Hepatitis C Virus Drives the Unconstrained Monoclonal Expansion of VH1–69-Expressing Memory B Cells in Type II Cryoglobulinemia: A Model of Infection-Driven Lymphomagenesis

Abstract

Chronic hepatitis C virus infection causes B cell lymphoproliferative disorders that include type II mixed cryoglobulinemia and lymphoma. This virus drives the monoclonal expansion and, occasionally, the malignant transformation of B cells producing a polyreactive natural Ab commonly encoded by the VH1–69 variable gene. Owing to their property of producing natural Ab, these cells are reminiscent of murine B-1 and marginal zone B cells. We used anti-Id Abs to track the stages of differentiation and clonal expansion of VH1–69+ cells in patients with type II mixed cryoglobulinemia. By immunophenotyping and cell size analysis, we could define three discrete stages of differentiation of VH1–69+ B cells: naive (small, IgMhighIgDhighCD38+CD27−CD21highCD95−CD5−), “early memory” (medium-sized, IgMhighIgDlowCD38−CD27+CD21lowCD95+CD5+), and “late memory” (large-sized, IgMlowIgDlow-negCD38−CD27lowCD21low-negCD5−CD95−). The B cells expanded in cryoglobulinemia patients have a “memory” phenotype; this fact, together with the evidence for intraclonal variation, suggests that antigenic stimulation by hepatitis C virus causes the unconstrained expansion of activated VH1–69+ B cells. In some cases, these cells replace the entire pool of circulating B cells, although the absolute B cell number remains within normal limits. Absolute monoclonal VH1–69+ B lymphocytosis was seen in three patients with cryoglobulinemia and splenic lymphoma; in two of these patients, expanded cells carried trisomy 3q. The data presented here indicate that the hepatitis C virus-driven clonal expansion of memory B cells producing a VH1–69+ natural Ab escapes control mechanisms and subverts B cell homeostasis. Genetic alterations may provide a further growth advantage leading to an overt lymphoproliferative disorder.

Correlation of clinical and virologic responses to antiviral treatment and regulatory T cell evolution in patients with hepatitis C virus–induced mixed cryoglobulinemia vasculitis

“…We also observed a decrease in the frequency of CD27ϩ (memory) B cells in patients who had a complete response to treatment, which suggests a decrease in the cryoglobulin-secreting B cell clones, since it has been shown that cryoglobulinproducing clones may be found in the CD27ϩ B cell subset (26), although this was not directly evaluated in the present study. These changes were not observed in the group of patients with a partial response/no response and were more marked in patients with MC vasculitis than in patients with HCV infection without MC vasculitis.…”

Telomere‐dependent replicative senescence of B and T cells from patients with type 1a common variable immunodeficiency

“…Thus, it is possible that more intense infectious stimuli drive, in certain CVID patients, accelerated telomere shortening and the development of the clinical and immunological profile characteristic of CVID 1a. In this regard, it is of interest that patients chronically stimulated by HCV or HIV have an expansion of CD21 low B cells [9,11,12]. However, this possibility is made unlikely by the fact that CVID 1a patients are characterized by idiopathic lymphoproliferation and autoimmunity, but not by a higher rate of infections than CVID non-1a patients [25].…”

“…The CD21 low B cells expanded in CVID 1a and in other conditions, such as HIV [6] or HCV [11,12] infection, are either naïve-like CD27 À or memory-like CD27 1 . However, only the phenotype and function of CD21 low CD27 À B cells has been investigated in detail [7][8][9], and the CD21 low CD27 1 B cells have been proposed as precursors of short-lived plasmablasts rather than exhausted cells as their CD27 À counterparts [13].…”

“…However, anergy is not limited to CD21 low B cells, since all mature B cells from CVID 1a patients fail to flux calcium upon BCR triggering [8]. CD21 low B cells are also increased in patients with HIV infection [9], systemic lupus erythematosus [10], or mixed cryoglobulinemia secondary to HCV infection [11,12], all conditions characterized by B-cell hyperactivation. Although the CD21 low B cells of patients with HIV infection or HCV-associated mixed cryoglobulinemia have mutated immunoglobulin genes [10][11][12], the CD21 low B cells of CVID 1a patients are unmutated and mostly autoreactive [6,7].…”

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

“…Over 70% of the persistently infected individuals develop chronic hepatic inflammation (hepatitis), which progresses to cirrhosis in approximately 20-30% of infected individuals usually over the course of 2-3 decades [2]. Hepatitis C infection is characterized by profound hyperglobulinemia consisting of nonvirus-specific antibodies [3,4] produced by oligoclonally-activated B-cells [5,6]. Somewhat unexpectedly, chronic B-cell activation in chronic hepatitis C does not result in expansion of the memory B-cell pool in cohorts of mostly non-cirrhotic individuals [7][8][9].…”