Activation of naïve B lymphocytes via CD81, a pathogenetic mechanism for hepatitis C virus-associated B lymphocyte disorders.
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.
Rosa
Domenico
D
Chiron Vaccines, 53100 Siena, Italy.
Saletti
Giulietta
G
De Gregorio
Ennio
E
Zorat
Francesca
F
Comar
Consuelo
C
D'Oro
Ugo
U
Nuti
Sandra
S
Houghton
Michael
M
Barnaba
Vincenzo
V
Pozzato
Gabriele
G
Abrignani
Sergio
S
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
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