Enhanced B-cell differentiation and reduced proliferative capacity in chronic hepatitis C and chronic hepatitis B virus infections

Barbara Oliviero, Antonella Cerino, Stefania Varchetta, Enrica Paudice, Somnath Pai, Serena Ludovisi, Marco Zaramella, Giuseppe Michelone, Paolo Pugnale, Francesco Negro, Vincenzo Barnaba, Mario U. Mondelli

Research output: Contribution to journalArticle

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Abstract

Background & Aims: Chronic microbial infections are frequently associated with B-cell activation and polyclonal proliferation, potentially leading to autoimmunity and lymphoproliferative disorders. We assessed B-cell phenotype and function in chronic hepatitis B (HBV) and chronic hepatitis C (HCV) virus infection. Methods: We studied 70 patients with chronic HCV infection, 34 with chronic HBV infection and 54 healthy controls. B-cell phenotype was assessed by flow cytometry using monoclonal antibodies specific for CD27, the CD69, CD71, and CD86 activation markers and the chemokine receptor CXCR3. Differentiation into immunoglobulin-producing cells (IPC) was analysed by ELISpot upon stimulation and with CD40 ligand ± IL-10 as surrogate bystander T-cell help or CpG oligodeoxynucleotide ± IL-2, as innate immunity signal. Proliferation was examined by flow cytometry using carboxyfluorescein diacetate succinimidyl ester (CFSE) after stimulation with CpG. Results: A significantly higher proportion of B cells from both HCV- and HBV-infected patients expressed activation markers compared with controls and a positive correlation was found between CXCR3+ B cells and HCV RNA values. Memory B cells from patients with chronic HCV and HBV infections showed enhanced differentiation into IPC compared with controls, although this was restricted to IgG and at a lower level in HCV-compared with HBV-infected patients. Moreover, patients' activated B cells displayed significantly lower proliferative ability compared to healthy donors despite low expression of the FcRL4 exhaustion marker. Conclusions: B-cell activation, but not exhaustion, is common in chronic viral hepatitis. However, enhanced B-cell differentiation and deficient proliferative capacity were not associated with commitment to terminal differentiation.

Original languageEnglish
Pages (from-to)53-60
Number of pages8
JournalJournal of Hepatology
Volume55
Issue number1
DOIs
Publication statusPublished - Jul 2011

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Chronic Hepatitis B
Chronic Hepatitis C
Virus Diseases
Hepatitis B virus
Cell Differentiation
B-Lymphocytes
Antibody-Producing Cells
Infection
Flow Cytometry
Phenotype
CD40 Ligand
Lymphoproliferative Disorders
Chemokine Receptors
Oligodeoxyribonucleotides
Chronic Hepatitis
Autoimmunity
Innate Immunity
Hepacivirus
Interleukin-10
Interleukin-2

Keywords

  • Activation markers
  • B cells
  • ELISpot
  • Flow cytometry
  • HBV
  • HCV

ASJC Scopus subject areas

  • Hepatology

Cite this

Enhanced B-cell differentiation and reduced proliferative capacity in chronic hepatitis C and chronic hepatitis B virus infections. / Oliviero, Barbara; Cerino, Antonella; Varchetta, Stefania; Paudice, Enrica; Pai, Somnath; Ludovisi, Serena; Zaramella, Marco; Michelone, Giuseppe; Pugnale, Paolo; Negro, Francesco; Barnaba, Vincenzo; Mondelli, Mario U.

In: Journal of Hepatology, Vol. 55, No. 1, 07.2011, p. 53-60.

Research output: Contribution to journalArticle

Oliviero, Barbara ; Cerino, Antonella ; Varchetta, Stefania ; Paudice, Enrica ; Pai, Somnath ; Ludovisi, Serena ; Zaramella, Marco ; Michelone, Giuseppe ; Pugnale, Paolo ; Negro, Francesco ; Barnaba, Vincenzo ; Mondelli, Mario U. / Enhanced B-cell differentiation and reduced proliferative capacity in chronic hepatitis C and chronic hepatitis B virus infections. In: Journal of Hepatology. 2011 ; Vol. 55, No. 1. pp. 53-60.
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AU - Oliviero, Barbara

AU - Cerino, Antonella

AU - Varchetta, Stefania

AU - Paudice, Enrica

AU - Pai, Somnath

AU - Ludovisi, Serena

AU - Zaramella, Marco

AU - Michelone, Giuseppe

AU - Pugnale, Paolo

AU - Negro, Francesco

AU - Barnaba, Vincenzo

AU - Mondelli, Mario U.

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N2 - Background & Aims: Chronic microbial infections are frequently associated with B-cell activation and polyclonal proliferation, potentially leading to autoimmunity and lymphoproliferative disorders. We assessed B-cell phenotype and function in chronic hepatitis B (HBV) and chronic hepatitis C (HCV) virus infection. Methods: We studied 70 patients with chronic HCV infection, 34 with chronic HBV infection and 54 healthy controls. B-cell phenotype was assessed by flow cytometry using monoclonal antibodies specific for CD27, the CD69, CD71, and CD86 activation markers and the chemokine receptor CXCR3. Differentiation into immunoglobulin-producing cells (IPC) was analysed by ELISpot upon stimulation and with CD40 ligand ± IL-10 as surrogate bystander T-cell help or CpG oligodeoxynucleotide ± IL-2, as innate immunity signal. Proliferation was examined by flow cytometry using carboxyfluorescein diacetate succinimidyl ester (CFSE) after stimulation with CpG. Results: A significantly higher proportion of B cells from both HCV- and HBV-infected patients expressed activation markers compared with controls and a positive correlation was found between CXCR3+ B cells and HCV RNA values. Memory B cells from patients with chronic HCV and HBV infections showed enhanced differentiation into IPC compared with controls, although this was restricted to IgG and at a lower level in HCV-compared with HBV-infected patients. Moreover, patients' activated B cells displayed significantly lower proliferative ability compared to healthy donors despite low expression of the FcRL4 exhaustion marker. Conclusions: B-cell activation, but not exhaustion, is common in chronic viral hepatitis. However, enhanced B-cell differentiation and deficient proliferative capacity were not associated with commitment to terminal differentiation.

AB - Background & Aims: Chronic microbial infections are frequently associated with B-cell activation and polyclonal proliferation, potentially leading to autoimmunity and lymphoproliferative disorders. We assessed B-cell phenotype and function in chronic hepatitis B (HBV) and chronic hepatitis C (HCV) virus infection. Methods: We studied 70 patients with chronic HCV infection, 34 with chronic HBV infection and 54 healthy controls. B-cell phenotype was assessed by flow cytometry using monoclonal antibodies specific for CD27, the CD69, CD71, and CD86 activation markers and the chemokine receptor CXCR3. Differentiation into immunoglobulin-producing cells (IPC) was analysed by ELISpot upon stimulation and with CD40 ligand ± IL-10 as surrogate bystander T-cell help or CpG oligodeoxynucleotide ± IL-2, as innate immunity signal. Proliferation was examined by flow cytometry using carboxyfluorescein diacetate succinimidyl ester (CFSE) after stimulation with CpG. Results: A significantly higher proportion of B cells from both HCV- and HBV-infected patients expressed activation markers compared with controls and a positive correlation was found between CXCR3+ B cells and HCV RNA values. Memory B cells from patients with chronic HCV and HBV infections showed enhanced differentiation into IPC compared with controls, although this was restricted to IgG and at a lower level in HCV-compared with HBV-infected patients. Moreover, patients' activated B cells displayed significantly lower proliferative ability compared to healthy donors despite low expression of the FcRL4 exhaustion marker. Conclusions: B-cell activation, but not exhaustion, is common in chronic viral hepatitis. However, enhanced B-cell differentiation and deficient proliferative capacity were not associated with commitment to terminal differentiation.

KW - Activation markers

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KW - ELISpot

KW - Flow cytometry

KW - HBV

KW - HCV

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