Persistence of a Large Population of Exhausted Monoclonal B cells in Mixed Cryoglobuliemia After the Eradication of Hepatitis C Virus Infection
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.
KeywordsB-cells exhaustion HCV cryoglobulinemia Toll-like receptor VH1-69
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