Accumulation of B Lymphocytes with a Naive, Resting Phenotype in a Subset of Hepatitis C Patients

Abstract

Chronic infection with hepatitis C virus (HCV) is associated with disturbances of B lymphocyte activation and function: autoantibody production, mixed cryoglobulinemia, and B cell lymphomas. It has been proposed that these abnormalities reflect chronic antigenic stimulation or aberrant signaling through the B cell coreceptor, the latter mediated by binding of the HCV E2 glycoprotein to CD81. To test this hypothesis, we measured expression of activation and differentiation markers on peripheral blood B cells from patients with chronic HCV infection. Thirty-six HCV patients with and without mixed cryoglobulinemia were compared with 18 healthy control volunteers and 17 sustained virologic responders who had cleared HCV infection. Ten of the 36 HCV patient samples showed increased B cell frequencies; B cell frequency was higher in patients with more severe hepatic fibrosis. However, these samples lacked evidence of Ag-driven activation or proliferation. The expanded cells were low in the activation markers CD25, CD69, CD71, CD80, and CD86. Proliferation of circulating B cells was unchanged in HCV patients. These cells did not express the differentiation marker CD27, suggesting that they were not enriched in memory B cells. Furthermore, the expanded B cells expressed both IgD and IgM, suggesting that they were antigenically naive. Together, these results indicate that B cell expansion in the peripheral blood of HCV patients is not associated with Ag-mediated activation and differentiation. Instead, factors other than antigenic stimulation may promote the accumulation of peripheral blood B cells with a naive phenotype in a subset of HCV patients.

3 Tesla diffusion-weighted MRI for assessing liver fibrosis in nonalcoholic fatty liver disease

“…Nonetheless, previous work found no increased prevalence of cryoglobulinemia in patients with B cell frequencies of >20% of the lymphocyte population. 7 The decreased B cell numbers in our study do not contradict the large expansions in specific B cell clones observed in cryoglobulinemia. Clonal B cell populations in the activated/memory B cell subset drive MC, and we did not identify reductions in this subset.…”

“…Respective cut-off values for the APRI, UTE, and MRE were 0.5, 5.2, and 3.2 kPa for significant fibrosis (!F2) and 2.0, 12.9, and 4.6 kPa for cirrhosis (F4). 6,7 Accuracy of fibrosis staging was com- F3), had an APRI of 1.65, indicating significant fibrosis, but not cirrhosis. A value of 16.0 kPa, by UTE, indicated cirrhosis, whereas noncirrhosis, but significant fibrosis, were suggested by a 3.6-kPa value by MRE.…”

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

“…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].…”

Identification of Conserved Residues in the E2 Envelope Glycoprotein of the Hepatitis C Virus That Are Critical for CD81 Binding

“…CD81 colocalizes with a number of other cell surface molecules, and its function varies greatly across cell types (30). CD81 engagement may be associated with a number of manifestations including mixed cryoglobulinemia and B-cell malignancies (55), B-cell proliferation (36), and immunoglobulin gene hypermutation (33). The HCV E2 binding region maps to the large extracellular loop (LEL) of CD81 (41).…”