Preferential association of hepatitis C virus with CD19+B cells is mediated by complement system

ABSTRACT Hepatitis C virus (HCV) induces inflammatory signals, leading to hepatitis, hepatocellular carcinomas, and lymphomas. The mechanism of HCV involvement in the host's innate immune responses has not been well characterized. In this study, we analyzed expression and regulation of the entire panel of toll-like receptors (TLRs) in human B cells following HCV infection in vitro. Among all of the TLRs (TLRs 1 to 10) examined, only TLR4 showed an altered expression (a three- to sevenfold up-regulation) after HCV infection. Peripheral blood mononuclear cells from HCV-infected individuals also showed a higher expression level of TLR4 compared with those of healthy individuals. HCV infection significantly increased beta interferon (IFN-β) and interleukin-6 (IL-6) secretion from B cells, particularly after lipopolysaccharide stimulation. The increased IFN-β and IL-6 production was mediated by TLR4 induction, since the introduction of the small interfering RNA against TLR4 specifically inhibited the HCV-induced cytokine production. Among all of the viral proteins, only NS5A caused TLR4 induction in hepatocytes and B cells. NS5A specifically activated the promoter of the TLR4 gene in both hepatocytes and B cells. In conclusion, HCV infection directly induces TLR4 expression and thereby activates B cells, which may contribute to the host's innate immune responses.

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Antibody Production and In Vitro Behavior of CD27-Defined B-Cell Subsets: Persistent Hepatitis C Virus Infection Changes the Rules

Journal of Virology ◽

10.1128/jvi.80.8.3923-3934.2006 ◽

2006 ◽

Vol 80 (8) ◽

pp. 3923-3934 ◽

Cited By ~ 56

Author(s):

Vito Racanelli ◽

Maria Antonia Frassanito ◽

Patrizia Leone ◽

Maria Galiano ◽

Valli De Re ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

T Cell ◽

B Cells ◽

B Cell ◽

Feedback Inhibition ◽

Cell Subset ◽

Functional Program ◽

Cell Functions

ABSTRACT There is growing interest in the tendency of B cells to change their functional program in response to overwhelming antigen loading, perhaps by regulating specific parameters, such as efficiency of activation, proliferation rate, differentiation to antibody-secreting cells (ASC), and rate of cell death in culture. We show that individuals persistently infected with hepatitis C virus (HCV) carry high levels of circulating immunoglobulin G (IgG) and IgG-secreting cells (IgG-ASC). Thus, generalized polyclonal activation of B-cell functions may be supposed. While IgGs include virus-related and unrelated antibodies, IgG-ASC do not include HCV-specific plasma cells. Despite signs of widespread activation, B cells do not accumulate and memory B cells seem to be reduced in the blood of HCV-infected individuals. This apparent discrepancy may reflect the unconventional activation kinetics and functional responsiveness of the CD27+ B-cell subset in vitro. Following stimulation with T-cell-derived signals in the absence of B-cell receptor (BCR) engagement, CD27+ B cells do not expand but rapidly differentiate to secrete Ig and then undergo apoptosis. We propose that their enhanced sensitivity to BCR-independent noncognate T-cell help maintains a constant level of nonspecific serum antibodies and ASC and serves as a backup mechanism of feedback inhibition to prevent exaggerated B-cell responses that could be the cause of significant immunopathology.

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Lymphomagenesis-related gene expression in B cells from sustained virological responders with occult hepatitis C virus infection

Journal of Viral Hepatitis ◽

10.1111/jvh.12526 ◽

2016 ◽

Vol 23 (8) ◽

pp. 606-613 ◽

Cited By ~ 2

Author(s):

M. C. Roque Cuéllar ◽

J. R. García-Lozano ◽

B. Sánchez ◽

J. M. Praena-Fernández ◽

C. Martínez Sierra ◽

...

Keyword(s):

Gene Expression ◽

Hepatitis C Virus ◽

Hepatitis C ◽

B Cells ◽

Virus Infection ◽

Hepatitis C Virus Infection ◽

Related Gene ◽

Occult Hepatitis ◽

Occult Hepatitis C

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Enhanced RIG-I expression is mediated by interferon regulatory factor-2 in peripheral blood B cells from hepatitis C virus-infected patients

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2009.12.092 ◽

2010 ◽

Vol 391 (4) ◽

pp. 1623-1628 ◽

Cited By ~ 10

Author(s):

Atsuko Masumi ◽

Masahiko Ito ◽

Keiko Mochida ◽

Isao Hamaguchi ◽

Takuo Mizukami ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

B Cells ◽

Peripheral Blood ◽

Interferon Regulatory Factor ◽

Regulatory Factor

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CD100 Up-Regulation Induced by Interferon-α on B Cells Is Related to Hepatitis C Virus Infection

PLoS ONE ◽

10.1371/journal.pone.0113338 ◽

2014 ◽

Vol 9 (12) ◽

pp. e113338 ◽

Cited By ~ 9

Author(s):

Yu He ◽

Yonghong Guo ◽

Yun Zhou ◽

Ying Zhang ◽

Chao Fan ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

B Cells ◽

Virus Infection ◽

Interferon Α ◽

Hepatitis C Virus Infection

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Persistent expression of the full genome of hepatitis C virus in B cells induces spontaneous development of B-cell lymphomas in vivo

Blood ◽

10.1182/blood-2010-05-283358 ◽

2010 ◽

Vol 116 (23) ◽

pp. 4926-4933 ◽

Cited By ~ 55

Author(s):

Yuri Kasama ◽

Satoshi Sekiguchi ◽

Makoto Saito ◽

Kousuke Tanaka ◽

Masaaki Satoh ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

B Cells ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Hcv Infection ◽

Mouse Serum ◽

B Cell Lymphomas ◽

Α Subunit

AbstractExtrahepatic manifestations of hepatitis C virus (HCV) infection occur in 40%-70% of HCV-infected patients. B-cell non-Hodgkin lymphoma is a typical extrahepatic manifestation frequently associated with HCV infection. The mechanism by which HCV infection of B cells leads to lymphoma remains unclear. Here we established HCV transgenic mice that express the full HCV genome in B cells (RzCD19Cre mice) and observed a 25.0% incidence of diffuse large B-cell non-Hodgkin lymphomas (22.2% in males and 29.6% in females) within 600 days after birth. Expression levels of aspartate aminotransferase and alanine aminotransferase, as well as 32 different cytokines, chemokines and growth factors, were examined. The incidence of B-cell lymphoma was significantly correlated with only the level of soluble interleukin-2 receptor α subunit (sIL-2Rα) in RzCD19Cre mouse serum. All RzCD19Cre mice with substantially elevated serum sIL-2Rα levels (> 1000 pg/mL) developed B-cell lymphomas. Moreover, compared with tissues from control animals, the B-cell lymphoma tissues of RzCD19Cre mice expressed significantly higher levels of IL-2Rα. We show that the expression of HCV in B cells promotes non-Hodgkin–type diffuse B-cell lymphoma, and therefore, the RzCD19Cre mouse is a powerful model to study the mechanisms related to the development of HCV-associated B-cell lymphoma.

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