Skip to main content
SpringerLink
Log in

Molecular Insights into the Disease Mechanisms of Type II Mixed Cryoglobulinemia

  • Chapter
  • First Online:
HCV Infection and Cryoglobulinemia

  • 695 Accesses

Abstract

Several epidemiological and clinico-pathological observations suggest that the pathogenesis of type II MC (MC-II) is multifactorial and multistep. Strongly associated with MC-II is the presence of cryoprecipitates, thought to be involved in the maintenance and perpetuation of the disease. The biological characteristics of MC-II cryoglobulins are extremely relevant to the etiopathogenetic mechanisms linking hepatitis C virus antigen stimulation to autoimmunity and to lymphoproliferation. Currently, there are no data clearly demonstrating the component responsible for cryoprecipitation. However, several findings from studies of cryoimmunoglobulin glycosylation together with the characterization of monoclonal IgM rheumatoid factor activity/recognition may provide a better understanding of the pathologic process linking cryoprecipitation with hepatitis C virus infection.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
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. Di Stasio E, Bizzarri P, Bove M et al (2003) Analysis of the dynamics of cryoaggregation by light-scattering spectrometry. Clin Chem Lab Med 41:152–158

    Article  PubMed  Google Scholar 

  2. Di Stasio E, Bizzarri P, Casato M et al (2004) Cl- regulates cryoglobulin structure: a new hypothesis for the physiopathological mechanism of temperature non-dependent cryoprecipitation. Clin Chem Lab Med 42:614–620

    Article  PubMed  Google Scholar 

  3. Vallas V, Farrugia W, Raison RL et al (2007) Dissimilar aggregation processes govern precipitation and gelation of human IgM cryoglobulins. J Mol Recognit 20:90–96

    Article  PubMed  CAS  Google Scholar 

  4. Fabris M, Quartuccio L, Salvin S et al (2008) Fibronectin gene polymorphisms are associated with the development of B-cell lymphoma in type II mixed cryoglobulinemia. Ann Rheum Dis 67:80–83

    Article  PubMed  CAS  Google Scholar 

  5. Banda NK, Wood AK, Takahashi K et al (2008) Initiation of the alternative pathway of murine complement by immune complexes is dependent on N-glycans in IgG antibodies. Arthritis Rheum 58:3081–3089

    Article  PubMed  Google Scholar 

  6. Kuroda Y, Kuroki A, Kikuchi S et al (2005) A critical role for sialylation in cryoglobulin activity of murine IgG3 monoclonal antibodies. J Immunol 175:1056–1061

    PubMed  CAS  Google Scholar 

  7. Yagi H, Takahashi N, Yamaguchi Y, Kato K (2004) Temperature-dependent isologous Fab-Fab interaction that mediates ­cryocrystallization of a monoclonal immunoglobulin G. Mol Immunol 41:1211–1215

    Article  PubMed  CAS  Google Scholar 

  8. 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) 45:685–693

    Article  Google Scholar 

  9. 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 96:3578–3584

    PubMed  Google Scholar 

  10. De Re V, De Vita S, Gasparotto D et al (2002) Salivary gland B cell lymphoproliferative disorders in Sjogren’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 32:903–910

    Article  PubMed  Google Scholar 

  11. Ramsland PA, Shan L, Moomaw CR et al (2000) An unusual human IgM antibody with a protruding HCDR3 and high avidity for its peptide ligands. Mol Immunol 37:295–310

    Article  PubMed  CAS  Google Scholar 

  12. Ramsland PA, Terzyan SS, Cloud G et al (2006) Crystal structure of a glycosylated Fab from an IgM cryoglobulin with properties of a natural proteolytic antibody. Biochem J 395:473–481

    Article  PubMed  CAS  Google Scholar 

  13. Kuroki A, Kuroda Y, Kikuchi S et al (2002) Level of galactosylation determines cryoglobulin activity of murine IgG3 monoclonal rheumatoid factor. Blood 99:2922–2928

    Article  PubMed  CAS  Google Scholar 

  14. 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 42:1019–1027

    Article  PubMed  CAS  Google Scholar 

  15. Mazzaro C, De Re V, Spina M et al (2009) Pegylated-interferon plus ribavirin for HCV-positive indolent non-Hodgkin lymphomas. Br J Haematol 145:255–257

    Article  PubMed  CAS  Google Scholar 

  16. 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 23:468–473

    Article  PubMed  CAS  Google Scholar 

  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 347:89–94

    Article  PubMed  CAS  Google Scholar 

  18. Sansonno D, De Re V, Lauletta G et al (2003) Monoclonal antibody treatment of mixed cryoglobulinemia resistant to interferon alpha with an anti-CD20. Blood 101:3818–3826

    Article  PubMed  CAS  Google Scholar 

  19. Zaja F, De Vita S, Mazzaro C et al (2003) Efficacy and safety of rituximab in type II mixed cryoglobulinemia. Blood 101:3827–3834

    Article  PubMed  CAS  Google Scholar 

  20. 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 80:3923–3934

    Article  PubMed  CAS  Google Scholar 

  21. Charles ED, Green RM, Marukian S et al (2008) Clonal expansion of immunoglobulin M+CD27+ B cells in HCV-associated mixed cryoglobulinemia. Blood 111:1344–1356

    Article  PubMed  CAS  Google Scholar 

  22. Sansonno D, Carbone A, De Re V, Dammacco F (2007) Hepatitis C virus infection, cryoglobulinaemia, and beyond. Rheumatology (Oxford) 46:572–578

    Article  CAS  Google Scholar 

  23. 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 20:1145–1154

    Article  PubMed  Google Scholar 

  24. Carayannopoulos MO, Potter KN, Li Y et al (2000) Evidence that human immunoglobulin M rheumatoid factors can be derived from the natural autoantibody pool and undergo an antigen driven immune response in which somatically mutated rheumatoid factors have lower affinities for immunoglobulin G Fc than their germline counterparts. Scand J Immunol 51:327–336

    Article  PubMed  CAS  Google Scholar 

  25. Yang L, Hakoda M, Iwabuchi K et al (2004) Rheumatoid factors induce signaling from B cells, leading to Epstein-Barr virus and B-cell activation. J Virol 78(18):9918–9923

    Article  PubMed  CAS  Google Scholar 

  26. Duquerroy S, Stura EA, Bressanelli S et al (2007) Crystal structure of a human autoimmune complex between IgM rheumatoid factor RF61 and IgG1 Fc reveals a novel epitope and evidence for affinity maturation. J Mol Biol 368:1321–1331

    Article  PubMed  CAS  Google Scholar 

  27. Corper AL, Sohi MK, Bonagura VR et al (1997) Structure of human IgM rheumatoid factor Fab bound to its autoantigen IgG Fc reveals a novel topology of antibody-antigen interaction. Nat Struct Biol 4:374–381

    Article  PubMed  CAS  Google Scholar 

  28. 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 1173:326–333

    Article  PubMed  Google Scholar 

  29. Tamir I, Stolpa JC, Helgason CD et al (2000) The RasGAP-binding protein p62dok is a mediator of inhibitory FcgammaRIIB signals in B cells. Immunity 12:347–358

    Article  PubMed  CAS  Google Scholar 

  30. Prikhod’ko EA, Prikhod’ko GG, Siegel RM et al (2004) The NS3 protein of hepatitis C virus induces caspase-8-mediated apoptosis independent of its protease or helicase activities. Virology 329:53–67

    Article  PubMed  Google Scholar 

  31. Foy E, Li K, Wang C et al (2003) Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science 300:1145–1148

    Article  PubMed  CAS  Google Scholar 

  32. Ferri S, Dal Pero F, Bortoletto G et al (2006) Detailed analysis of the E2-IgM complex in hepatitis C-related type II mixed cryoglobulinaemia. J Viral Hepat 13:166–176

    Article  PubMed  CAS  Google Scholar 

  33. Landau DA, Saadoun D, Calabrese LH, Cacoub P (2007) The pathophysiology of HCV induced B-cell clonal disorders. Autoimmun Rev 6:581–587

    Article  PubMed  CAS  Google Scholar 

  34. Rosa D, Saletti G, De Gregorio E et al (2005) Activation of naive B lymphocytes via CD81, a pathogenetic mechanism for hepatitis C virus-associated B lymphocyte disorders. Proc Natl Acad Sci USA 102:18544–18549

    Article  PubMed  CAS  Google Scholar 

  35. Perotti M, Ghidoli N, Altara R et al (2008) Hepatitis C virus (HCV)-driven stimulation of subfamily-restricted natural IgM antibodies in mixed cryoglobulinemia. Autoimmun Rev 7:468–472

    Article  PubMed  CAS  Google Scholar 

  36. Charles ED, Dustin LB (2009) Hepatitis C virus-induced cryoglobulinemia. Kidney Int 76:818–824

    Article  PubMed  Google Scholar 

  37. Cacoub P, Renou C, Kerr G et al (2001) Influence of HLA-DR phenotype on the risk of hepatitis C virus-­associated mixed cryoglobulinemia. Arthritis Rheum 44:2118–2124

    Article  PubMed  CAS  Google Scholar 

  38. De Re V, Caggiari L, De Vita S et al (2007) Genetic insights into the disease mechanisms of type II mixed cryoglobulinemia induced by hepatitis C virus. Dig Liver Dis 39:S65–S71

    Article  PubMed  Google Scholar 

  39. De Re V, Caggiari L, Simula MP et al (2007) Role of the HLA class II: HCV-related disorders. Ann N Y Acad Sci 1107:308–318

    Article  PubMed  Google Scholar 

  40. Abbas OM, Omar NA, Zaghla HE, Faramawi MF (2009) Schistosoma mansoni coinfection could have a protective effect against mixed cryoglobulinaemia in hepatitis C patients. Liver Int 29:1065–1070

    Article  PubMed  CAS  Google Scholar 

  41. Artandi SE, Canfield SM, Tao MH et al (1991) Molecular analysis of IgM rheumatoid factor binding to chimeric IgG. J Immunol 146:603–610

    PubMed  CAS  Google Scholar 

  42. Bonagura VR, Artandi SE, Davidson A et al (1993) Mapping studies reveal unique epitopes on IgG recognized by rheumatoid arthritis-derived monoclonal rheumatoid factors. J Immunol 151:3840–3852

    PubMed  CAS  Google Scholar 

  43. Sene D, Ghillani-Dalbin P, Amoura Z et al (2009) Rituximab may form a complex with IGmkappa mixed cryoglobulin and induce severe systemic reactions in patients with hepatitis C virus-induced vasculitis. Arthritis Rheum 60:3848–3855

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Clinical and Experimental Pharmacology, Department of Molecular Oncology and Translational Medicine, (DOMERT), Centro di Riferimento Oncologico, IRCCS, National Cancer Institute, Aviano, Italy

    Valli De Re

  2. Clinical and Experimental Pharmacology, Department of Molecular Oncology and Translational Medicine, DOMERT, Centro di Riferimento Oncologico, IRCCS, National Cancer Institute, Aviano, Italy

    Marica Garziera

Authors
  1. Valli De Re
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marica Garziera
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Valli De Re .

Editor information

Editors and Affiliations

  1. , Department of Internal Medicine and Clin, University of Bari, Piazza Giulio Cesare 11, Bari, 70124, Italy

    Franco Dammacco

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer-Verlag Italia

About this chapter

Cite this chapter

De Re, V., Garziera, M. (2012). Molecular Insights into the Disease Mechanisms of Type II Mixed Cryoglobulinemia. In: Dammacco, F. (eds) HCV Infection and Cryoglobulinemia. Springer, Milano. https://doi.org/10.1007/978-88-470-1705-4_13

Download citation

  • DOI: https://doi.org/10.1007/978-88-470-1705-4_13

  • Published:

  • Publisher Name: Springer, Milano

  • Print ISBN: 978-88-470-1704-7

  • Online ISBN: 978-88-470-1705-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation