Clonal B cells of HCV-associated mixed cryoglobulinemia patients contain exhausted marginal zone-like and CD21 low cells overexpressing Stra13

Marcella Visentini, Maria Cagliuso, Valentina Conti, Maurizio Carbonari, Marina Cibati, Giulia Siciliano, Cristina Cristofoletti, Giandomenico Russo, Milvia Casato, Massimo Fiorilli

Research output: Contribution to journalArticle

Abstract

A clonal population of B cells expressing a V H1-69-encoded idiotype accumulates in hepatitis C virus (HCV) associated mixed cryoglobulinemia (MC). These cells are phenotypically heterogeneous, resembling either typical marginal zone (MZ) B cells (IgM +IgD +CD27 +CD21 +) or the exhausted CD21 low B cells that accumulate in HIV infection or in common variable immunodeficiency. We show that both the MZ-like and the CD21 low V H1-69 + B cells of MC patients are functionally exhausted, since they fail to respond to TLR and BCR ligands. The proliferative defect of V H1-69 + B cells can be overcome by co-stimulation of TLR9 and BCR in the presence of interleukin(IL)-2 and IL-10. The MZ-like V H1-69 + B cells do not express the inhibitory receptors distinctive of CD21 low B cells, but display constitutive activation of extracellular signal regulated kinase (ERK) and attenuated BCR/ERK signaling. These cells also express abundant transcripts of Stra13 (DEC1, Bhlhb2, Sharp2, Clast5), a basic helix-loop-helix transcription factor that acts as a powerful negative regulator of B-cell proliferation and homeostasis. Our findings suggest that MZ B cells activated by HCV undergo functional exhaustion associated with BCR signaling defects and overexpression of a key antiproliferative gene, and may subsequently become terminally spent CD21 low B cells. Premature exhaustion may serve to prevent the outgrowth of chronically stimulated MZ B cells.

Original languageEnglish
Pages (from-to)1468-1476
Number of pages9
JournalEuropean Journal of Immunology
Volume42
Issue number6
DOIs
Publication statusPublished - Jun 2012

Keywords

  • Anergy
  • B cells
  • HCV
  • Mixed cryoglobulinemia
  • Stra13

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Fingerprint Dive into the research topics of 'Clonal B cells of HCV-associated mixed cryoglobulinemia patients contain exhausted marginal zone-like and CD21 low cells overexpressing Stra13'. Together they form a unique fingerprint.

  • Cite this

    Visentini, M., Cagliuso, M., Conti, V., Carbonari, M., Cibati, M., Siciliano, G., Cristofoletti, C., Russo, G., Casato, M., & Fiorilli, M. (2012). Clonal B cells of HCV-associated mixed cryoglobulinemia patients contain exhausted marginal zone-like and CD21 low cells overexpressing Stra13. European Journal of Immunology, 42(6), 1468-1476. https://doi.org/10.1002/eji.201142313