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(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.
Department of Clinical Immunology, Sapienza University of Rome, Rome, Italy.
Marcella
M
Visentini
Maria
M
Cagliuso
Valentina
V
Conti
Maurizio
M
Carbonari
Marina
M
Cibati
Giulia
G
Siciliano
Cristina
C
Cristofoletti
Giandomenico
G
Russo
Milvia
M
Casato
Massimo
M
Fiorilli
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001402:B-Lymphocytes / Q000276:immunology*; D003449:Cryoglobulinemia / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000502:physiology*; D005260:Female; D006526:Hepatitis C / Q000150:complications*; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000032:analysis / Q000502:physiology*; D010641:Phenotype; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D017464:Receptors, Complement 3d / Q000032:analysis*; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000502:physiology
C551977:CENPX protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011947:Receptors, Antigen, B-Cell; D017464:Receptors, Complement 3d; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9