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

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. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.