Skip to main content

Advertisement

Log in

Lymphoproliferation in autoimmunity and Sjögren’s syndrome

  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

Sjögren’s syndrome is a chronic inflammatory process involving primarily the exocrine glands. Its association with lymphoma is well documented. A low-grade marginal-zone lymphoma related to mucosa-associated lymphoid tissue is the most common lymphoid neoplasia in Sjögren’s syn-drome. Among all autoimmune diseases, Sjögren’s syn-drome is the best tool to clarify the multiple components of autoimmunity and lymphomatogenesis. Herewith, the authors review the literature and discuss the molecular, clinical, histopathologic, and therapeutic aspects of these tumors in Sjögren’s syndrome.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

  1. Kassan SS, Thomas TL, Moutsopoulos HM, et al.: Increased risk of lymphoma in sicca syndrome. Ann Inter Med 1978, 89:888–892.

    CAS  Google Scholar 

  2. Ansell SM, Grant CS, Habermann TM: Primary thyroid lym-phoma. Semin Oncol 1999, 26:316–323.

    PubMed  CAS  Google Scholar 

  3. Sokol RJ, Hewitt S, Stamps BK: Autoimmune hemolysis: an 18- year study of 865 cases referred to a regional transfusion cen-ter. Br Med J 1981, 282:2023–2027.

    CAS  Google Scholar 

  4. Abu-Shakra M, Gladman DD, Urowitz MB: Malignancy in sys-temic lupus erythematosus. Arthritis Rheum 1996, 39:1050–1054.

    Article  PubMed  CAS  Google Scholar 

  5. Mellemkjaer L, Linet MS, Gridley G, et al.: Rheumatoid arthri-tis and cancer risk. Eur J Cancer 1996, 32A:1753–1757.

    Article  PubMed  CAS  Google Scholar 

  6. Valesini G, Priori R, Bavoillot D, et al.: Differential risk of non-Hodgkin’s lymphoma in Italian patients with primary Sjögren’s syndrome. J Rheumatol 1997, 24:2376–2380.

    PubMed  CAS  Google Scholar 

  7. Youinou P, Mackenzie L, le Masson G, et al.: CD5-expressing B lymphocytes in the blood and salivary glands of patients with primary Sjogren’s syndrome. J Autoimmun 1988, 1:185–194.

    Article  PubMed  CAS  Google Scholar 

  8. Bunim JJ, Talal N: Development of malignant lymphoma in the course of Sjögren’s syndrome. Trans Assoc Am Physicians 1963, 76:45–56.

    Google Scholar 

  9. Pisa EK, Pisa P, Kang HI, Fox RI: High frequency of t(14;18) translocation in salivary gland lymphomas from Sjögren’s syndrome patients. J Exp Med 1991, 174:1245–1250.

    Article  PubMed  CAS  Google Scholar 

  10. Sutcliffe N, Inanc M, Speight P, Isenberg D: Predictors of lym-phoma development of primary Sjögren’s syndrome. Semin Arthritis Rheum 1998, 28:80–87.

    Article  PubMed  CAS  Google Scholar 

  11. DiGiuseppe JA, Corio RL, Westa WH: Lymphoid infiltrates of the salivary glands: pathology, biology and clinical signifi-cance. Curr Opin Oncol 1996, 8:232–237.

    Article  PubMed  CAS  Google Scholar 

  12. Stott DI, Hiepe F, Hummel M, et al.: Antigen-driven clonal pro-liferation of B cells within target tissue of an autoimmune disease: the salivary glands of patients with Sjögren’s syn-drome. J Clin Invest 1998, 102:938–946.

    PubMed  CAS  Google Scholar 

  13. Fox RI, Bumol T, Fantozzi R, et al.: Expression of histocompat-ibility antigen HLA-DR by salivary gland epithelial cells in Sjögren’s syndrome. Arthritis Rheum 1986, 29:1105–1111.

    Article  PubMed  CAS  Google Scholar 

  14. Xanthou G, Policronis M, Tzioufas AG, 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 lym-phoid structure formation. Arthritis Rheum 2001, 44:408–418.

    Article  PubMed  CAS  Google Scholar 

  15. Dimitriou ID, Kapsogeorgou EK, Moutsopoulos HM, Manous-sakis MN: CD40 on salivary gland epithelial cells: high con-stitutive expression by cultured cells from Sjogren’s syndrome patients indicating their intrinsic activation. Clin Exp Immunol 2002, 127:386–392.

    Article  PubMed  CAS  Google Scholar 

  16. Adamson TC, Fox RI, Frisman DM, Howell FV: Immunohisto-logic analysis of lymphoid infiltrates in primary Sjogren’s syndrome using monoclonal antibodies. J Immunol 1983, 130:203–208.

    PubMed  Google Scholar 

  17. Fox RI, Kang HI, Ando D, et al.: Cytokine mRNA expression in salivary gland biopsies of Sjögren’s syndrome. J Immunol 1994, 152:5532–5539.

    PubMed  CAS  Google Scholar 

  18. 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, 34:326–333.

    Article  PubMed  CAS  Google Scholar 

  19. Freimark B, Fantozzi R, Bone R, et al.: Detection of clonally expanded salivary gland lymphocytes in Sjögren’s syndrome. Arthritis Rheum 1989, 32:859–869.

    PubMed  CAS  Google Scholar 

  20. Bahler DW, Swerdlow SH: Clonal salivary gland infiltrates associated with myoepithelial sialadenitis (Sjögren’s syn-drome) begin as nonmalignant antigen-selected expansions. Blood 1998, 91:1864–1872.

    PubMed  CAS  Google Scholar 

  21. De Vita S, Boiocchi M, Sorrentino D, et al.: Characterization of prelymphomatous stages of B cell lymphoproliferation in Sjögren’s syndrome. Arthritis Rheum 1997, 40:318–331.

    Article  PubMed  Google Scholar 

  22. Anaya JM, McGuff HS, Banks PM, Talal N: Clinicopathological factors relating malignant lymphoma with Sjogren’s syn-drome. Semin Arthritis Rheum 1996, 25:337–346.

    Article  PubMed  CAS  Google Scholar 

  23. Fong S, Chen PP, Gilbertson TA, et al.: Expression of three cross-reactive idiotypes on rheumatoid factor autoantibodies from patients with autoimmune diseases and seropositive adults. J Immunol 1986, 137:122–128.

    PubMed  CAS  Google Scholar 

  24. Fox RI, Chen P, Carson DA, Fong S: Expression of a cross-reac-tive idiotypes on rheumatoid factor in patients with Sjögren’s syndrome. J Immunol 1986, 136:477–483.

    PubMed  CAS  Google Scholar 

  25. Katsikis PD, Youinou PY, Galanopoulou V, et al.: Monoclonal process in primary Sjögren’s syndrome and cross-reactive idiotype associated with rheumatoid factor. Clin Exp Immunol 1990, 82:509–514.

    Article  PubMed  CAS  Google Scholar 

  26. Bahler DW, Miklos JA, Swerdlow SH: Ongoing Ig gene hyper-mutation in salivary gland mucossa-associated lymphoid tis-sue- type lymphomas. Blood 1997, 89:3335–3344.

    PubMed  CAS  Google Scholar 

  27. Royer B, Cazals-Hatem D, Sibilia J, et al.: Lymphomas in patients with Sjögren’s syndrome are marginal zone B-cell neoplasms, arise in diverse extranodal and nodal sites and are not associated with viruses. Blood 1997, 90:766–775.

    PubMed  CAS  Google Scholar 

  28. Peng H, Chen G, Du M, et al.: Replication error phenotype and p53 gene mutation in lymphomas of mucosa-associated lymphoid tissue. Am J Pathol 1996, 148:643–648.

    PubMed  CAS  Google Scholar 

  29. Du M, Peng H, Singh N, Isaacson PG, Pan L: The accumulation of p53 abnormalities is associated with progression of mucosa-associated lymphoid tissue lymphoma. Blood 1995, 86:4587–4593.

    PubMed  CAS  Google Scholar 

  30. Soussi T: The humoral response to the tumor-suppressor gene-product p53 in human cancer: implications for diagno-sis and therapy. Immunol Today 1996, 17:354–356.

    Article  PubMed  CAS  Google Scholar 

  31. Tapinos NI, Polihronis M, Moutsopoulos HM: Lymphoma development in Sjögren’s syndrome: novel p53 mutations. Arthritis Rheum 1999, 42:1466–1472. Described two novel mutations in exon 5 of the p53 gene in four patients with SS-associated low-grade NHLs. The authors postulate that inactivation of p53 tumor-suppressor activity is a potential mech-anism of SS lymphomatogenesis.

    Article  PubMed  CAS  Google Scholar 

  32. Kuppers R, Klein U, Hansmann ML, Rajewsky K: Cellular ori-gin of human B-cell lymphomas. N Engl J Med 1999, 341:1520–1529. This is an excellent review about the origin of B cell NHLs. The authors review the literature and focus on variable IgH genes recom-binational events proposing mechanisms for B cell clonal expansion after antigen-driven stimulation.

    Article  PubMed  CAS  Google Scholar 

  33. Ihrler S, Baretton GB, Menauer F, et al.: Sjögren’s syndrome and MALT lymphomas of salivary glands: a DNA-cytometric and interphase-cytogenetic study. Mod Pathol 2000, 13:4–12.

    Article  PubMed  CAS  Google Scholar 

  34. Gronbaek K, Straten PT, Palfkiaer E, et al.: Somatic Fas muta-tions in non-Hodgkin’s lymphoma: association with extran-odal disease and autoimmunity. Blood 1998, 92:3018–3024.

    PubMed  CAS  Google Scholar 

  35. Bertolo F, De Vita S, Dolcetti R, et al.: Lack of Fas and Fas-L mutations in patients with lymphoproliferative disorders associated with Sjögren’s syndrome and type II mixed cryo-globulinemia. Clin Exp Rheumatol 1999, 17:339–342.

    PubMed  CAS  Google Scholar 

  36. Dammacco F, Sansonno D, Piccoli C, et al.: The lymphoid sys-tem in hepatitis C virus infection: autoimmunity, mixed cryo-globulinemia, and overt B-cell malignancy. Semin Liver Dis 2000, 20:143–157. An interesting review focusing on the pathogenetic mechanisms involved in B cell expansion and progression to frank lymphoid malignancy in patients with HCV.

    Article  PubMed  CAS  Google Scholar 

  37. Ivanovski M, Silvestri F, Pozzato G, et al.: Somatic hypermuta-tion, clonal diversity, and preferential expression of the VH 51p1/VL kv325 immunoglobulin gene combination in hepa-titis C virus-associated immunocytomas. Blood 1998, 91:2433–442.

    PubMed  CAS  Google Scholar 

  38. De Re V, De Vita S, Marzotto A, et al.: Sequence analysis of the immunoglobulin antigen receptor of hepatitis C virus-associ-ated non-Hodgkin lymphomas suggests that the malignant cells are derived from the rheumatoid factor-producing cells that occur mainly in type II cryoglobulinemia. Blood 2000, 96:3578–3584. Describes that a large proportion of HCV-associated NHLs derives from RF-producing B cell clones chronically stimulated by a viral anti-gen, such as E2 protein.

    PubMed  Google Scholar 

  39. Miklos JA, Swerdlow SH, Bahler DW: Salivary gland mucosa-associated lymphoid tissue lymphoma immunoglobulin V(H) genes show frequent use of V1-69 with distinctive CDR3 features. Blood 2000, 95:3878–3884. The article indicates that salivary gland MALT lymphomas represent a highly selected B cell population that may recognize the same epitopes.

    PubMed  CAS  Google Scholar 

  40. Martin T, Weber JC, Levallois H, et al.: Salivary gland lympho-mas in patients with Sjögren’s syndrome may frequently develop from rheumatoid factors B cells. Arthritis Rheum 2000, 43:908–916. An excellent molecular study attempting to prove the hypothesis that SS-associated B cell clones have RF activity. This article illustrates the link among primary SS, autoantibody-producing cells, and lymphoma.

    Article  PubMed  CAS  Google Scholar 

  41. Anderson LG, Talal N: The spectrum of benign to malignant lymphoproliferation in Sjögren’s syndrome. Clin Exp Immunol 1972, 10:199–221.

    PubMed  CAS  Google Scholar 

  42. Tzioufas AG, Boumba DS, Skopouli FN, Moutsopoulos HM: Mixed monoclonal cryoglobulinemia and monoclonal rheu-matoid factor cross-reactive idiotypes as predictive factors for the development of lymphoma in primary Sjögren’s syn-drome. Arthritis Rheum 1996, 39:767–772.

    Article  PubMed  CAS  Google Scholar 

  43. Walters MT, Stevenson FK, Herbert A, et al.: Urinary mono-clonal free light chains in the primary Sjögren’s syndrome: an aid to the diagnosis of malignant lymphoma. Ann Rheum Dis 1986, 45:210–219.

    Article  PubMed  CAS  Google Scholar 

  44. Skopouli FN, Dafni U, Ioannidis JP, Moutsopoulos HM: Clini-cal evolution, and morbidity and mortality of primary Sjögren’s syndrome. Semin Arthritis Rheum 2000, 29:296–304. This is an interesting retrospective study of the clinical course and outcome of 261 patients with primary SS. The article provides predic-tors for lymphoma development in a large cohort of patients and clearly delineates the patients with SS in low- and high-risk groups.

    Article  PubMed  CAS  Google Scholar 

  45. Harris NL: Lymphoid proliferations of the salivary glands. Am J Clin Pathol 1999, 111 (suppl): S94-S103.

    PubMed  CAS  Google Scholar 

  46. Voulgarelis M, Dafni UG, Isenberg DA, Moutsopoulos HM: Malignant lymphoma in primary Sjögren’s syndrome: a mul-ticenter, retrospective, clinical study by the European Con-certed Action on Sjögren’s Syndrome. Arthritis Rheum 1999, 42:1765–1772. A large European multicenter retrospective study that provides clearly the clinical and pathologic characteristics, the treatment outcome and prognosis of SS-associated NHLs.

    Article  PubMed  CAS  Google Scholar 

  47. Mariette X: Lymphomas in patients with Sjögren’s syndrome: review of the literature and physiopathologic hypothesis. Leuk Lymphoma 1999, 33:93–99. An overall review of SS-associated lymphomas focusing on the clini-cal parameters, but also highlighting important pathologic and pathogenetic aspects.

    PubMed  CAS  Google Scholar 

  48. Pelstring RJ, Essell JH, Kurtin PJ, et al.: Diversity of organ site involvement among malignant lymphomas of mucosa-asso-ciated tissues. Am J Clin Pathol 1991, 96:738–745.

    PubMed  CAS  Google Scholar 

  49. Dogan A, Du M, Koulis A, et al.: Expression of lymphocyte homing receptors and vascular addressing in low-grade gas-tric B-cell lymphomas of mucosa-associated lymphoid tissue. Am J Pathol 1997, 151:1361–1369.

    PubMed  CAS  Google Scholar 

  50. Voulgarelis M, Petroutsos G, Moutsopoulos HM, Skopouli FN: 2-chloro-2-deoxyadenosine in the treatment of Sjögren’s syn-drome- associated B cell lymphoproliferation. Arthritis Rheum 2002, 46:2248–2249.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Voulgarelis, M., Moutsopoulos, H.M. Lymphoproliferation in autoimmunity and Sjögren’s syndrome. Curr Rheumatol Rep 5, 317–323 (2003). https://doi.org/10.1007/s11926-003-0011-y

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11926-003-0011-y

Keywords

Navigation