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

Eur J Immunol. 2012 Jun;42(6):1468-76. doi: 10.1002/eji.201142313.


A clonal population of B cells expressing a V(H) 1-69-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(H) 1-69(+) B cells of MC patients are functionally exhausted, since they fail to respond to TLR and BCR ligands. The proliferative defect of V(H) 1-69(+) 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(H) 1-69(+) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • B-Lymphocytes / immunology*
  • Cryoglobulinemia / immunology*
  • DNA-Binding Proteins / analysis
  • DNA-Binding Proteins / physiology*
  • Female
  • Hepatitis C / complications*
  • Humans
  • Lymphocyte Activation
  • Male
  • Middle Aged
  • Nuclear Proteins / analysis
  • Nuclear Proteins / physiology*
  • Phenotype
  • Receptors, Antigen, B-Cell / physiology
  • Receptors, Complement 3d / analysis*
  • Signal Transduction
  • Toll-Like Receptor 9 / physiology


  • CENPX protein, human
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Receptors, Antigen, B-Cell
  • Receptors, Complement 3d
  • TLR9 protein, human
  • Toll-Like Receptor 9