 176: 1645-656CrossRefPubMedGoogle Scholar
  83. Weaver CT, Hatton RD, Mangan PR et al(2007) IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol 25: 821-52CrossRefPubMedGoogle Scholar

Copyright information

© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2009

Authors and Affiliations

  • Byung Ha Lee
    • 1
  • Mauro A. Tudares
    • 1
  • Cuong Q. Nguyen
    • 1
  1. 1.Department of Oral Biology, College of DentistryUniversity of FloridaGainesvilleUSA

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