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

Abstract

Homeostasis of peripheral B cell subsets is disturbed during chronic hepatitis C virus (HCV) infection, leading to the occurrence of autoimmunity and B cell lymphoproliferation. However, mechanisms by which HCV causes lymphoproliferation remain controversial. We report in this article on the elevated number of clonal CD21−/lowIgM+CD27+ marginal zone (MZ)-like B cells, which correlates with autoimmunity and lymphoproliferation in HCV patients. We found an increase in autoreactive BCRs using VH1–69 and VH4–34 genes in CD21−/low MZ B cells. CD21−/low MZ B cells showed impaired calcium-mediated signaling, did not upregulate activation markers, and did not proliferate in response to BCR triggering. CD21−/low MZ B cells also were prone to dying faster than their CD21+ counterparts, suggesting that these B cells were anergic. CD21−/low MZ B cells, in contrast, remained responsive to TLR9 stimulation. Gene array analyses revealed the critical role of Early growth response 2 and Cbl-b in the induction of anergy. Therefore, HCV patients who display high frequencies of unresponsive CD21−/low MZ B cells are more susceptible to developing autoimmunity and/or lymphoproliferation. These cells remain in peripheral blood controlled by functional anergy instead of being eliminated, and chronic antigenic stimulation through TLR stimulation may create a favorable environment for breaking tolerance and activating these cells.

Lentiviral-mediated gene therapy restores B cell tolerance in Wiskott-Aldrich syndrome patients

“…In agreement with these data, the defective peripheral B cell tolerance checkpoint in WAS patients was associated with Tregs displaying an abnormal phenotype and showing defect in homeostasis regulation and suppressive capacities. WAS patients' Tregs exhibited an activated phenotype illustrated by increased CTLA4 expression and contained an increased proportion of Ki67 + proliferating clones in the patients' CD45RO + Tregs, a feature associated with proinflammatory cytokine production combined with reduced suppressive capabilities (32)(33)(34)(35). Indeed, CD4 + CD25 hi CD127 lo Tregs from WAS patients showed impaired suppressive activity, further supporting previous observations obtained with CD4 + CD25 hi T cells (5-8).…”

“…+ Tregs that coexpress Ki67 were previously reported to express proinflammatory cytokines and to display reduced suppressive abilities (32)(33)(34)(35). We therefore assessed Treg function by testing the capability of CD4 + CD25 hi CD127 lo T cells isolated from HDs and WAS patients to suppress the proliferation induced by beads coated with was further evidenced by the increased frequency of polyreactive mature naive B cells, which ranged from 10.5%-20.0% in WAS patients vs. 3.5%-13.6% in HDs ( Figure 3C Central B cell tolerance checkpoint is restored after HSC gene therapy in WAS patients.…”

CD21–/low B cells in human blood are memory cells

“…certain pathogenic infections (viral, parasitic) and autoimmune diseases, e.g. RA, SLE, Sj€ ogren's syndrome and common variable immunodeficiency (CVID) type Ia [13][14][15][16][17][18][19]. Depending on disease and study design, the CD21 -/low B cells have been described as CD27 …”

“…human immunodeficiency virus (HIV) infection, malaria, CVID, RA and Sj€ ogren's syndrome [13][14][15][16][17][18][19], and in most disorders the cells express CD11c, by analogy to the ABCs in aged and lupus-prone mice [6,7]. Moreover, in disease the CD21 -/low B cells seemingly belong to the memory B cell pool based on their expression of either CD27, mutated and/or switched BCRs.…”

Persistence of exhaustion in cured hep C

“…ixed cryoglobulinemia is one of several B-cell proliferative disorders that may result from chronic hepatitis C infection, and it is thought to be driven by expansion of HCV envelope-specific B cells that preferentially use immunoglobulin gene segments V H 1-69 and V k [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]3 and to evolve rheumatoid factor activity through somatic hypermutation.…”