Up-Regulation of B-Lymphocyte Stimulator (BLyS) in Patients with Mixed Cryoglobulinemia



The B-lymphocyte stimulator BLyS is one of the key regulators of B cell survival and proliferation. Consistent with this function, high BLyS levels in the serum and/or in affected tissues have been documented in several autoimmune and lymphoproliferative diseases. In patients with mixed cryoglobulinemic syndrome (MCsn), BLyS serum levels are significantly elevated and correlate with markers of HCV-associated B-cell lymphoproliferation. BlyS is also increased, however, in HCV-infected individuals without MCsn. Thus, HCV infection appears to be a crucial, early trigger of BLyS up-regulation. BLyS expression induced by HCV infection or by other pathogenetic events may therefore favor the development of autoimmune and lymphoproliferative features. While the etiologic role of chronic infection is well established in MCsn, such information is lacking in other autoimmune diseases, in which the role of a putative infectious trigger is strongly hypothesized. Accordingly, BLyS up-regulation in HCV-positive MC is an important model linking viral infection, B cell proliferation, and autoimmune disease. Besides direct targeting of the infectious trigger HCV and the B-cell autoimmune/lymphoproliferative disorder, indirect B-cell targeting might likewise prove effective in the treatment of HCV-related MCsn.


Systemic Lupus Erythematosus Celiac Disease Mixed Cryoglobulinemia Infectious Trigger BLyS Level 
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.
    Moore PA, Belvedere O, Orr A et al (1999) BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science 285(5425):260–263PubMedCrossRefGoogle Scholar
  2. 2.
    Shu HB, Hu WH, Johnson H (1999) TALL-1 is a novel member of the TNF family that is down-regulated by mitogens. J Leukoc Biol 65(5):680–683PubMedGoogle Scholar
  3. 3.
    Schneider P, MacKay F, Steiner V et al (1999) BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med 189(11):1747–1756PubMedCrossRefGoogle Scholar
  4. 4.
    Nardelli B, Belvedere O, Roschke V et al (2001) Synthesis and release of B-lymphocyte stimulator from myeloid cells. Blood 97(1):198–2045PubMedCrossRefGoogle Scholar
  5. 5.
    Huard B, Arlettaz L, Ambrose C et al (2004) BAFF production by antigen-presenting cells provides T cell co-stimulation. Int Immunol 16(3):467–475PubMedCrossRefGoogle Scholar
  6. 6.
    Schaumann DH, Tuischer J, Ebell W et al (2007) VCAM-1-positive stromal cells from human bone marrow producing cytokines for B lineage progenitors and for plasma cells: SDF-1, flt3L, and BAFF. Mol Immunol 44(7):1606–1612PubMedCrossRefGoogle Scholar
  7. 7.
    Ohata J, Zvaifler NJ, Nishio M et al (2005) Fibroblast-like synoviocytes of mesenchymal origin express functional B cell-activating factor of the TNF family in response to proinflammatory cytokines. J Immunol 174(2):864–870PubMedGoogle Scholar
  8. 8.
    Krumbholz M, Theil D, Derfuss T et al (2005) BAFF is produced by astrocytes and up-regulated in multiple sclerosis lesions and primary central nervous system lymphoma. J Exp Med 201(2):195–200PubMedCrossRefGoogle Scholar
  9. 9.
    Ittah M, Miceli-Richard C, Gottenberg JE et al (2008) Viruses induce high expression of BAFF by salivary gland epithelial cells through TLR- and type-I IFN-dependent and -independent pathways. Eur J Immunol 38(4):1058–1064PubMedCrossRefGoogle Scholar
  10. 10.
    Xu W, He B, Chiu A et al (2007) Epithelial cells trigger frontline immunoglobulin class switching through a pathway regulated by the inhibitor SLPI. Nat Immunol 8(3):294–303PubMedCrossRefGoogle Scholar
  11. 11.
    Ogden CA, Pound JD, Batth BK et al (2005) Enhanced apoptotic cell clearance capacity and B cell survival factor production by IL-10-activated macrophages: implications for Burkitt’s lymphoma. J Immunol 174(5):3015–3023PubMedGoogle Scholar
  12. 12.
    Batten M, Groom J, Cachero TG et al (2000) BAFF mediates survival of peripheral immature B lymphocytes. J Exp Med 192(10):1453–1466PubMedCrossRefGoogle Scholar
  13. 13.
    Thien M, Phan TG, Gardam S et al (2004) Excess BAFF rescues self-reactive B cells from peripheral deletion and allows them to enter forbidden follicular and marginal zone niches. Immunity 20(6):785–798PubMedCrossRefGoogle Scholar
  14. 14.
    Zhang W, Wen L, Huang X et al (2008) hsBAFF enhances activity of NK cells by regulation of CD4(+) T lymphocyte function. Immunol Lett 120(1–2):96–102PubMedCrossRefGoogle Scholar
  15. 15.
    Shu H-B, Johnson H (2000) B cell maturation protein is a receptor for the tumor necrosis factor family member TALL-1. Proc Natl Acad Sci USA 97:9156–9161PubMedCrossRefGoogle Scholar
  16. 16.
    Mackay F, Schneider P (2008) TACI, an enigmatic BAFF/APRIL receptor, with new unappreciated biochemical and biological properties. Cytokine Growth Factor Rev 19(3–4):263–276PubMedCrossRefGoogle Scholar
  17. 17.
    Thompson JS et al (2001) BAFF-R, a novel TNF receptor that specifically interacts with BAFF. Science 293:2108–2111PubMedCrossRefGoogle Scholar
  18. 18.
    Treml JF, Hao Y, Stadanlick JE, Cancro MP (2009) The BLyS family: toward a molecular understanding of B cell homeostasis. Cell Biochem Biophys 53(1):1–16PubMedCrossRefGoogle Scholar
  19. 19.
    Yu G et al (2000) APRIL and TALL-1 and receptors BCMA and TACI: system for regulating humoral immunity. Nat Immunol 1:252–256PubMedCrossRefGoogle Scholar
  20. 20.
    Mackay F, Schneider P, Rennert P, Browning J (2003) BAFF AND APRIL: a tutorial on B cell survival. Annu Rev Immunol 21:231–264PubMedCrossRefGoogle Scholar
  21. 21.
    Woodland RT, Fox CJ, Schmidt MR et al (2008) Multiple signaling pathways promote B lymphocyte stimulator dependent B-cell growth and survival. Blood 111(2):750–760PubMedCrossRefGoogle Scholar
  22. 22.
    Fu L, Lin-Lee YC, Pham LV et al (2009) BAFF-R promotes cell proliferation and survival through interaction with IKKbeta and NF-kappaB/c-Rel in the nucleus of normal and neoplastic B-lymphoid cells. Blood 113(19):4627–4636PubMedCrossRefGoogle Scholar
  23. 23.
    Gross JA et al (2001) TACI-Ig neutralizes molecules critical for B cell development and autoimmune disease: impaired B cell maturation in mice lacking BLyS. Immunity 15:289–302PubMedCrossRefGoogle Scholar
  24. 24.
    Mackay F, Woodcock SA, Lawton P et al (1999) Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J Exp Med 190(11):1697–1710PubMedCrossRefGoogle Scholar
  25. 25.
    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(2):812–822PubMedGoogle Scholar
  26. 26.
    Groom J, Kalled SL, Cutler AH et al (2002) Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjögren’s syndrome. J Clin Invest 109(1):59–68PubMedGoogle Scholar
  27. 27.
    Cheema GS, Roschke V, Hilbert DM, Stohl W (2001) Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases. Arthritis Rheum 44:1313–1319PubMedCrossRefGoogle Scholar
  28. 28.
    Mariette X, Roux S, Zhang J et al (2003) The level of BLyS (BAFF) correlates with the titre of autoantibodies in human Sjögren’s syndrome. Ann Rheum Dis 62(2):168–171PubMedCrossRefGoogle Scholar
  29. 29.
    Stohl W (2003) SLE – systemic lupus erythematosus: a BLySful, yet BAFFling, disorder. Arthritis Res Ther 5(3):136–138PubMedCrossRefGoogle Scholar
  30. 30.
    Bosello S, Youinou P, Daridon C et al (2008) Concentrations of BAFF correlate with autoantibody levels, clinical disease activity, and response to treatment in early rheumatoid arthritis. J Rheumatol 35(7):1256–1264PubMedGoogle Scholar
  31. 31.
    Matsushita T, Hasegawa M, Matsushita Y et al (2007) Elevated serum BAFF levels in patients with localized scleroderma in contrast to other organ-specific autoimmune diseases. Exp Dermatol 16(2):87–93PubMedCrossRefGoogle Scholar
  32. 32.
    Thangarajh M, Gomes A, Masterman T et al (2004) Expression of B-cell-activating factor of the TNF family (BAFF) and its receptors in multiple sclerosis. J Neuroimmunol 152(1–2):183–190PubMedCrossRefGoogle Scholar
  33. 33.
    Mackay IR, Groom J, Mackay CR (2003) Levels of BAFF in serum in primary biliary cirrhosis and autoimmune diabetes. Autoimmunity 35(8):551–553CrossRefGoogle Scholar
  34. 34.
    Fabris M, Visentini D, De Re V et al (2010) Elevated B cell-activating factor of the tumour necrosis factor family in coeliac disease. Scand J Gastroenterol 42(12):1434–1439CrossRefGoogle Scholar
  35. 35.
    Fabris M, Grimaldi F, Villalta D et al (2010) BLyS and April serum levels in patients with autoimmune thyroid diseases. Autoimmun Rev 9(3):165–169PubMedCrossRefGoogle Scholar
  36. 36.
    Becker-Merok A, Nikolaisen C, Nossent HC (2006) B-lymphocyte activating factor in systemic lupus erythematosus and rheumatoid arthritis in relation to autoantibody levels, disease measures and time. Lupus 15(9):570–576PubMedCrossRefGoogle Scholar
  37. 37.
    Pers JO, Daridon C, Devauchelle V et al (2005) BAFF overexpression is associated with autoantibody production in autoimmune diseases. Ann N Y Acad Sci 1050:34–39PubMedCrossRefGoogle Scholar
  38. 38.
    Szodoray P, Alex P, Jonsson MV et al (2005) Distinct profiles of Sjögren’s syndrome patients with ectopic salivary gland germinal centers revealed by serum cytokines and BAFF. Clin Immunol 117(2):168–176PubMedCrossRefGoogle Scholar
  39. 39.
    Jonsson MV, Szodoray P, Jellestad S et al (2005) 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(3):189–201PubMedCrossRefGoogle Scholar
  40. 40.
    Neusser MA, Lindenmeyer MT, Edenhofer I et al (2011) Intrarenal production of B-cell survival factors in human lupus nephritis. Mod Pathol 24(1):98–107PubMedCrossRefGoogle Scholar
  41. 41.
    Cancro MP (2006) The BLyS/BAFF family of ligands and receptors: key targets in the therapy and understanding of autoimmunity. Ann Rheum Dis 65(Suppl 3):iii34–iii36PubMedCrossRefGoogle Scholar
  42. 42.
    Ota M, Duong BH, Torkamani A et al (2010) Regulation of the B cell receptor repertoire and self-reactivity by BAFF. J Immunol 185(7):4128–4136PubMedCrossRefGoogle Scholar
  43. 43.
    Toubi E, Gordon S, Kessel A et al (2006) Elevated serum B-Lymphocyte activating factor (BAFF) in chronic hepatitis C virus infection: association with autoimmunity. J Autoimmun 27(2):134–139PubMedCrossRefGoogle Scholar
  44. 44.
    Fabris M, Quartuccio L, Sacco S et al (2007) B-Lymphocyte stimulator (BLyS) up-regulation in mixed cryoglobulinaemia syndrome and hepatitis-C virus infection. Rheumatology (Oxford) 46(1):37–43CrossRefGoogle Scholar
  45. 45.
    Sène D, Limal N, Ghillani-Dalbin P et al (2007) Hepatitis C virus-associated B-cell proliferation–the role of serum B lymphocyte stimulator (BLyS/BAFF). Rheumatology (Oxford) 46(1):65–69CrossRefGoogle Scholar
  46. 46.
    Tarantino G, Marco VD, Petta S et al (2009) Serum BLyS/BAFF predicts the outcome of acute hepatitis C virus infection. J Viral Hepat 16(6):397–405PubMedCrossRefGoogle Scholar
  47. 47.
    Giannini C, Gragnani L, Piluso A et al (2008) Can BAFF promoter polymorphism be a predisposing condition for HCV-related mixed cryoglobulinemia? Blood 112(10):4353–4354PubMedCrossRefGoogle Scholar
  48. 48.
    Novak AJ, Slager SL, Fredericksen ZS et al (2009) Genetic variation in B-cell-activating factor is associated with an increased risk of developing B-cell non-Hodgkin lymphoma. Cancer Res 69(10):4217–4224PubMedCrossRefGoogle Scholar
  49. 49.
    Nossent JC, Lester S, Zahra D et al (2008) 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) 47(9):1311–1316CrossRefGoogle Scholar
  50. 50.
    De Vita S, Quartuccio L, Fabris M (2008) Hepatitis C virus infection, mixed cryoglobulinemia and BLyS upregulation: targeting the infectious trigger, the autoimmune response, or both? Autoimmun Rev 8(2):95–99PubMedCrossRefGoogle Scholar
  51. 51.
    De Re V, De Vita S, Gasparotto D et al (2002) Salivary gland B cell lymphoproliferative disorders in Sjögren’s syndrome present a restricted use of antigen receptor gene segments similar to those used by hepatitis C virus-associated non-Hodgkins’s lymphomas. Eur J Immunol 32(3):903–910PubMedCrossRefGoogle Scholar
  52. 52.
    Lavie F, Miceli-Richard C, Quillard J et al (2004) Expression of BAFF (BLyS) in T cells infiltrating labial salivary glands from patients with Sjögren’s syndrome. J Pathol 202(4):496–502PubMedCrossRefGoogle Scholar
  53. 53.
    Varin MM, Le Pottier L, Youinou P et al (2010) B-cell tolerance breakdown in Sjögren’s syndrome: focus on BAFF. Autoimmun Rev 9(9):604–608PubMedCrossRefGoogle Scholar
  54. 54.
    Quartuccio L, Fabris M, Moretti M et al (2008) Resistance to Rituximab therapy and local BAFF overexpression in Sjögren’s syndrome-related myoepithelial sialadenitis and low-grade parotid B-cell lymphoma. Open Rheumatol J 2:38–43PubMedCrossRefGoogle Scholar
  55. 55.
    Novak AJ, Grote DM, Stenson M et al (2004) Expression of BLyS and its receptors in B-cell non-Hodgkin lymphoma: correlation with disease activity and patient outcome. Blood 104(8):2247–2253PubMedCrossRefGoogle Scholar
  56. 56.
    Ju S, Wang Y, Ni H et al (2009) Correlation of expression levels of BLyS and its receptors with multiple myeloma. Clin Biochem 42(4–5):387–399PubMedCrossRefGoogle Scholar
  57. 57.
    Tecchio C, Nadali G, Scapini P et al (2007) High serum levels of B-lymphocyte stimulator are associated with clinical-pathological features and outcome in classical Hodgkin lymphoma. Br J Haematol 137(6):553–559PubMedCrossRefGoogle Scholar
  58. 58.
    Mackay F, Tangye SG (2004) The role of the BAFF/APRIL system in B cell homeostasis and lymphoid cancers. Curr Opin Pharmacol 4(4):347–354PubMedCrossRefGoogle Scholar
  59. 59.
    Landau DA, Rosenzwajg M, Saadoun D et al (2009) The B lymphocyte stimulator receptor-ligand system in hepatitis C virus-induced B cell clonal disorders. Ann Rheum Dis 68(3):337–344PubMedCrossRefGoogle Scholar
  60. 60.
    Sansonno D, Carbone A, De Re V, Dammacco F (2007) Hepatitis C virus infection, cryoglobulinaemia, and beyond. Rheumatology (Oxford) 46(4):572–578CrossRefGoogle Scholar
  61. 61.
    De Re V, De Vita S, Sansonno D et al (2006) Type II mixed cryoglobulinaemia as an oligo rather than a mono B-cell disorder: evidence from GeneScan and MALDI-TOF analyses. Rheumatology (Oxford) 45(6):685–693, 58CrossRefGoogle Scholar
  62. 62.
    De Re V, De Vita S, Marzotto A et al (2000) Pre-malignant and malignant lymphoproliferations in an HCV-infected type II mixed cryoglobulinemic patient are sequential phases of an antigen-driven pathological process. Int J Cancer 87:211–216PubMedCrossRefGoogle Scholar
  63. 63.
    Fu L, Lin-Lee YC, Pham LV et al (2006) Constitutive NF-kappaB and NFAT activation leads to stimulation of the BLyS survival pathway in aggressive B-cell lymphomas. Blood 107(11):4540–4548PubMedCrossRefGoogle Scholar
  64. 64.
    Pham LV, Fu L, Tamayo AT et al (2011) Constitutive BR3 receptor signaling in diffuse large B-cell lymphomas stabilizes NF-{kappa}B-inducing kinase, while activating both canonical and alternative NF-{kappa}B pathways. Blood 117(1):200–210PubMedCrossRefGoogle Scholar
  65. 65.
    De Re V, De Vita S, Sansonno D, Toffoli G (2008) Mixed cryoglobulinemia syndrome as an additional autoimmune disorder associated with risk for lymphoma development. Blood 111(12):5760PubMedCrossRefGoogle Scholar
  66. 66.
    Libra M, De Re V, Gloghini A et al (2004) Detection of bcl-2 rearrangement in mucosa-associated lymphoid tissue lymphomas from patients with hepatitis C virus infection. Haematologica 89(7):873–874PubMedGoogle Scholar
  67. 67.
    Saadoun D, Suarez F, Lefrere F et al (2005) Splenic lymphoma with villous lymphocytes, associated with type II cryoglobulinemia and HCV infection: a new entity? Blood 105:74–76PubMedCrossRefGoogle Scholar
  68. 68.
    Ramos-Casals M, De Vita S, Tzioufas AG (2005) Hepatitis C virus, Sjögren’s syndrome and B-cell lymphoma: linking infection, autoimmunity and cancer. Autoimmun Rev 4:8–15PubMedCrossRefGoogle Scholar
  69. 69.
    Landau DA, Saadoun D, Calabrese LH, Cacoub P (2007) The pathophysiology of HCV induced B-cell clonal disorders. Autoimmun Rev 6(8):581–587PubMedCrossRefGoogle Scholar
  70. 70.
    Dispenzieri A, Gorevic PD (1999) Cryoglobulinemia. Hematol Oncol Clin North Am 13(6):1315–1349PubMedCrossRefGoogle Scholar
  71. 71.
    Levine W, Gota C, Fessler B et al (2005) Persistent cryoglobulinemic vasculitis following successful treatment of Hepatitis C Virus. J Rheumatol 32:1164–1167PubMedGoogle Scholar
  72. 72.
    La Civita L, Zignego AL, Lombardini F et al (1996) Exacerbation of peripheral neuropathy during alpha- interferon therapy in a patient with mixed cryoglobulinemia and hepatitis B virus infection. J Rheumatol 23(9):1641–1643PubMedGoogle Scholar
  73. 73.
    Beuthien W, Mellinghoff HU, Kempis J (2005) Vasculitic complications of interferon-alpha treatment for chronic hepatitis C virus infection: case report and review of the literature. Clin Rheumatol 24(5):507–515PubMedCrossRefGoogle Scholar
  74. 74.
    Quartuccio L, De Marchi G, Fabris M, De Vita S (2007) Development of type II mixed cryoglobulinaemic syndrome after effective and persistent hepatitis C virus eradication. Rheumatology (Oxford) 46(2):367–368CrossRefGoogle Scholar
  75. 75.
    Carson DA, Chen PP, Fox RI et al (1987) Rheumatoid factor and immune networks. Annu Rev Immunol 5:109–126PubMedCrossRefGoogle Scholar
  76. 76.
    Cambridge G, Isenberg DA, Edwards J et al (2008) B cell depletion therapy in systemic lupus erythematosus: relationships among serum B lymphocyte stimulator levels, autoantibody profile and clinical response. Ann Rheum Dis 67(7):1011–1016PubMedCrossRefGoogle Scholar
  77. 77.
    Cambridge G, Stohl W, Leandro MJ et al (2006) Circulating levels of B lymphocyte stimulator in patients with rheumatoid arthritis following rituximab treatment: relationships with B cell depletion, circulating antibodies, and clinical relapse. Arthritis Rheum 54(3):723–732PubMedCrossRefGoogle Scholar
  78. 78.
    Navarra S, Ilianova E, Bae SC, BLISS-52 Study Group, et al (2010) Belimumab, a BlyS-specific inhibitor reduced disease activity, flares and steroid use in patients with seropositive systemic lupus erythematosus (SLE): BLISS-52 study. Ann Rheum Dis 69(S1)Google Scholar
  79. 79.
    Furie RA, Gladman D, d’Cruz D et al (2010) Belimumab: a BLyS specific inhibitor, reduced disease activity and severe flares with seropositive SLE: BLISS-76 study. Lupus 19S:13Google Scholar
  80. 80.
    De Vita S, Quartuccio L (2010) Rituximab monotherapy, rather than rituximab plus antiviral drugs, for initial treatment of severe hepatitis C virus-associated mixed cryoglobulinemia syndrome: comment on the article by Terrier et al. Arthritis Rheum 62(3):908–909PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2012

Authors and Affiliations

  1. 1.Clinical Pathology and Clinic of RheumatologyAzienda Ospedaliero – Universitaria of UdineUdineItaly
  2. 2.Clinic of Rheumatology, Deparment of Medical and Biological SciencesAzienda Ospedaliero – Universitaria of UdineUdineItaly

Personalised recommendations