title: Peripheral blood B cell subset skewing is associated with altered cell cycling and intrinsic resistance to apoptosis and reflects a state of immune activation in chronic hepatitis C virus infection.
abstract: Chronic hepatitis C virus (HCV) infection is associated with B cell activation, although underlying mechanisms are unclear. To investigate B cell regulation during HCV infection, we measured bulk B cell CpG and Staphylococcus aureus Cowan-induced IgG Ab-secreting cell (ASC) frequency, HCV and tetanus-specific ASC frequency, BCR- and CD40L-dependent CD80/CD86 expression, and activation of memory CD4 cells. Immature transitional, naive, resting memory, mature activated, tissue-like memory, and plasma B cell subset frequencies, cell cycling, and intrinsic apoptosis were quantified. We observed intact or enhanced tetanus-specific and total IgG ASC frequency, serum IgG, BCR- and CD40L-dependent CD80/CD86 expression, and CD40L-dependent bulk B cell activation of memory CD4 cells in HCV infection. HCV-specific ASCs were observed in HCV-infected but not control subjects, although frequencies were lower compared with tetanus-specific cells. Immature transitional and mature activated B cell subset frequencies were increased in HCV-infected subjects, with immature transitional frequency associated with liver inflammation and serum B cell-activating factor. Mature activated B cells less commonly expressed Ki67, more commonly expressed Bcl2, and were more intrinsically resistant to apoptosis, whereas immature transitional B cells more commonly expressed Ki67, the latter associated with plasma HCV level. Taken together, these results indicate that in the setting of chronic HCV infection, a state of activation results in B cell subset skewing that is likely the result of alterations in homeostasis, cell cycling, and intrinsic resistance to apoptosis and that results in an overall intact or enhanced B cell response to BCR and CD40L.
authors.affiliation: Department of Medicine, Case Western Reserve University Center for AIDS Research and VA Medical Center, Cleveland, OH 44106, USA.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Sugalski
authors.forename: Benigno
authors.initials: B
authors.lastname: Rodriguez
authors.forename: Susan
authors.initials: S
authors.lastname: Moir
authors.forename: Donald D
authors.initials: DD
authors.lastname: Anthony
mesh_terms: D017209:Apoptosis / Q000276:immunology*; D053264:B-Cell Activating Factor / Q000097:blood; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D006526:Hepatitis C / Q000097:blood / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D007113:Immunity, Innate; D007156:Immunologic Memory; D007249:Inflammation / Q000097:blood / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology*; D018655:Lymphocyte Count; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000097:blood
chemical_list: D053264:B-Cell Activating Factor; D019253:Proto-Oncogene Proteins c-bcl-2; C505719:TNFSF13B protein, human