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J Clin Immunol. 2012 Aug;32(4):729-35. doi: 10.1007/s10875-012-9677-0. Epub 2012 Mar 2.

Persistence of a large population of exhausted monoclonal B cells in mixed cryoglobuliemia after the eradication of hepatitis C virus infection.

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Department of Clinical Immunology, Sapienza University of Rome, Viale dell'Università 37, 00185, Rome, Italy.



Functionally exhausted and mostly autoreactive B-cells with a peculiar CD21(low)CD11c(+) 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 V(H)1-69-encoded cross-reactive idiotype; these cells are phenotypically heterogeneous, displaying either a CD21(low)CD11c(+) or a marginal zone (MZ)-like (IgM(+)CD27(+)CD21(+)CD11c(-)) phenotype. Irrespective of their phenotype, V(H)1-69(+) 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. V(H)1-69(+) 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 V(H)1-69(+) B cells remained substantially unchanged. By contrast, in sustained viral responders cryoglobulinemia subsided and the number of V(H)1-69(+) B cells declined. However, high proportions of MZ-like V(H)1-69(+) B cells retaining unresponsiveness to TLR9 stimulation persisted for several months in these patients.


Clonal expansion of CD21(low) V(H)1-69(+) 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.

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