Molecular Features of Lymphoproliferation in Mixed Cryoglobulinemia

  • Valli De Re
  • Maria Paola Simula


The identification and characterization of the B-cell population responsible for the production of IgM with rheumatoid factor activity are important in order to understand the pathogenetic mechanism leading to type II cryoglobulinemia and overt B-cell lymphoma development. Based on recent progress in the molecular and cell biology of self-reactive B cells in HCV-associated mixed cryoglobulinemia, it has become clear that a substantial proportion of clonal B cells consist of unswitched CD27+ memory B cells with the inherent property of IgM receptor expression. In this chapter, we report the latest information on the molecular implication of IgM receptors in the context of HCV infection, transinfection, and autoimmune B-cell survival. A relationship between the Blys receptor, BR3, and IgM+VH1-69+ B cells, including the regulation of B-cell receptor signaling and cell homeostasis, has been suggested; however, many questions remain to be answered.


Mixed Cryoglobulinemia Splenic Marginal Zone Lymphoma Lymphoma Development BLys Receptor Overt Lymphoma 
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.
    De Re V, De Vita S, Marzotto A et al (2000) Sequence analysis of the immunoglobulin antigen receptor of hepatitis C virus-associated non-Hodgkin lymphomas suggests that the malignant cells are derived from the rheumatoid factor-producing cells that occur mainly in type II cryoglobulinemia. Blood 96:3578–3584PubMedGoogle Scholar
  2. 2.
    Sansonno D, Carbone A, De Re V, Dammacco F (2007) Hepatitis C virus infection, cryoglobulinaemia, and beyond. Rheumatology (Oxford) 46:572–578CrossRefGoogle Scholar
  3. 3.
    Sansonno D, Lauletta G, De Re V et al (2004) Intrahepatic B-cell clonal expansions and extrahepatic manifestations of chronic HCV infection. Eur J Immunol 34:126–136PubMedCrossRefGoogle Scholar
  4. 4.
    Sansonno D, Tucci FA, De Re V et al (2005) HCV-associated B-cell clonalities in the liver do not carry the t(14;18) chromosomal translocation. Hepatology 42:1019–1027PubMedCrossRefGoogle Scholar
  5. 5.
    De Vita S, De Re V, Gasparotto D et al (2000) Oligoclonal non-neoplastic B-cell expansion is the key feature of type II mixed cryoglobulinemia: clinical and molecular findings do not support a bone marrow pathologic diagnosis of indolent B-cell lymphoma. Arthritis Rheum 43:94–102PubMedCrossRefGoogle Scholar
  6. 6.
    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
  7. 7.
    Ohtsubo K, Sata M, Kawaguchi T et al (2009) Charac­terization of the light chain-restricted clonal B-cells in peripheral blood of HCV-positive patients. Int J Hematol 89:452–459PubMedCrossRefGoogle Scholar
  8. 8.
    Roulland S, Suarez F, Hermine O, Nadel B (2008) Patho­physiological aspects of memory B-cell development. Trends Immunol 29:25–33PubMedCrossRefGoogle Scholar
  9. 9.
    De Vita S, De Re V, Sansonno D et al (2002) Lack of HCV infection in malignant cells refutes the hypothesis of a direct transforming action of the virus in the pathogenesis of HCV-associated B-cell NHLs. Tumori 88:400–406PubMedGoogle Scholar
  10. 10.
    Sansonno D, Tucci FA, Lauletta G et al (2007) Hepatitis C virus productive infection in mononuclear cells from patients with cryoglobulinaemia. Clin Exp Immunol 147:241–248PubMedCrossRefGoogle Scholar
  11. 11.
    Inokuchi M, Ito T, Uchikoshi M et al (2009) Infection of B-cells with hepatitis C virus for the development of lymphoproliferative disorders in patients with chronic hepatitis C. J Med Virol 81:619–627PubMedCrossRefGoogle Scholar
  12. 12.
    Stamataki Z, Shannon-Lowe C, Shaw J et al (2009) Hepatitis C virus association with peripheral blood B lymphocytes potentiates viral infection of liver-derived hepatoma cells. Blood 113:585–593PubMedCrossRefGoogle Scholar
  13. 13.
    Charles ED, Green RM, Marukian S et al (2008) Clonal expansion of immunoglobulin M+CD27+ B-cells in HCV-associated mixed cryoglobulinemia. Blood 111:1344–1356PubMedCrossRefGoogle Scholar
  14. 14.
    Duty JA, Szodoray P, Zheng NY et al (2009) Functional anergy in a subpopulation of naive B-cells from healthy humans that express autoreactive immunoglobulin receptors. J Exp Med 206:139–151PubMedCrossRefGoogle Scholar
  15. 15.
    De Re V, Caggiari L, Simula MP et al (2007) B-cell lymphomas associated with HCV infection. Gastroenterology 132:1205–1207PubMedCrossRefGoogle Scholar
  16. 16.
    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 111:5760PubMedCrossRefGoogle Scholar
  17. 17.
    Hermine O, Lefrere F, Bronowicki JP et al (2002) Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med 347:89–94PubMedCrossRefGoogle Scholar
  18. 18.
    Mazzaro C, De Re V, Spina M et al (2009) Pegylated-interferon plus ribavirin for HCV-positive indolent non-Hodgkin lymphomas. Br J Haematol 145:255–257PubMedCrossRefGoogle Scholar
  19. 19.
    De Vita S, De Re V, Sansonno D et al (2000) Gastric mucosa as an additional extrahepatic localization of hepatitis C virus: viral detection in gastric low-grade lymphoma associated with autoimmune disease and in chronic gastritis. Hepatology 31:182–189PubMedCrossRefGoogle Scholar
  20. 20.
    Sorrentino D, Ferraccioli GF, De Vita S et al (1997) Hepatitis C virus infection and gastric lymphoproliferation in patients with Sjogren’s syndrome. Blood 90:2116–2117PubMedGoogle Scholar
  21. 21.
    Cammarota G, Cianci R, Grillo RL et al (2002) Relationship between gastric localization of hepatitis C virus and mucosa-associated lymphoid tissue in Helicobacter pylori infection. Scand J Gastroenterol 37:1126–1132PubMedCrossRefGoogle Scholar
  22. 22.
    Takeshita M, Sakai H, Okamura S et al (2006) Prevalence of hepatitis C virus infection in cases of B-cell lymphoma in Japan. Histopathology 48:189–198PubMedCrossRefGoogle Scholar
  23. 23.
    Visco C, Arcaini L, Brusamolino E et al (2006) Distinctive natural history in hepatitis C virus positive diffuse large B-cell lymphoma: analysis of 156 patients from northern Italy. Ann Oncol 17:1434–1440PubMedCrossRefGoogle Scholar
  24. 24.
    De Vita S, Sacco C, Sansonno D et al (1997) Characterization of overt B-cell lymphomas in patients with hepatitis C virus infection. Blood 90:776–782PubMedGoogle Scholar
  25. 25.
    Tursi A, Brandimarte G, Torello M (2004) Disappearance of gastric mucosa-associated lymphoid tissue in hepatitis C virus-positive patients after anti-hepatitis C virus therapy. J Clin Gastroenterol 38:360–363PubMedCrossRefGoogle Scholar
  26. 26.
    De Re V, Simula MP, Cannizzaro R et al (2008) HCV ­inhibits antigen processing and presentation and induces ­oxidative stress response in gastric mucosa. Proteom Clin Appl 2:1290–1299CrossRefGoogle Scholar
  27. 27.
    Nanji AA (2004) Animal models of nonalcoholic fatty liver disease and steatohepatitis. Clin Liver Dis 8:559–574PubMedCrossRefGoogle Scholar
  28. 28.
    Albano E, Mottaran E, Vidali M et al (2005) Immune response towards lipid peroxidation products as a predictor of progression of non-alcoholic fatty liver disease to advanced fibrosis. Gut 54:987–993PubMedCrossRefGoogle Scholar
  29. 29.
    Tsutsumi T, Matsuda M, Aizaki H et al (2009) Proteomics analysis of mitochondrial proteins reveals overexpression of a mitochondrial protein chaperon, prohibitin, in cells expressing hepatitis C virus core protein. Hepatology 50:378–386PubMedCrossRefGoogle Scholar
  30. 30.
    Joyce MA, Walters KA, Lamb SE et al (2009) HCV induces oxidative and ER stress, and sensitizes infected cells to apoptosis in SCID/Alb-uPA mice. PLoS Pathog 5:e1000291PubMedCrossRefGoogle Scholar
  31. 31.
    Piccoli C, Quarato G, Ripoli M et al (2009) HCV infection induces mitochondrial bioenergetic unbalance: causes and effects. Biochim Biophys Acta 1787:539–546PubMedCrossRefGoogle Scholar
  32. 32.
    Monteverde A, Sabattini E, Poggi S et al (1995) Bone marrow findings further support the hypothesis that essential mixed cryoglobulinemia type II is characterized by a monoclonal B-cell proliferation. Leuk Lymphoma 20:119–124PubMedCrossRefGoogle Scholar
  33. 33.
    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) 45:685–693CrossRefGoogle Scholar
  34. 34.
    Kubo T, Uchida Y, Watanabe Y et al (2009) Augmented TLR9-induced Btk activation in PIR-B-deficient B-1 cells provokes excessive autoantibody production and autoimmunity. J Exp Med 206:1971–1982PubMedCrossRefGoogle Scholar
  35. 35.
    Davtyan TK, Hovsepyan MP, Mkhitaryan LM et al (2009) The 1F7 idiotype is selectively expressed on CD5(+) B-cells and elevated in chronic hepatitis C virus infection. Immunol Cell Biol 87:457–463PubMedCrossRefGoogle Scholar
  36. 36.
    Kipps TJ, Robbins BA, Tefferi A et al (1990) CD5-positive B-cell malignancies frequently express cross-reactive idiotypes associated with IgM autoantibodies. Am J Pathol 136:809–816PubMedGoogle Scholar
  37. 37.
    Zuckerman E (2003) Expansion of CD5+ B-cell overexpressing CD81 in HCV infection: towards better understanding the link between HCV infection, B-cell activation and lymphoproliferation. J Hepatol 38:674–676PubMedCrossRefGoogle Scholar
  38. 38.
    Krishnan C, Cupp JS, Arber DA, Faix JD (2007) Lymphoplasmacytic lymphoma arising in the setting of hepatitis C and mixed cryoglobulinemia. J Clin Oncol 25:4312–4314PubMedCrossRefGoogle Scholar
  39. 39.
    Racanelli V, Frassanito MA, Leone P et al (2006) Antibody production and in vitro behavior of CD27-defined B-cell subsets: persistent hepatitis C virus infection changes the rules. J Virol 80:3923–3934PubMedCrossRefGoogle Scholar
  40. 40.
    Rosa D, Saletti G, De Gregorio E (2005) Activation of naive B lymphocytes via CD81, a pathogenetic mechanism for hepatitis C virus-associated B lymphocyte disorders. Proc Natl Acad Sci USA 102:18544–18549PubMedCrossRefGoogle Scholar
  41. 41.
    Jakubik JJ, Saifuddin M, Takefman DM, Spear GT (1999) B lymphocytes in lymph nodes and peripheral blood are important for binding immune complexes containing HIV-1. Immunology 96:612–619PubMedCrossRefGoogle Scholar
  42. 42.
    Halstead SB (2003) Neutralization and antibody-dependent enhancement of dengue viruses. Adv Virus Res 60:421–467PubMedCrossRefGoogle Scholar
  43. 43.
    De Re V, Sansonno D, Simula MP et al (2006) HCV-NS3 and IgG-Fc crossreactive IgM in patients with type II mixed cryoglobulinemia and B-cell clonal proliferations. Leukemia 20:1145–1154PubMedCrossRefGoogle Scholar
  44. 44.
    De Re V, Pavan A, Sansonno S et al (2009) Clonal CD27+ CD19+ B-cell expansion through inhibition of FC gammaIIR in HCV(+) cryoglobulinemic patients. Ann N Y Acad Sci 1173:326–333PubMedCrossRefGoogle Scholar
  45. 45.
    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) 46:37–43CrossRefGoogle Scholar
  46. 46.
    Landau DA, Saadoun D, Calabrese LH, Cacoub P (2007) The pathophysiology of HCV induced B-cell clonal disorders. Autoimmun Rev 6:581–587PubMedCrossRefGoogle Scholar
  47. 47.
    Briones J, Timmerman JM, Hilbert DM, Levy R (2002) BLyS and BLyS receptor expression in non-Hodgkin’s lymphoma. Exp Hematol 30:135–141PubMedCrossRefGoogle Scholar
  48. 48.
    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 104:2247–2253PubMedCrossRefGoogle Scholar
  49. 49.
    Matteucci C, Bracci M, Barba G et al (2008) Different genomic imbalances in low- and high-grade HCV-related lymphomas. Leukemia 22:219–222PubMedCrossRefGoogle Scholar
  50. 50.
    Machida K, Liu JC, McNamara G et al (2009) Hepatitis C virus causes uncoupling of mitotic checkpoint and chromosomal polyploidy through the Rb pathway. J Virol 83:12590–12600PubMedCrossRefGoogle Scholar
  51. 51.
    De Re V, Caggiari L, Simula MP et al (2007) Role of the HLA class II: HCV-related disorders. Ann N Y Acad Sci 1107:308–318PubMedCrossRefGoogle Scholar
  52. 52.
    De Re V, Caggiari L, Monti G et al (2010) HLA DR-DQ combination associated with the increased risk of developing HCV+ non-Hodgkin’s lymphoma is related to the type-II mixed ­cryoglobulinema syndrome. Tissue Antigens 75:127–135PubMedCrossRefGoogle Scholar
  53. 53.
    Vallisa D, Bernuzzi P, Arcaini L et al (2005) Role of anti-hepatitis C virus (HCV) treatment in HCV-related, low-grade, B-cell, non-Hodgkin’s lymphoma: a multicenter Italian experience. J Clin Oncol 23:468–473PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2012

Authors and Affiliations

  1. 1.Clinical and Experimental Pharmacology, Department of Molecular Oncology and Translational Medicine (DOMERT), Centro di Riferimento Oncologico, IRCCSNational Cancer InstituteAvianoItaly

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