Clonal B cells in patients with hepatitis C virus–associated mixed cryoglobulinemia contain an expanded anergic CD21low B-cell subset

Abstract

Hepatitis C virus (HCV) is associated with the B-cell lymphoproliferative disorders mixed cryoglobulinemia (MC) and non-

Expansion of Functionally Anergic CD21−/low Marginal Zone-like B Cell Clones in Hepatitis C Virus Infection-Related Autoimmunity

“…These findings suggest that the defective BCR signaling pathway displayed by CD21 2/low MZ B cells could be bypassed by an alternative pathway, such as TLR and MyD88. Our findings contrast with those from Charles et al (48), except for common differentially regulated genes, including CD11C, CD84, STS1, or PELI2. These discrepancies might be explained by differences in the experimental procedures: 1) cells for transcriptomic analysis in our study were sorted using cell sorter, whereas magnetic bead selection was used by Charles et al (48); 2) we compared CD21 2/low MZ B cells and their CD21 + counterparts from the same patients, whereas Charles et al (48) compared MZ B cells from HCV-MC patients and HCV patients without MC; 3) finally, we used the PredictSearch software, a powerful bioinformatic solution dedicated to identifying relevant correlations between genes and concepts, to generate functional networks, whereas Charles et al (48) made a descriptive and not a functional analysis of genes differentially expressed between groups.…”

“…However, we provided additional data on the pathophysiology of the disease: 1) to better characterize CD21 2/low MZ B cells, we compared CD21 2/low MZ B cells to their CD21 + counterparts from the same HCV-MC patients; 2) using single-cell analysis, we found an increase in autoreactive BCRs using V H 1-69 and V H 4-34 genes in CD21 2/low MZ B cells; 3) besides the unresponsiveness of CD21 2/low MZ B cells to BCR stimulation, we observed that CD21 2/low MZ B cells remained responsive to TLR9 stimulation. Gene array analyses, comparing CD21 2/low MZ B cells and their CD21 + counterparts from the same HCV-MC patients, in contrast to Charles et al (48) who compared MZ B cells from HCV-MC patients and HCV patients without MC, revealed the critical role of EGR2 and Cbl-b, which are potent negative regulators of intracellular signaling, in the induction of anergy. In addition, gene array analyses also identified a cluster of downregulated genes in CD21 2/low MZ B cells that is related mainly to cell cycle events.…”

Peripheral CD27−CD21− B-cells represent an exhausted lymphocyte population in hepatitis C cirrhosis

“…We similarly found impaired proliferation in the CD27 − CD21 − B-cell subset with BCR stimulation alone and with CD40 stimulation, but partially recovered with combined BCR/CD40 stimulation. Contrasting with this study in HIV infection, and concurring with findings from Charles et al [17], we found no significant association of the CD27 − CD21 − with the expression of the putative inhibitory receptor FcRL4 in HCV infected patients. Interestingly, FcRL4 was highly expressed on a small population of CD27 hi CD21 − that are likely plasmablasts [35], the significance of which needs further exploration.…”

“…However, successful viral control under ART therapy of HIV disease has been associated with reduction of CD27 − CD21 lo B-cells in one study [32]. In HCV, CD27 − CD21 lo B-cells have been associated with virus-induced clonally expanded Bcells [17,38]. A similar expansion of clonally expanded, autoreactive, hypoproliferative CD27 − CD21 lo B-cells in autoimmune processes [39] provides additional evidence for the importance of chronic antigen exposure in the induction of this subpopulation.…”

“…In common variable immunodeficiency, a tissue-homing peripheral CD21 lo B-cell population with impaired proliferation but exaggerated IgM secretory capacity with phenotypic similarities to the CD27 − CD21 lo B-cell population in HIV has also been described [16]. Limited investigation in HCV disease has not identified an expansion of a similar CD27 − CD21 − FcRL4 + B-cell population [9,17] but did suggest that a hyporesponsive CD27 − CD21 lo B-cell population does exist in HCV patients with cryoglobulinemia [17]. FcRL4 putatively mediates its inhibitory effect on B-cell activation via its cytoplasmic immunoreceptor tyrosine-based inhibitory motif (ITIM).…”