Antibody Production and In Vitro Behavior of CD27-Defined B-Cell Subsets: Persistent Hepatitis C Virus Infection Changes the Rules

Abstract

؉ B cells do not expand but rapidly differentiate to secrete Ig and then undergo apoptosis. We propose that their enhanced sensitivity to BCR-independent noncognate T-cell help maintains a constant level of nonspecific serum antibodies and ASC and serves as a backup mechanism of feedback inhibition to prevent exaggerated B-cell responses that could be the cause of significant immunopathology.Exploration of the conditions that stimulate and modulate B-cell proliferation and differentiation is critical to both the understanding of normal B-cell function and the detection of alterations leading to humoral or neoplastic B-cell disorders. In humans, this exploration is confined to in vitro models in which combinations of surrogate signals mimic the range of physiological stimulations that may occur in vivo (12,27). Most of these signals are relatively well understood. They include B-cell receptor (BCR) cross-linking with antigen (9, 45), cell contact-mediated interactions with T cells (6,11,18,26,46), and secretion of soluble regulatory cytokines (2,3,13,15,36,56,57). The current consensus is that BCR engagement followed by cognate T-cell help drives the proliferation of antigen-specific naive B cells and their differentiation into memory B cells and plasma cells (7,54). Whereas plasma cells are mitotically quiescent and terminally differentiated antibodysecreting cells (ASC) (62), memory B cells may be consecutively stimulated, expanded, selected, and turned into effector cells. When reexposed to antigen, they rapidly proliferate and differentiate. Their memory lineage is thus preserved, and large numbers of plasma cells are concomitantly generated (4). Unlike naive B cells, which are totally dependent on BCR signaling, memory B cells may be activated by bystander T-cell help without BCR triggering (10,23,68). This ability to respond to such a polyclonal stimulus, in the absence of cognate interaction, seems essential for maintenance of their serological memory.The functional specialization of naive B cells, memory B cells, and plasma cells is instrumental in driving new and anamnestic antibody-mediated immune responses but seems critical in some chronic inflammatory conditions, including persistent viral infections. For instance, patients with chronic hepatitis C virus (HCV) are often hypergammaglobulinemic. They produce autoantibodies, have circulating immune complexes with cryoprecipitating properties, and display an increased risk of B-cell tumors (25,52,58,63,76). This is paradoxical considering the lack of antiviral function associated with anti-HCV antibodies (22) and considering that B cells seem not to be direct targets for productive HCV replication (35). Several investigators, including ourselves, have suggested that continued and indiscriminate virus-driven polyclonal stimulation is a plausible mechanism whereby abnormal clonal B-cell proliferation and antibody production are maintained throughout HCV infection (17).Based on this model and the roles of naive B cells, memory B cells, and plasma cells with...

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

“…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]. Possible reasons cited for the lack of peripheral memory B-cell expansion include increased plasma cell differentiation [8], increased activation-induced B-cell apoptosis [8], and intrahepatic compartmentalization [10]. Among these explanations, activation-induced apoptosis has been contradicted by more recent data suggesting that B-cells in HCV-infected individuals are relatively resistant to apoptosis [11,12].…”

“…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]. Possible reasons cited for the lack of peripheral memory B-cell expansion include increased plasma cell differentiation [8], increased activation-induced B-cell apoptosis [8], and intrahepatic compartmentalization [10].…”

Reply: B-cell frequency in HCV-related mixed cryoglobulinemia

“…Cacoub and colleagues 4 found reductions in the percentage of naïve B cells in MC patients compared with normal controls and, as in our study, the size of the naïve B cell subset was restored after rituximab therapy. Racanelli et al 5 and Oliviero et al 6 found no changes in B cell frequency, whereas Ni et al 7 observed an increase, but only in patients suffering from severe liver disease. In the figure that Sansonno et al included in their letter, it is unusual that the patients were categorized based on B cell percentages of <5%, 6%-10%, 11%-20%, and >20%.…”

Cxcr3 Chemokine Receptor Expression on Peripheral Blood B-Cell Subsets in Patients With Chronic Hepatitis C

“…Наши ре-зультаты согласуются с данными литературы, свидетельствующими, что количество общих В-лимфоцитов (CD19 + ) в крови больных ХВГС не изменяется [16,19]. Вместе с тем, некоторые авторы отмечают снижение уровня CD27 + В-лимфоцитов при ХВГС, что может объясняться несколькими причинами.…”