title: Activation of naïve B lymphocytes via CD81, a pathogenetic mechanism for hepatitis C virus-associated B lymphocyte disorders.
abstract: Infection with hepatitis C virus (HCV), a leading cause of chronic liver diseases, can associate with B lymphocyte proliferative disorders, such as mixed cryoglobulinemia and non-Hodgkin lymphoma. The major envelope protein of HCV (HCV-E2) binds, with high affinity CD81, a tetraspanin expressed on several cell types. Here, we show that engagement of CD81 on human B cells by a combination of HCV-E2 and an anti-CD81 mAb triggers the JNK pathway and leads to the preferential proliferation of the naïve (CD27-) B cell subset. In parallel, we have found that B lymphocytes from the great majority of chronic hepatitis C patients are activated and that naïve cells display a higher level of activation markers than memory (CD27+) B lymphocytes. Moreover, eradication of HCV infection by IFN therapy is associated with normalization of the activation-markers expression. We propose that CD81-mediated activation of B cells in vitro recapitulates the effects of HCV binding to B cell CD81 in vivo and that polyclonal proliferation of naïve B lymphocytes is a key initiating factor for the development of the HCV-associated B lymphocyte disorders.
authors.affiliation: Chiron Vaccines, 53100 Siena, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Rosa
authors.forename: Giulietta
authors.initials: G
authors.lastname: Saletti
authors.forename: Ennio
authors.initials: E
authors.lastname: De Gregorio
authors.forename: Francesca
authors.initials: F
authors.lastname: Zorat
authors.forename: Consuelo
authors.initials: C
authors.lastname: Comar
authors.forename: Ugo
authors.initials: U
authors.lastname: D'Oro
authors.forename: Sandra
authors.initials: S
authors.lastname: Nuti
authors.forename: Michael
authors.initials: M
authors.lastname: Houghton
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Barnaba
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pozzato
authors.forename: Sergio
authors.initials: S
authors.lastname: Abrignani
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D002908:Chronic Disease; D004789:Enzyme Activation; D005260:Female; D015967:Gene Expression Regulation, Viral; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000150:complications* / Q000276:immunology / Q000378:metabolism / Q000821:virology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008213:Lymphocyte Activation; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D008297:Male; D008875:Middle Aged; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000378:metabolism; D015398:Signal Transduction; D060225:Tetraspanin 28
chemical_list: D015703:Antigens, CD; C554798:CD81 protein, human; C515187:CXCR3 protein, human; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D060225:Tetraspanin 28; D048031:JNK Mitogen-Activated Protein Kinases