title: Chronic hepatitis C virus infection breaks tolerance and drives polyclonal expansion of autoreactive B cells.
abstract: Chronic Hepatitis C virus (HCV) infection has been linked with B cell lymphoproliferative disorders and several autoimmune-related diseases. The mechanisms of how chronic viral infection affects B cell development and predisposes the patients to autoimmune manifestations are poorly understood. In this study, we established an experimental system to probe the B cell responses and characterize the antibodies from chronic-HCV-infected individuals. We identified an unusual polyclonal expansion of the IgM memory B cell subset in some patients. This B cell subset is known to be tightly regulated, and autoreactive cells are eliminated by tolerance mechanisms. Genetic analysis of the immunoglobulin (Ig) heavy chain variable gene (V(H)) sequences of the expanded cell population showed that the levels of somatic hypermutation (SHM) correlate with the extent of cell expansion in the patients and that the V(H) genes exhibit signs of antigen-mediated selection. Functional analysis of the cloned B cell receptors demonstrated autoreactivity in some of the expanded IgM memory B cells in the patients which is not found in healthy donors. In summary, this study demonstrated that, in some patients, chronic HCV infection disrupts the tolerance mechanism that normally deletes autoreactive B cells, therefore increasing the risk of developing autoimmune antibodies. Long-term follow-up of this expanded B cell subset within the infected individuals will help determine whether these cells are predictors of more-serious clinical manifestations.
authors.affiliation: Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Jill E
authors.initials: JE
authors.lastname: Roughan
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Reardon
authors.forename: Kristin E
authors.initials: KE
authors.lastname: Cogburn
authors.forename: Heribert
authors.initials: H
authors.lastname: Quendler
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Pockros
authors.forename: Mansun
authors.initials: M
authors.lastname: Law
mesh_terms: D000328:Adult; D000368:Aged; D001323:Autoantibodies / Q000097:blood; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology; D016175:B-Lymphocyte Subsets / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D005260:Female; D019698:Hepatitis C, Chronic / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000097:blood; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007075:Immunoglobulin M / Q000097:blood; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007156:Immunologic Memory; D008297:Male; D008875:Middle Aged
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region