Journal of Clinical Immunology

, Volume 32, Issue 4, pp 729–735 | Cite as

Persistence of a Large Population of Exhausted Monoclonal B cells in Mixed Cryoglobuliemia After the Eradication of Hepatitis C Virus Infection

  • Marcella Visentini
  • Valentina Conti
  • Maria Cagliuso
  • Giulia Siciliano
  • Carolina Scagnolari
  • Milvia Casato
  • Massimo Fiorilli



Functionally exhausted and mostly autoreactive B-cells with a peculiar CD21lowCD11c+ phenotype accumulate in several human immunological disorders including common variable immunodeficiency, HIV infection and rheumatoid arthritis. In HCV-associated mixed cryoglobulinemia (MC) there is accumulation of exhausted clonal B cells expressing a VH1-69-encoded cross-reactive idiotype; these cells are phenotypically heterogeneous, displaying either a CD21lowCD11c+ or a marginal zone (MZ)-like (IgM+CD27+CD21+CD11c-) phenotype. Irrespective of their phenotype, VH1-69+ B-cells are unresponsive to the stimulation of Toll-like receptor 9 (TLR9). We investigated the fate of these cells after the eradication of HCV.


Fourteen MC patients were studied before and after antiviral therapy. VH1-69+ B-cells were identified using the G6 monoclonal antibody and their phenotype and responsiveness to the stimulation of TLR9 were investigated.


In seven virological non-responders, cryoglobulin levels and the number and phenotype of VH1-69+ B cells remained substantially unchanged. By contrast, in sustained viral responders cryoglobulinemia subsided and the number of VH1-69+ B cells declined. However, high proportions of MZ-like VH1-69+ B cells retaining unresponsiveness to TLR9 stimulation persisted for several months in these patients.


Clonal expansion of CD21low VH1-69+ B cells may depend on continual stimulation by HCV, whereas their MZ-like counterparts may persist for years after the eradication of infection. Prolonged survival of exhausted MZ-like B cells after withdrawal of the initial inciting stimulus may contribute to the accumulation of autoreactive B cells in immunological disorders.


B-cells exhaustion HCV cryoglobulinemia Toll-like receptor VH1-69 

Supplementary material

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Marcella Visentini
    • 1
  • Valentina Conti
    • 1
  • Maria Cagliuso
    • 1
  • Giulia Siciliano
    • 1
  • Carolina Scagnolari
    • 2
  • Milvia Casato
    • 1
  • Massimo Fiorilli
    • 1
  1. 1.Department of Clinical ImmunologySapienza University of RomeRomeItaly
  2. 2.Department of Molecular Medicine, Laboratory of VirologySapienza University of RomeRomeItaly

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