Skip to main content
SpringerLink
Log in

Sjögren’s Syndrome

  • Chapter
  • First Online:
Genetics of Rare Autoimmune Diseases

Part of the book series: Rare Diseases of the Immune System ((RDIS))

Abstract

Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by sicca symptoms and a broad variety of systemic clinical manifestations. Indeed, even though keratoconjunctivitis sicca, resulting from the involvement of lacrimal glands, and xerostomia, resulting from the involvement of salivary glands, are usually prominent, pSS presents as a multifaceted and systemic condition with a broad variety of clinical manifestations. The spectrum of pSS extends from an organ-specific autoimmune disorder (referred to as an autoimmune exocrinopathy) to a systemic process and in addition to an increased risk of non-Hodgkin’s lymphoma. More than 50 years ago, genetic involvement was suggested in the etiology of pSS. The idea that genetic and epigenetic factors contribute to the etiology of systemic autoimmune diseases such as pSS is supported by familial autoimmunity and poly-autoimmunity. Most of the genes associated with susceptibility to pSS have been identified because the proteins involved have been previously associated with the pathogenesis of pSS or because the genes had already been associated with another autoimmune disease such as SLE or RA. Consequently, in this chapter, we will first focus on the immunopathology of pSS in order to better understand the genetic and epigenetic alterations described in the disease. The last section will be dedicated to genetic alterations in pSS related to lymphoma.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 119.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Cornec D, Chiche L. Is primary Sjogren’s syndrome an orphan disease? A critical appraisal of prevalence studies in Europe. Ann Rheum Dis. 2015;74(3):e25. https://doi.org/10.1136/annrheumdis-2014-206860.

    Article  PubMed  Google Scholar 

  2. Binard A, Le Pottier L, Devauchelle-Pensec V, Saraux A, Youinou P, Pers JO. Is the blood B-cell subset profile diagnostic for Sjogren syndrome? Ann Rheum Dis. 2009;68(9):1447–52. https://doi.org/10.1136/ard.2008.096172.

    Article  CAS  PubMed  Google Scholar 

  3. 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(8):1765–72. https://doi.org/10.1002/1529-0131(199908)42:8<1765::AID-ANR28>3.0.CO;2-V.

    Article  CAS  PubMed  Google Scholar 

  4. Gayral L, Gayral J. A familial strain of 11 cases of the Marinesco-Sjogren syndrome. J Genet Hum. 1966;15(1):63–9.

    CAS  PubMed  Google Scholar 

  5. Cardenas-Roldan J, Rojas-Villarraga A, Anaya JM. How do autoimmune diseases cluster in families? A systematic review and meta-analysis. BMC Med. 2013;11:73. https://doi.org/10.1186/1741-7015-11-73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Longhi BS, Appenzeller S, Centeville M, Gusmao RJ, Marini R. Primary Sjogren’s syndrome in children: is a family approach indicated? Clinics (Sao Paulo). 2011;66(11):1991–3.

    Article  Google Scholar 

  7. Kuo CF, Grainge MJ, Valdes AM, See LC, Luo SF, Yu KH, et al. Familial risk of Sjogren’s syndrome and co-aggregation of autoimmune diseases in affected families: a Nationwide population study. Arthritis Rheumatol. 2015;67(7):1904–12. https://doi.org/10.1002/art.39127.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Christodoulou MI, Kapsogeorgou EK, Moutsopoulos HM. Characteristics of the minor salivary gland infiltrates in Sjogren’s syndrome. J Autoimmun. 2010;34(4):400–7. https://doi.org/10.1016/j.jaut.2009.10.004.

    Article  CAS  PubMed  Google Scholar 

  9. Varin MM, Guerrier T, Devauchelle-Pensec V, Jamin C, Youinou P, Pers JO. In Sjogren’s syndrome, B lymphocytes induce epithelial cells of salivary glands into apoptosis through protein kinase C delta activation. Autoimmun Rev. 2012;11(4):252–8. https://doi.org/10.1016/j.autrev.2011.10.005.

    Article  CAS  PubMed  Google Scholar 

  10. Zheng L, Zhang Z, Yu C, Yang C. Expression of Toll-like receptors 7, 8, and 9 in primary Sjogren’s syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010;109(6):844–50. https://doi.org/10.1016/j.tripleo.2010.01.006.

    Article  PubMed  Google Scholar 

  11. Konsta OD, Thabet Y, Le Dantec C, Brooks WH, Tzioufas AG, Pers JO, et al. The contribution of epigenetics in Sjogren’s syndrome. Front Genet. 2014;5:71. https://doi.org/10.3389/fgene.2014.00071.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Thabet Y, Le Dantec C, Ghedira I, Devauchelle V, Cornec D, Pers JO, et al. Epigenetic dysregulation in salivary glands from patients with primary Sjogren’s syndrome may be ascribed to infiltrating B cells. J Autoimmun. 2013;41:175–81. https://doi.org/10.1016/j.jaut.2013.02.002.

    Article  CAS  PubMed  Google Scholar 

  13. Hamm-Alvarez SF, Janga SR, Edman MC, Madrigal S, Shah M, Frousiakis SE, et al. Tear cathepsin S as a candidate biomarker for Sjogren’s syndrome. Arthritis Rheumatol. 2014;66(7):1872–81. https://doi.org/10.1002/art.38633.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Nocturne G, Seror R, Fogel O, Belkhir R, Boudaoud S, Saraux A, et al. CXCL13 and CCL11 serum levels and lymphoma and disease activity in primary Sjogren syndrome. Arthritis Rheumatol. 2015;67(12):3226–33. https://doi.org/10.1002/art.39315.

    Article  CAS  PubMed  Google Scholar 

  15. Brkic Z, Versnel MA. Type I IFN signature in primary Sjogren’s syndrome patients. Expert Rev Clin Immunol. 2014;10(4):457–67. https://doi.org/10.1586/1744666X.2014.876364.

    Article  CAS  PubMed  Google Scholar 

  16. 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(4):1058–64. https://doi.org/10.1002/eji.200738013.

    Article  CAS  PubMed  Google Scholar 

  17. Quartuccio L, Salvin S, Fabris M, Maset M, Pontarini E, Isola M, et al. BLyS upregulation in Sjogren’s syndrome associated with lymphoproliferative disorders, higher ESSDAI score and B-cell clonal expansion in the salivary glands. Rheumatology (Oxford). 2013;52(2):276–81. https://doi.org/10.1093/rheumatology/kes180.

    Article  CAS  Google Scholar 

  18. Le Pottier L, Devauchelle V, Fautrel A, Daridon C, Saraux A, Youinou P, et al. Ectopic germinal centers are rare in Sjogren’s syndrome salivary glands and do not exclude autoreactive B cells. J Immunol. 2009;182(6):3540–7. https://doi.org/10.4049/jimmunol.0803588.

    Article  CAS  PubMed  Google Scholar 

  19. Haacke EA, van der Vegt B, Vissink A, Spijkervet FKL, Bootsma H, Kroese FGM. Germinal centres in diagnostic labial gland biopsies of patients with primary Sjogren’s syndrome are not predictive for parotid MALT lymphoma development. Ann Rheum Dis. 2017;76(10):1781–4. https://doi.org/10.1136/annrheumdis-2017-211290.

    Article  CAS  PubMed  Google Scholar 

  20. Goodnow CC, Vinuesa CG, Randall KL, Mackay F, Brink R. Control systems and decision making for antibody production. Nat Immunol. 2010;11(8):681–8. https://doi.org/10.1038/ni.1900.

    Article  CAS  PubMed  Google Scholar 

  21. Szabo K, Papp G, Barath S, Gyimesi E, Szanto A, Zeher M. Follicular helper T cells may play an important role in the severity of primary Sjogren’s syndrome. Clin Immunol. 2013;147(2):95–104. https://doi.org/10.1016/j.clim.2013.02.024.

    Article  CAS  PubMed  Google Scholar 

  22. Barone F, Nayar S, Campos J, Cloake T, Withers DR, Toellner KM, et al. IL-22 regulates lymphoid chemokine production and assembly of tertiary lymphoid organs. Proc Natl Acad Sci U S A. 2015;112(35):11024–9. https://doi.org/10.1073/pnas.1503315112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 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(5):1389–96. https://doi.org/10.2353/ajpath.2008.080246.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Nguyen CQ, Hu MH, Li Y, Stewart C, Peck AB. Salivary gland tissue expression of interleukin-23 and interleukin-17 in Sjogren's syndrome: findings in humans and mice. Arthritis Rheum. 2008;58(3):734–43. https://doi.org/10.1002/art.23214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lemoine S, Morva A, Youinou P, Jamin C. Regulatory B cells in autoimmune diseases: how do they work? Ann N Y Acad Sci. 2009;1173:260–7. https://doi.org/10.1111/j.1749-6632.2009.04651.x.

    Article  CAS  PubMed  Google Scholar 

  26. Nouel A, Pochard P, Simon Q, Segalen I, Le Meur Y, Pers JO, et al. B-cells induce regulatory T cells through TGF-beta/IDO production in A CTLA-4 dependent manner. J Autoimmun. 2015;59:53–60. https://doi.org/10.1016/j.jaut.2015.02.004.

    Article  CAS  PubMed  Google Scholar 

  27. Devauchelle-Pensec V, Mariette X, Jousse-Joulin S, Berthelot JM, Perdriger A, Puechal X, et al. Treatment of primary Sjogren syndrome with rituximab: a randomized trial. Ann Intern Med. 2014;160(4):233–42. https://doi.org/10.7326/M13-1085.

    Article  PubMed  Google Scholar 

  28. Nezos A, Papageorgiou A, Fragoulis G, Ioakeimidis D, Koutsilieris M, Tzioufas AG, et al. B-cell activating factor genetic variants in lymphomagenesis associated with primary Sjogren’s syndrome. J Autoimmun. 2014;51:89–98. https://doi.org/10.1016/j.jaut.2013.04.005.

    Article  CAS  PubMed  Google Scholar 

  29. Tobon GJ, Renaudineau Y, Hillion S, Cornec D, Devauchelle-Pensec V, Youinou P, et al. The Fms-like tyrosine kinase 3 ligand, a mediator of B cell survival, is also a marker of lymphoma in primary Sjogren’s syndrome. Arthritis Rheum. 2010;62(11):3447–56. https://doi.org/10.1002/art.27611.

    Article  CAS  PubMed  Google Scholar 

  30. Solans-Laque R, Lopez-Hernandez A, Bosch-Gil JA, Palacios A, Campillo M, Vilardell-Tarres M. Risk, predictors, and clinical characteristics of lymphoma development in primary Sjogren’s syndrome. Semin Arthritis Rheum. 2011;41(3):415–23. https://doi.org/10.1016/j.semarthrit.2011.04.006.

    Article  PubMed  Google Scholar 

  31. Nishishinya MB, Pereda CA, Munoz-Fernandez S, Pego-Reigosa JM, Rua-Figueroa I, Andreu JL, et al. Identification of lymphoma predictors in patients with primary Sjogren’s syndrome: a systematic literature review and meta-analysis. Rheumatol Int. 2015;35(1):17–26. https://doi.org/10.1007/s00296-014-3051-x.

    Article  CAS  PubMed  Google Scholar 

  32. Kauppi L, Stumpf MP, Jeffreys AJ. Localized breakdown in linkage disequilibrium does not always predict sperm crossover hot spots in the human MHC class II region. Genomics. 2005;86(1):13–24. https://doi.org/10.1016/j.ygeno.2005.03.011.

    Article  CAS  PubMed  Google Scholar 

  33. Westra HJ, Peters MJ, Esko T, Yaghootkar H, Schurmann C, Kettunen J, et al. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet. 2013;45(10):1238–43. https://doi.org/10.1038/ng.2756.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gershwin ME, Terasaki I, Graw R, Chused TM. Increased frequency of HL-A8 in Sjogren’s syndrome. Tissue Antigens. 1975;6(5):342–6.

    CAS  PubMed  Google Scholar 

  35. Matzaraki V, Kumar V, Wijmenga C, Zhernakova A. The MHC locus and genetic susceptibility to autoimmune and infectious diseases. Genome Biol. 2017;18(1):76. https://doi.org/10.1186/s13059-017-1207-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lessard CJ, Li H, Adrianto I, Ice JA, Rasmussen A, Grundahl KM, et al. Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjogren’s syndrome. Nat Genet. 2013;45(11):1284–92. https://doi.org/10.1038/ng.2792.

    Article  CAS  PubMed  Google Scholar 

  37. Li Y, Zhang K, Chen H, Sun F, Xu J, Wu Z, et al. A genome-wide association study in Han Chinese identifies a susceptibility locus for primary Sjogren’s syndrome at 7q11.23. Nat Genet. 2013;45(11):1361–5. https://doi.org/10.1038/ng.2779.

    Article  CAS  PubMed  Google Scholar 

  38. Nakken B, Jonsson R, Bolstad AI. Polymorphisms of the Ro52 gene associated with anti-Ro 52-kd autoantibodies in patients with primary Sjogren’s syndrome. Arthritis Rheum. 2001;44(3):638–46. https://doi.org/10.1002/1529-0131(200103)44:3<638::AID-ANR112>3.0.CO;2-J.

    Article  CAS  PubMed  Google Scholar 

  39. Gottenberg JE, Busson M, Loiseau P, Cohen-Solal J, Lepage V, Charron D, et al. In primary Sjogren’s syndrome, HLA class II is associated exclusively with autoantibody production and spreading of the autoimmune response. Arthritis Rheum. 2003;48(8):2240–5. https://doi.org/10.1002/art.11103.

    Article  CAS  PubMed  Google Scholar 

  40. Song IW, Chen HC, Lin YF, Yang JH, Chang CC, Chou CT, et al. Identification of susceptibility gene associated with female primary Sjogren’s syndrome in Han Chinese by genome-wide association study. Hum Genet. 2016;135(11):1287–94. https://doi.org/10.1007/s00439-016-1716-0.

    Article  CAS  PubMed  Google Scholar 

  41. Kumagai S, Kanagawa S, Morinobu A, Takada M, Nakamura K, Sugai S, et al. Association of a new allele of the TAP2 gene, TAP2*Bky2 (Val577), with susceptibility to Sjogren’s syndrome. Arthritis Rheum. 1997;40(9):1685–92. https://doi.org/10.1002/1529-0131(199709)40:9<1685::AID-ART19>3.0.CO;2-I.

    Article  CAS  PubMed  Google Scholar 

  42. Bolstad AI, Le Hellard S, Kristjansdottir G, Vasaitis L, Kvarnstrom M, Sjowall C, et al. Association between genetic variants in the tumour necrosis factor/lymphotoxin alpha/lymphotoxin beta locus and primary Sjogren’s syndrome in Scandinavian samples. Ann Rheum Dis. 2012;71(6):981–8. https://doi.org/10.1136/annrheumdis-2011-200446.

    Article  CAS  PubMed  Google Scholar 

  43. Gottenberg JE, Busson M, Loiseau P, Dourche M, Cohen-Solal J, Lepage V, et al. 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. 2004;50(2):570–80. https://doi.org/10.1002/art.20060.

    Article  CAS  PubMed  Google Scholar 

  44. Rusakiewicz S, Nocturne G, Lazure T, Semeraro M, Flament C, Caillat-Zucman S, et al. NCR3/NKp30 contributes to pathogenesis in primary Sjogren’s syndrome. Sci Transl Med. 2013;5(195):195ra96. https://doi.org/10.1126/scitranslmed.3005727.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Reksten TR, Johnsen SJ, Jonsson MV, Omdal R, Brun JG, Theander E, et al. Genetic associations to germinal centre formation in primary Sjogren’s syndrome. Ann Rheum Dis. 2014;73(6):1253–8. https://doi.org/10.1136/annrheumdis-2012-202500.

    Article  CAS  PubMed  Google Scholar 

  46. Petrek M, Cermakova Z, Hutyrova B, Micekova D, Drabek J, Rovensky J, et al. CC chemokine receptor 5 and interleukin-1 receptor antagonist gene polymorphisms in patients with primary Sjogren’s syndrome. Clin Exp Rheumatol. 2002;20(5):701–3.

    CAS  PubMed  Google Scholar 

  47. Hulkkonen J, Pertovaara M, Antonen J, Lahdenpohja N, Pasternack A, Hurme M. Genetic association between interleukin-10 promoter region polymorphisms and primary Sjogren’s syndrome. Arthritis Rheum. 2001;44(1):176–9. https://doi.org/10.1002/1529-0131(200101)44:1<176::AID-ANR23>3.0.CO;2-K.

    Article  CAS  PubMed  Google Scholar 

  48. Font J, Garcia-Carrasco M, Ramos-Casals M, Aldea AI, Cervera R, Ingelmo M, et al. The role of interleukin-10 promoter polymorphisms in the clinical expression of primary Sjogren’s syndrome. Rheumatology (Oxford). 2002;41(9):1025–30.

    Article  CAS  Google Scholar 

  49. Origuchi T, Kawasaki E, Ide A, Kamachi M, Tanaka F, Ida H, et al. Correlation between interleukin 10 gene promoter region polymorphisms and clinical manifestations in Japanese patients with Sjogren’s syndrome. Ann Rheum Dis. 2003;62(11):1117–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Maiti AK, Kim-Howard X, Viswanathan P, Guillen L, Rojas-Villarraga A, Deshmukh H, et al. Confirmation of an association between rs6822844 at the Il2-Il21 region and multiple autoimmune diseases: evidence of a general susceptibility locus. Arthritis Rheum. 2010;62(2):323–9. https://doi.org/10.1002/art.27222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Nordmark G, Kristjansdottir G, Theander E, Appel S, Eriksson P, Vasaitis L, et al. Association of EBF1, FAM167A(C8orf13)-BLK and TNFSF4 gene variants with primary Sjogren’s syndrome. Genes Immun. 2011;12(2):100–9. https://doi.org/10.1038/gene.2010.44.

    Article  CAS  PubMed  Google Scholar 

  52. Sun F, Li P, Chen H, Wu Z, Xu J, Shen M, et al. Association studies of TNFSF4, TNFAIP3 and FAM167A-BLK polymorphisms with primary Sjogren’s syndrome in Han Chinese. J Hum Genet. 2013;58(7):475–9. https://doi.org/10.1038/jhg.2013.26.

    Article  CAS  PubMed  Google Scholar 

  53. Kong F, Li JX, Li P, Li YZ, Zhang FC, Zhang J. Association of TNFSF4 polymorphisms with susceptibility to primary Sjogren’s syndrome and primary biliary cirrhosis in a Chinese Han population. Clin Exp Rheumatol. 2013;31(4):546–51.

    PubMed  Google Scholar 

  54. Nossent JC, Lester S, Zahra D, Mackay CR, Rischmueller M. Polymorphism in the 5′ regulatory region of the B-lymphocyte activating factor gene is associated with the Ro/La autoantibody response and serum BAFF levels in primary Sjogren’s syndrome. Rheumatology (Oxford). 2008;47(9):1311–6. https://doi.org/10.1093/rheumatology/ken246.

    Article  CAS  Google Scholar 

  55. Papageorgiou A, Mavragani CP, Nezos A, Zintzaras E, Quartuccio L, De Vita S, et al. A BAFF receptor His159Tyr mutation in Sjogren’s syndrome-related lymphoproliferation. Arthritis Rheumatol. 2015;67(10):2732–41. https://doi.org/10.1002/art.39231.

    Article  PubMed  Google Scholar 

  56. Bolstad AI, Wargelius A, Nakken B, Haga HJ, Jonsson R. Fas and Fas ligand gene polymorphisms in primary Sjogren’s syndrome. J Rheumatol. 2000;27(10):2397–405.

    CAS  PubMed  Google Scholar 

  57. Mullighan CG, Heatley S, Lester S, Rischmueller M, Gordon TP, Bardy PG. Fas gene promoter polymorphisms in primary Sjogren’s syndrome. Ann Rheum Dis. 2004;63(1):98–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Musone SL, Taylor KE, Nititham J, Chu C, Poon A, Liao W, et al. Sequencing of TNFAIP3 and association of variants with multiple autoimmune diseases. Genes Immun. 2011;12(3):176–82. https://doi.org/10.1038/gene.2010.64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Nordmark G, Wang C, Vasaitis L, Eriksson P, Theander E, Kvarnstrom M, et al. Association of genes in the NF-kappaB pathway with antibody-positive primary Sjogren’s syndrome. Scand J Immunol. 2013;78(5):447–54. https://doi.org/10.1111/sji.12101.

    Article  CAS  PubMed  Google Scholar 

  60. Qu S, Du Y, Chang S, Guo L, Fang K, Li Y, et al. Common variants near IKZF1 are associated with primary Sjogren’s syndrome in Han Chinese. PLoS One. 2017;12(5):e0177320. https://doi.org/10.1371/journal.pone.0177320.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Ou TT, Lin CH, Lin YC, Li RN, Tsai WC, Liu HW, et al. IkappaBalpha promoter polymorphisms in patients with primary Sjogren’s syndrome. J Clin Immunol. 2008;28(5):440–4. https://doi.org/10.1007/s10875-008-9212-5.

    Article  CAS  PubMed  Google Scholar 

  62. Miceli-Richard C, Gestermann N, Ittah M, Comets E, Loiseau P, Puechal X, et al. The CGGGG insertion/deletion polymorphism of the IRF5 promoter is a strong risk factor for primary Sjogren’s syndrome. Arthritis Rheumatol. 2009;60(7):1991–7. https://doi.org/10.1002/art.24662.

    Article  CAS  Google Scholar 

  63. 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(1):68–76. https://doi.org/10.1038/gene.2008.94.

    Article  CAS  PubMed  Google Scholar 

  64. Korman BD, Kastner DL, Gregersen PK, Remmers EF. STAT4: genetics, mechanisms, and implications for autoimmunity. Curr Allergy Asthma Rep. 2008;8(5):398–403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Appel S, Le Hellard S, Bruland O, Brun JG, Omdal R, Kristjansdottir G, et al. Potential association of muscarinic receptor 3 gene variants with primary Sjogren’s syndrome. Ann Rheum Dis. 2011;70(7):1327–9. https://doi.org/10.1136/ard.2010.138966.

    Article  CAS  PubMed  Google Scholar 

  66. Downie-Doyle S, Bayat N, Rischmueller M, Lester S. Influence of CTLA4 haplotypes on susceptibility and some extraglandular manifestations in primary Sjogren’s syndrome. Arthritis Rheum. 2006;54(8):2434–40. https://doi.org/10.1002/art.22004.

    Article  CAS  PubMed  Google Scholar 

  67. Sun F, Xu J, Wu Z, Li P, Chen H, Su J, et al. Polymorphisms in the FAM167A-BLK, but not BANK1, are associated with primary Sjogren’s syndrome in a Han Chinese population. Clin Exp Rheumatol. 2013;31(5):704–10.

    PubMed  Google Scholar 

  68. Mamtani M, Anaya JM, He W, Ahuja SK. Association of copy number variation in the FCGR3B gene with risk of autoimmune diseases. Genes Immun. 2010;11(2):155–60. https://doi.org/10.1038/gene.2009.71.

    Article  CAS  PubMed  Google Scholar 

  69. Nossent JC, Rischmueller M, Lester S. Low copy number of the Fc-gamma receptor 3B gene FCGR3B is a risk factor for primary Sjogren’s syndrome. J Rheumatol. 2012;39(11):2142–7. https://doi.org/10.3899/jrheum.120294.

    Article  CAS  PubMed  Google Scholar 

  70. Cobb BL, Fei Y, Jonsson R, Bolstad AI, Brun JG, Rischmueller M, et al. Genetic association between methyl-CpG binding protein 2 (MECP2) and primary Sjogren’s syndrome. Ann Rheum Dis. 2010;69(9):1731–2. https://doi.org/10.1136/ard.2009.122903.

    Article  CAS  PubMed  Google Scholar 

  71. Li H, Reksten TR, Ice JA, Kelly JA, Adrianto I, Rasmussen A, et al. Identification of a Sjogren’s syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons. PLoS Genet. 2017;13(6):e1006820. https://doi.org/10.1371/journal.pgen.1006820.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Gomez LM, Anaya JM, Gonzalez CI, Pineda-Tamayo R, Otero W, Arango A, et al. PTPN22 C1858T polymorphism in Colombian patients with autoimmune diseases. Genes Immun. 2005;6(7):628–31. https://doi.org/10.1038/sj.gene.6364261.

    Article  CAS  PubMed  Google Scholar 

  73. Ittah M, Gottenberg JE, Proust A, Hachulla E, Puechal X, Loiseau P, et al. No evidence for association between 1858 C/T single-nucleotide polymorphism of PTPN22 gene and primary Sjogren’s syndrome. Genes Immun. 2005;6(5):457–8. https://doi.org/10.1038/sj.gene.6364229.

    Article  CAS  PubMed  Google Scholar 

  74. 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(4):521–4.

    CAS  PubMed  Google Scholar 

  75. Brooks WH, Le Dantec C, Pers JO, Youinou P, Renaudineau Y. Epigenetics and autoimmunity. J Autoimmun. 2010;34(3):J207–19. https://doi.org/10.1016/j.jaut.2009.12.006.

    Article  CAS  PubMed  Google Scholar 

  76. Le Dantec C, Varin MM, Brooks WH, Pers JO, Youinou P, Renaudineau Y. Epigenetics and Sjogren’s syndrome. Curr Pharm Biotechnol. 2012;13(10):2046–53.

    Article  PubMed  Google Scholar 

  77. Kivity S, Arango MT, Ehrenfeld M, Tehori O, Shoenfeld Y, Anaya JM, et al. Infection and autoimmunity in Sjogren’s syndrome: a clinical study and comprehensive review. J Autoimmun. 2014;51:17–22. https://doi.org/10.1016/j.jaut.2014.02.008.

    Article  CAS  PubMed  Google Scholar 

  78. Thabet Y, Canas F, Ghedira I, Youinou P, Mageed RA, Renaudineau Y. Altered patterns of epigenetic changes in systemic lupus erythematosus and auto-antibody production: is there a link? J Autoimmun. 2012;39(3):154–60. https://doi.org/10.1016/j.jaut.2012.05.015.

    Article  CAS  PubMed  Google Scholar 

  79. Brooks WH, Renaudineau Y. Epigenetics and autoimmune diseases: the X chromosome-nucleolus nexus. Front Genet. 2015;6:22. https://doi.org/10.3389/fgene.2015.00022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Konsta OD, Le Dantec C, Charras A, Cornec D, Kapsogeorgou EK, Tzioufas AG, et al. Defective DNA methylation in salivary gland epithelial acini from patients with Sjogren’s syndrome is associated with SSB gene expression, anti-SSB/LA detection, and lymphocyte infiltration. J Autoimmun. 2016;68:30–8. https://doi.org/10.1016/j.jaut.2015.12.002.

    Article  CAS  PubMed  Google Scholar 

  81. Altorok N, Coit P, Hughes T, Koelsch KA, Stone DU, Rasmussen A, et al. Genome-wide DNA methylation patterns in naive CD4+ T cells from patients with primary Sjogren’s syndrome. Arthritis Rheumatol. 2014;66(3):731–9. https://doi.org/10.1002/art.38264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Miceli-Richard C, Wang-Renault SF, Boudaoud S, Busato F, Lallemand C, Bethune K, et al. Overlap between differentially methylated DNA regions in blood B lymphocytes and genetic at-risk loci in primary Sjogren’s syndrome. Ann Rheum Dis. 2016;75(5):933–40. https://doi.org/10.1136/annrheumdis-2014-206998.

    Article  CAS  PubMed  Google Scholar 

  83. Imgenberg-Kreuz J, Sandling JK, Almlof JC, Nordlund J, Signer L, Norheim KB, et al. Genome-wide DNA methylation analysis in multiple tissues in primary Sjogren’s syndrome reveals regulatory effects at interferon-induced genes. Ann Rheum Dis. 2016;75(11):2029–36. https://doi.org/10.1136/annrheumdis-2015-208659.

    Article  CAS  PubMed  Google Scholar 

  84. Cole MB, Quach H, Quach D, Baker A, Taylor KE, Barcellos LF, et al. Epigenetic signatures of salivary gland inflammation in Sjogren’s syndrome. Arthritis Rheumatol. 2016;68(12):2936–44. https://doi.org/10.1002/art.39792.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Charras A, Konsta OD, Le Dantec C, Bagacean C, Kapsogeorgou EK, Tzioufas AG, et al. Cell-specific epigenome-wide DNA methylation profile in long-term cultured minor salivary gland epithelial cells from patients with Sjogren’s syndrome. Ann Rheum Dis. 2017;76(3):625–8. https://doi.org/10.1136/annrheumdis-2016-210167.

    Article  CAS  PubMed  Google Scholar 

  86. Pratt AJ, MacRae IJ. The RNA-induced silencing complex: a versatile gene-silencing machine. J Biol Chem. 2009;284(27):17897–901. https://doi.org/10.1074/jbc.R900012200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Goodier JL, Kazazian HH Jr. Retrotransposons revisited: the restraint and rehabilitation of parasites. Cell. 2008;135(1):23–35. https://doi.org/10.1016/j.cell.2008.09.022.

    Article  CAS  PubMed  Google Scholar 

  88. Mavragani CP, Sagalovskiy I, Guo Q, Nezos A, Kapsogeorgou EK, Lu P, et al. Expression of long interspersed nuclear element 1 retroelements and induction of type I interferon in patients with systemic autoimmune disease. Arthritis Rheumatol. 2016;68(11):2686–96. https://doi.org/10.1002/art.39795.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Hung T, Pratt GA, Sundararaman B, Townsend MJ, Chaivorapol C, Bhangale T, et al. The Ro60 autoantigen binds endogenous retroelements and regulates inflammatory gene expression. Science. 2015;350(6259):455–9. https://doi.org/10.1126/science.aac7442.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Mavragani CP, Nezos A, Sagalovskiy I, Seshan S, Kirou KA, Crow MK. Defective regulation of L1 endogenous retroelements in primary Sjogren’s syndrome and systemic lupus erythematosus: role of methylating enzymes. J Autoimmun. 2018;88:75–82. https://doi.org/10.1016/j.jaut.2017.10.004.

    Article  CAS  PubMed  Google Scholar 

  91. Konsta OD, Charras A, Le Dantec C, Kapsogeorgeou E, Bordron A, Brooks WH, et al. Epigenetic modifications in salivary glands from patients with Sjogren’s syndrome affect cytokeratin 19 expression. Bull Group Int Rech Sci Stomatol Odontol. 2016;53(1):e01.

    CAS  PubMed  Google Scholar 

  92. Burbelo PD, Ambatipudi K, Alevizos I. Genome-wide association studies in Sjogren’s syndrome: what do the genes tell us about disease pathogenesis? Autoimmun Rev. 2014;13(7):756–61. https://doi.org/10.1016/j.autrev.2014.02.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Streubel B, Huber D, Wohrer S, Chott A, Raderer M. Frequency of chromosomal aberrations involving MALT1 in mucosa-associated lymphoid tissue lymphoma in patients with Sjogren’s syndrome. Clin Cancer Res. 2004;10(2):476–80.

    Article  CAS  PubMed  Google Scholar 

  94. Nocturne G, Mariette X. Sjogren syndrome-associated lymphomas: an update on pathogenesis and management. Br J Haematol. 2015;168(3):317–27. https://doi.org/10.1111/bjh.13192.

    Article  CAS  PubMed  Google Scholar 

  95. Sutton LA, Agathangelidis A, Belessi C, Darzentas N, Davi F, Ghia P, et al. Antigen selection in B-cell lymphomas—tracing the evidence. Semin Cancer Biol. 2013;23(6):399–409. https://doi.org/10.1016/j.semcancer.2013.07.006.

    Article  CAS  PubMed  Google Scholar 

  96. Fragkioudaki S, Nezos A, Souliotis VL, Chatziandreou I, Saetta AA, Drakoulis N, et al. MTHFR gene variants and non-MALT lymphoma development in primary Sjogren’s syndrome. Sci Rep. 2017;7(1):7354. https://doi.org/10.1038/s41598-017-07347-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Dierlamm J, Baens M, Wlodarska I, Stefanova-Ouzounova M, Hernandez JM, Hossfeld DK, et al. The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue lymphomas. Blood. 1999;93(11):3601–9.

    CAS  PubMed  Google Scholar 

  98. Du MQ. MALT lymphoma: a paradigm of NF-kappaB dysregulation. Semin Cancer Biol. 2016;39:49–60. https://doi.org/10.1016/j.semcancer.2016.07.003.

    Article  CAS  PubMed  Google Scholar 

  99. Murga Penas EM, Hinz K, Roser K, Copie-Bergman C, Wlodarska I, Marynen P, et al. Translocations t(11;18)(q21;q21) and t(14;18)(q32;q21) are the main chromosomal abnormalities involving MLT/MALT1 in MALT lymphomas. Leukemia. 2003;17(11):2225–9. https://doi.org/10.1038/sj.leu.2403122.

    Article  CAS  PubMed  Google Scholar 

  100. Lahiri A, Pochard P, Le Pottier L, Tobon GJ, Bendaoud B, Youinou P, et al. The complexity of the BAFF TNF-family members: implications for autoimmunity. J Autoimmun. 2012;39(3):189–98. https://doi.org/10.1016/j.jaut.2012.05.009.

    Article  CAS  PubMed  Google Scholar 

  101. Novak AJ, Grote DM, Ziesmer SC, Kline MP, Manske MK, Slager S, et al. Elevated serum B-lymphocyte stimulator levels in patients with familial lymphoproliferative disorders. J Clin Oncol. 2006;24(6):983–7. https://doi.org/10.1200/JCO.2005.02.7938.

    Article  CAS  PubMed  Google Scholar 

  102. Hildebrand JM, Luo Z, Manske MK, Price-Troska T, Ziesmer SC, Lin W, et al. A BAFF-R mutation associated with non-Hodgkin lymphoma alters TRAF recruitment and reveals new insights into BAFF-R signaling. J Exp Med. 2010;207(12):2569–79. https://doi.org/10.1084/jem.20100857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Zintzaras E, Voulgarelis M, Moutsopoulos HM. The risk of lymphoma development in autoimmune diseases: a meta-analysis. Arch Intern Med. 2005;165(20):2337–44. https://doi.org/10.1001/archinte.165.20.2337.

    Article  PubMed  Google Scholar 

  104. Zhang M, Peng LL, Wang Y, Wang JS, Liu J, Liu MM, et al. Roles of A20 in autoimmune diseases. Immunol Res. 2016;64(2):337–44. https://doi.org/10.1007/s12026-015-8677-6.

    Article  CAS  PubMed  Google Scholar 

  105. Tavares RM, Turer EE, Liu CL, Advincula R, Scapini P, Rhee L, et al. The ubiquitin modifying enzyme A20 restricts B cell survival and prevents autoimmunity. Immunity. 2010;33(2):181–91. https://doi.org/10.1016/j.immuni.2010.07.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Nocturne G, Boudaoud S, Miceli-Richard C, Viengchareun S, Lazure T, Nititham J, et al. Germline and somatic genetic variations of TNFAIP3 in lymphoma complicating primary Sjogren’s syndrome. Blood. 2013;122(25):4068–76. https://doi.org/10.1182/blood-2013-05-503383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Bi Y, Zeng N, Chanudet E, Huang Y, Hamoudi RA, Liu H, et al. A20 inactivation in ocular adnexal MALT lymphoma. Haematologica. 2012;97(6):926–30. https://doi.org/10.3324/haematol.2010.036798.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Nocturne G, Tarn J, Boudaoud S, Locke J, Miceli-Richard C, Hachulla E, et al. Germline variation of TNFAIP3 in primary Sjogren’s syndrome-associated lymphoma. Ann Rheum Dis. 2016;75(4):780–3. https://doi.org/10.1136/annrheumdis-2015-207731.

    Article  CAS  PubMed  Google Scholar 

  109. van Krieken JH. New developments in the pathology of malignant lymphoma: a review of the literature published from May to August 2017. J Hematopathol. 2017;10(2):65–73. https://doi.org/10.1007/s12308-017-0303-1.

    Article  Google Scholar 

  110. Lee KM, Lan Q, Kricker A, Purdue MP, Grulich AE, Vajdic CM, et al. One-carbon metabolism gene polymorphisms and risk of non-Hodgkin lymphoma in Australia. Hum Genet. 2007;122(5):525–33. https://doi.org/10.1007/s00439-007-0431-2.

    Article  CAS  PubMed  Google Scholar 

  111. Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461(7267):1071–8. https://doi.org/10.1038/nature08467.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Chen JQ, Papp G, Poliska S, Szabo K, Tarr T, Balint BL, et al. MicroRNA expression profiles identify disease-specific alterations in systemic lupus erythematosus and primary Sjogren’s syndrome. PLoS One. 2017;12(3):e0174585. https://doi.org/10.1371/journal.pone.0174585.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Shi H, Zheng LY, Zhang P, Yu CQ. miR-146a and miR-155 expression in PBMCs from patients with Sjogren’s syndrome. J Oral Pathol Med. 2014;43(10):792–7. https://doi.org/10.1111/jop.12187.

    Article  CAS  PubMed  Google Scholar 

  114. Wang-Renault SF, Boudaoud S, Nocturne G, Roche E, Sigrist N, Daviaud C, et al. Deregulation of microRNA expression in purified T and B lymphocytes from patients with primary Sjogren’s syndrome. Ann Rheum Dis. 2018;77(1):133–40. https://doi.org/10.1136/annrheumdis-2017-211417.

    Article  CAS  PubMed  Google Scholar 

  115. Lopez-Ramirez MA, Wu D, Pryce G, Simpson JE, Reijerkerk A, King-Robson J, et al. MicroRNA-155 negatively affects blood-brain barrier function during neuroinflammation. FASEB J. 2014;28(6):2551–65. https://doi.org/10.1096/fj.13-248880.

    Article  CAS  PubMed  Google Scholar 

  116. Gourzi VC, Kapsogeorgou EK, Kyriakidis NC, Tzioufas AG. Study of microRNAs (miRNAs) that are predicted to target the autoantigens Ro/SSA and La/SSB in primary Sjogren’s syndrome. Clin Exp Immunol. 2015;182(1):14–22. https://doi.org/10.1111/cei.12664.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Kapsogeorgou EK, Gourzi VC, Manoussakis MN, Moutsopoulos HM, Tzioufas AG. Cellular microRNAs (miRNAs) and Sjogren’s syndrome: candidate regulators of autoimmune response and autoantigen expression. J Autoimmun. 2011;37(2):129–35. https://doi.org/10.1016/j.jaut.2011.05.003.

    Article  CAS  PubMed  Google Scholar 

  118. Gallo A, Jang SI, Ong HL, Perez P, Tandon M, Ambudkar I, et al. Targeting the Ca2+ sensor STIM1 by exosomal transfer of Ebv-miR-BART13-3p is associated with Sjogren’s syndrome. EBioMedicine. 2016;10:216–26. https://doi.org/10.1016/j.ebiom.2016.06.041.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Ghorbani S, Talebi F, Chan WF, Masoumi F, Vojgani M, Power C, et al. MicroRNA-181 variants regulate T cell phenotype in the context of autoimmune neuroinflammation. Front Immunol. 2017;8:758. https://doi.org/10.3389/fimmu.2017.00758.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Peng L, Ma W, Yi F, Yang YJ, Lin W, Chen H, et al. MicroRNA profiling in Chinese patients with primary Sjogren syndrome reveals elevated miRNA-181a in peripheral blood mononuclear cells. J Rheumatol. 2014;41(11):2208–13. https://doi.org/10.3899/jrheum.131154.

    Article  CAS  PubMed  Google Scholar 

  121. Tandon M, Gallo A, Jang SI, Illei GG, Alevizos I. Deep sequencing of short RNAs reveals novel microRNAs in minor salivary glands of patients with Sjogren's syndrome. Oral Dis. 2012;18(2):127–31. https://doi.org/10.1111/j.1601-0825.2011.01849.x.

    Article  CAS  PubMed  Google Scholar 

  122. Williams AE, Choi K, Chan AL, Lee YJ, Reeves WH, Bubb MR, et al. Sjogren’s syndrome-associated microRNAs in CD14(+) monocytes unveils targeted TGFbeta signaling. Arthritis Res Ther. 2016;18(1):95. https://doi.org/10.1186/s13075-016-0987-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Yang Y, Peng L, Ma W, Yi F, Zhang Z, Chen H, et al. Autoantigen-targeting microRNAs in Sjogren’s syndrome. Clin Rheumatol. 2016;35(4):911–7. https://doi.org/10.1007/s10067-016-3203-3.

    Article  PubMed  Google Scholar 

  124. Michael A, Bajracharya SD, Yuen PS, Zhou H, Star RA, Illei GG, et al. Exosomes from human saliva as a source of microRNA biomarkers. Oral Dis. 2010;16(1):34–8. https://doi.org/10.1111/j.1601-0825.2009.01604.x.

    Article  CAS  PubMed  Google Scholar 

  125. Alevizos I, Alexander S, Turner RJ, Illei GG. MicroRNA expression profiles as biomarkers of minor salivary gland inflammation and dysfunction in Sjogren’s syndrome. Arthritis Rheum. 2011;63(2):535–44. https://doi.org/10.1002/art.30131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Univ Brest, UMR1227, Lymphocytes B et Autoimmunité, Brest, France

    Laëtitia Le Pottier, Kahina Amrouche, Amandine Charras, Anne Bordron & Jacques-Olivier Pers

Authors
  1. Laëtitia Le Pottier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kahina Amrouche
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amandine Charras
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anne Bordron
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jacques-Olivier Pers
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jacques-Olivier Pers .

Editor information

Editors and Affiliations

  1. Institute of Parasitology and Biomedicine, Lopez-Neyra, CSIC, Granada, Spain

    Javier Martín

  2. Department of Genetics, University of Granada, Armilla, Granada, Spain

    Francisco David Carmona

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Le Pottier, L., Amrouche, K., Charras, A., Bordron, A., Pers, JO. (2019). Sjögren’s Syndrome. In: Martín, J., Carmona, F. (eds) Genetics of Rare Autoimmune Diseases. Rare Diseases of the Immune System. Springer, Cham. https://doi.org/10.1007/978-3-030-03934-9_4

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-03934-9_4

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-03933-2

  • Online ISBN: 978-3-030-03934-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation