Skip to main content
Log in

Association Between Circulating Levels of the Novel TNF Family Members APRIL and BAFF and Lymphoid Organization in Primary Sjögren’s Syndrome

  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are members of the tumour necrosis factor superfamily. We have examined circulating BAFF and APRIL in relation to serological deviations and lymphoid organization in the salivary glands of the chronic, autoimmune disorder Sjögren’s syndrome. Lymphoid organization in the shape of ectopic germinal centers were detected in 33 of 130 consecutive minor salivary gland biopsies and coincided with increased focus score and elevated levels of serum IgG. Follicular dendritic cell networks, proliferation of mononuclear cells and altered B/T cell ratio also separated the two subgroups. Serum levels of sBAFF and sAPRIL were increased in Sjögren’s syndrome compared to healthy blood donors, especially in anti-Ro/La+ patients. Though the differences could not be related to germinal center formation, positive correlations between serum levels of sBAFF and sAPRIL, focus score and IgG denotes their possible role in the disease progression of primary 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.

Institutional subscriptions

Similar content being viewed by others

References

  1. Jonsson R, Bowman S, Gordon TP: Sjögren’s syndrome. In Arthritis and Allied Conditions—A Textbook of Rheumatology, WJ Koopman, LW Morland (eds). 15th edn. Philadelphia, Lippincott Williams and Wilkins, 2004, pp 1681–1705

    Google Scholar 

  2. Jonsson R, Gordon TP, Konttinen YT: Recent advances in understanding molecular mechanisms in the pathogenesis and antibody profile of Sjögren’s syndrome. Curr Rheumatol Rep 5:311–316, 2003

    PubMed  Google Scholar 

  3. Jonsson R, Kroneld U, Bäckman K, Magnusson B, Tarkowski A: Progression of sialadenitis in Sjögren’s syndrome. Br J Rheumatol 32:578–581, 1993

    CAS  PubMed  Google Scholar 

  4. Halse A, Harley JB, Kroneld U, Jonsson R: Ro/SS-A-reactive B lymphocytes in salivary glands and peripheral blood of patients with Sjögren’s syndrome. Clin Exp Immunol 115:203–207, 1999

    Article  CAS  PubMed  Google Scholar 

  5. Salomonsson S, Jonsson MV, Skarstein K, Brokstad KA, Hjelmström P, Wahren-Herlenius M, Jonsson R: Cellular basis of ectopic germinal center formation and autoantibody production in the target organ of patients with Sjögren’s syndrome. Arthritis Rheum 48:3187–3201, 2003

    Article  CAS  PubMed  Google Scholar 

  6. 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 Sjögren’s syndrome. J Clin Invest 102:938–946, 1998

    CAS  PubMed  Google Scholar 

  7. Amft N, Bowman SJ: Chemokines and cell trafficking in Sjögren’s syndrome. Scand J Immunol 54:62–69, 2001

    Article  CAS  PubMed  Google Scholar 

  8. Janeway CA, Travers P, Walport M, Schlomchik M: The humoral immune response. In Immunobiology: The Immunesystem in Health and Disease, S Gibbs (ed). 5th edn. New York, Garland Publishing, 2001, pp 343–380

  9. Schneider P, MacKay F, Steiner V, Hofmann K, Bodmer JL, Holler N, Ambrose C, Lawton P, Bixler S, Acha-Orbea H, Valmori D, Romero P, Werner-Favre C, Zubler RH, Browning JL, Tschopp J: BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med 189:1747–1756, 1999

    Google Scholar 

  10. Shu HB, Hu WH, Johnson H: TALL-1 is a novel member of the TNF family that is down-regulated by mitogens. J Leukoc Biol 65:680–683, 1999

    CAS  PubMed  Google Scholar 

  11. Mukhopadhyay A, Ni J, Zhai Y, Yu GL, Aggarwal BB: Identification and characterization of a novel cytokine, THANK, a TNF homologue that activates apoptosis, nuclear factor-kappaB, and c-Jun NH2-terminal kinase. J Biol Chem 274:15978–15981, 1999

    Article  CAS  PubMed  Google Scholar 

  12. Moore PA, Belvedere O, Orr A, Pieri K, LaFleur DW, Feng P, Soppet D, Charters M, Gentz R, Parmelee D, Li Y, Galperina O, Giri J, Roschke V, Nardelli B, Carrell J, Sosnovtseva S, Greenfield W, Ruben SM, Olsen HS, Fikes J, Hilbert DM, BLyS: Member of the tumor necrosis factor family and B lymphocyte stimulator. Science 285:260–263, 1999

    Article  CAS  PubMed  Google Scholar 

  13. Gross JA, Johnston J, Mudri S, Enselman R, Dillon SR, Madden K, Xu W, Parrish-Novak J, Foster D, Lofton-Day C, Moore M, Littau A, Grossman A, Haugen H, Foley K, Blumberg H, Harrison K, Kindsvogel W, Clegg CH: TACI and BCMA are receptors for a TNF homologue implicated in B cell autoimmune disease. Nature 404:995–999, 2000

    Article  PubMed  Google Scholar 

  14. Lavie F, Miceli-Richard C, Quillard J, Roux S, Leclerc P, Mariette X: Expression of BAFF (BLyS) in T cells infiltrating labial salivary glands from patients with Sjögren’s syndrome. J Pathol 202:496–502, 2004

    Article  CAS  PubMed  Google Scholar 

  15. Mackay F, Ambrose C: The TNF family members BAFF and APRIL: The growing complexity. Cytokine Growth Factor Rev 14:311–324, 2003

    Article  CAS  PubMed  Google Scholar 

  16. Stohl W, Metyas S, Tan SM, Cheema GS, Oamar B, Xu D, Roschke V, Wu Y, Baker KP, Hilbert DM: B lymphocyte stimulator over expression in patients with systemic lupus erythematosus: Longitudinal observations. Arthritis Rheum 48:3475–3486, 2003

    Article  PubMed  Google Scholar 

  17. Stohl W, Metyas S, Tan SM, Cheema GS, Oamar B, Roschke V, Wu Y, Baker KP, Hilbert DM: Inverse association between circulating APRIL levels and serological and clinical disease activity in patients with systemic lupus erythematosus. Ann Rheum Dis 63:1096–1103, 2004

    Article  CAS  PubMed  Google Scholar 

  18. Szodoray P, Jellestad S, Teague MO, Jonsson R: Attenuated apoptosis of B cell activating factor-expressing cells in primary Sjögren’s syndrome. Lab Invest 83:357–365, 2003

    Article  CAS  PubMed  Google Scholar 

  19. Szodoray P, Jellestad S, Alex P, Zhou T, Wilson PC, Centola M, Brun JG, Jonsson R: Programmed cell death of peripheral blood B cells determined by laser scanning cytometry in Sjögrenás syndrome with a special emphasis on BAFF. J Clin Immunol 24:600–611, 2004

    Article  PubMed  Google Scholar 

  20. Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, Daniels TE, Fox PC, Fox RI, Kassan SS, Pillemer SR, Talal N, Weisman MH: Classification criteria for Sjögren’s syndrome: A revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 61:554–558, 2002

    CAS  PubMed  Google Scholar 

  21. Takemura S, Braun A, Crowson C, Kurtin PJ, Cofield RH, O’Fallon WM, Goronzy JJ, Weyand CM: Lymphoid neogenesis in rheumatoid synovitis. J Immunol 167:1072–1080, 2001

    CAS  PubMed  Google Scholar 

  22. Armengol MP, Juan M, Lucas-Martin A, Fernandez-Figueras MT, Jaraquemada D, Gallart T, Pujol-Borrell R: Thyroid autoimmune disease: Demonstration of thyroid antigen-specific B cells and recombination-activating gene expression in chemokine-containing active intrathyroidal germinal centers. Am J Pathol 159:861–873, 2001

    CAS  PubMed  Google Scholar 

  23. Sims GP, Shiono H, Willcox N, Stott DI: Somatic hypermutation and selection of B cells in thymic germinal centers responding to acetylcholine receptor in myasthenia gravis. J Immunol 167:1935–1944, 2001

    CAS  PubMed  Google Scholar 

  24. Mazzucchelli L, Blaser A, Kappeler A, Scharli P, Laissue JA, Baggiolini M, Uguccioni M: BCA-1 is highly expressed in Helicobacter pylori-induced mucosa-associated lymphoid tissue and gastric lymphoma. J Clin Invest 104:R49–R54, 1999

    CAS  PubMed  Google Scholar 

  25. Grant AJ, Goddard S, Ahmed-Choudhury J, Reynolds G, Jackson DG, Briskin M, Wu L, Hubscher SG, Adams DH: Hepatic expression of secondary lymphoid chemokine (CCL21) promotes the development of portal-associated lymphoid tissue in chronic inflammatory liver disease. Am J Pathol 160:1445–1455, 2002

    CAS  PubMed  Google Scholar 

  26. Magalhaes R, Stiehl P, Morawietz L, Berek C, Krenn V: Morphological and molecular pathology of the B cell response in synovitis of rheumatoid arthritis. Virchows Arch 441:415–427, 2002

    Article  CAS  PubMed  Google Scholar 

  27. Kim HJ, Krenn V, Steinhauser G, Berek C: Plasma cell development in synovial germinal centers in patients with rheumatoid and reactive arthritis. J Immunol 162:3053–3062, 1999

    CAS  PubMed  Google Scholar 

  28. Weyand CM, Goronzy JJ: Ectopic germinal center formation in rheumatoid synovitis. Ann N Y Acad Sci 987:140–149, 2003

    CAS  PubMed  Google Scholar 

  29. Aziz KE, McCluskey PJ, Wakefield D: Characterisation of follicular dendritic cells in labial salivary glands of patients with primary Sjögren syndrome: Comparison with tonsillar lymphoid follicles. Ann Rheum Dis 56:140–143, 1997

    CAS  PubMed  Google Scholar 

  30. Xanthou G, Tapinos NI, Polihronis M, Nezis IP, Margaritis LH, Moutsopoulos HM: CD4 cytotoxic and dendritic cells in the immunopathologic lesion of Sjögren’s syndrome. Clin Exp Immunol 118:154–163, 1999

    Article  CAS  PubMed  Google Scholar 

  31. Cuida M, Brun JG, Johannessen AC, Jonsson R: Immunohistochemical characterization of the cellular infiltrates in Sjögren’s syndrome, rheumatoid arthritis and osteoarthritis with special reference to calprotectin-producing cells. APMIS 104:881–890, 1996

    CAS  PubMed  Google Scholar 

  32. van Blokland SC, van Helden-Meeuwsen CG, Wierenga-Wolf AF, Drexhage HA, Hooijkaas H, van de Merwe JP, Versnel MA: Two different types of sialoadenitis in the NOD- and MRL/lpr mouse models for Sjögren’s syndrome: A differential role for dendritic cells in the initiation of sialoadenitis? Lab Invest 80:575–585, 2000

    CAS  PubMed  Google Scholar 

  33. Tengner P, Halse AK, Haga HJ, Jonsson R, Wahren-Herlenius M: Detection of anti-Ro/SSA and anti-La/SSB autoantibody-producing cells in salivary glands from patients with Sjögren’s syndrome. Arthritis Rheum 41:2238–2248, 1998

    Article  CAS  PubMed  Google Scholar 

  34. Groom J, Kalled SL, Cutler AH, Olson C, Woodcock SA, Schneider P, Tschopp J, Cachero TG, Batten M, Wheway J, Mauri D, Cavill D, Gordon TP, Mackay CR, Mackay F: Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjögren’s syndrome. J Clin Invest 109:59–68, 2002

    Article  CAS  PubMed  Google Scholar 

  35. Mariette X, Roux S, Zhang J, Bengoufa D, Lavie F, Zhou T, Kimberly R: The level of BLyS (BAFF) correlates with the titre of autoantibodies in human Sjögren’s syndrome. Ann Rheum Dis 62:168–171, 2003

    Article  CAS  PubMed  Google Scholar 

  36. Vora KA, Wang LC, Rao SP, Liu ZY, Majeau GR, Cutler AH, Hochman PS, Scott ML, Kalled SL, Cutting edge: Germinal centers formed in the absence of B cell-activating factor belonging to the TNF family exhibit impaired maturation and function. J Immunol 171:547–551, 2003

    CAS  PubMed  Google Scholar 

  37. Yu G, Boone T, Delaney J, Hawkins N, Kelley M, Ramakrishnan M, McCabe S, Qiu WR, Kornuc M, Xia XZ, Guo J, Stolina M, Boyle WJ, Sarosi I, Hsu H, Senaldi G, Theill LE: APRIL and TALL-I and receptors BCMA and TACI: System for regulating humoral immunity. Nat Immunol 1:252–256, 2000

    Article  CAS  PubMed  Google Scholar 

  38. Szodoray P, Alex P, Brun JG, Centola M, Jonsson R: Circulating cytokines in primary Sjögren’s syndrome determined by a multiplex cytokine array system. Scand J Immunol 59:592–599, 2004

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Malin V. Jonsson.

Additional information

The first two authors contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jonsson, M.V., Szodoray, P., Jellestad, S. et al. Association Between Circulating Levels of the Novel TNF Family Members APRIL and BAFF and Lymphoid Organization in Primary Sjögren’s Syndrome. J Clin Immunol 25, 189–201 (2005). https://doi.org/10.1007/s10875-005-4091-5

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-005-4091-5

Key Words

Navigation