Presence of Rheumatoid Factor during Chronic HCV Infection Is Associated with Expansion of Mature Activated Memory B-Cells that Are Hypo-Responsive to B-Cell Receptor Stimulation and Persist during the Early Stage of IFN Free Therapy

Abstract

Approximately half of those with chronic hepatitis C virus (HCV) infection have circulating rheumatoid factor (RF), and a portion of these individuals develop cryoglobulinemic vasculitis. B cell phenotype/function in relation to RF in serum has been unclear. We examined B cell subset distribution, activation state (CD86), cell cycle state (Ki67), and ex-vivo response to BCR, TLR9 and TLR7/8 stimulation, in chronic HCV-infected donors with or without RF, and uninfected donors. Mature-activated B-cells of HCV-infected donors had lower CD86 expression compared to uninfected donors, and in the presence of RF they also showed reduced CD86 expression in response to BCR and TLR9 stimulation. Additionally, mature activated memory B cells of HCV RF+ donors less commonly expressed Ki67+ than HCV RF- donors, and did not proliferate as well in response to BCR stimulation. Proportions of mature-activated B cells were enhanced, while naïve B-cells were lower in the peripheral blood of HCV-RF+ compared to RF- and uninfected donors. None of these parameters normalize by week 8 of IFN free direct acting antiviral (DAA) therapy in HCV RF+ donors, while in RF- donors, mature activated B cell proportions did normalize. These data indicate that while chronic HCV infection alone results in a lower state of activation in mature activated memory B cells, the presence of RF in serum is associated with a more pronounced state of unresponsiveness and an overrepresentation of these B cells in the blood. This phenotype persists at least during the early time window after removal of HCV from the host.

Virologic, Clinical, and Immune Response Outcomes of Patients With Hepatitis C Virus–Associated Cryoglobulinemia Treated With Direct-Acting Antivirals

“…31,32 These results suggest that clinical recovery occurs first after viral clearance, and immunologic response seems to arise later, probably depending on the time required for reversion of the B-lymphocyte clonal expansion producing immunologic changes. 3,33 Indeed, a longer treatment course, which implies a longer virus-free period, appears to favor an immunologic response. In the Gragnani et al 17 study, the rate of complete immunologic response increased slightly from 32% at week 12 to 39% at week 24, (although not all patients had been assessed at this time point).…”

Direct-acting antiviral agents in the therapy of hepatitis C virus-related mixed cryoglobulinaemia: a single-centre experience

“…The long-term evolution of these features is totally unknown, and whether an early antiviral approach with DAAs, before the occurrence of severe organ damage, might be able to prevent the occurrence of these initially virus-induced and then virus-cleared vasculitides remains to be elucidated. In addition, at variance from patients with MC achieving SVR and a successful vasculitic response, in whom the regression of B-cell monoclonal expansion in the bone marrow has been described [19], the presence of circulating RF may be associated with the over-representation of mature activated memory B cells, which persist at least during the early phase following eradication of HCV [38]. To ascertain whether an HCV-independent, B-cell lymphoproliferative disorder may eventually appear in this particular group of patients, more prolonged follow-up after viral clearance is necessary.…”

Increased killer B cells in chronic HCV infection may lead to autoimmunity and increased viral load

“…Seeking to understand that HCV chronicity and its escape from efficient immune responses is frequent, researchers have looked for the mechanisms by which this evasion occurs. The presence of RF in the serum of these patients with chronic HCV infection, however, was found to be associated with a more pronounced state of over-representation of these memory B cells, and that by persisting in the blood, the latter probably play a role in the attempt to clean HCV from the host [22]. Many researchers have linked the failure of HCV clearance and progression to chronic infection with significantly higher IL-10 production and a relative absence of IFN-g and IL-2 production.…”

“…Chronic HCV infection, by itself, is not sufficient to activate mature memory B cells. The presence of RF in the serum of these patients with chronic HCV infection, however, was found to be associated with a more pronounced state of over-representation of these memory B cells, and that by persisting in the blood, the latter probably play a role in the attempt to clean HCV from the host [22]. So far, little is known about the role of B reg cells in the persistence of HCV.…”