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- Title
Clonal B cells of HCV-associated mixed cryoglobulinemia patients contain exhausted marginal zone-like and CD21 low cells overexpressing Stra13.
- Authors
Visentini, Marcella; Cagliuso, Maria; Conti, Valentina; Carbonari, Maurizio; Cibati, Marina; Siciliano, Giulia; Cristofoletti, Cristina; Russo, Giandomenico; Casato, Milvia; Fiorilli, Massimo
- Abstract
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
European journal of immunology, 2012, Vol 42, Issue 6, p1468
- ISSN
1521-4141
- Publication type
Journal Article
- DOI
10.1002/eji.201142313