Clonal CD27+ CD19+ B cell expansion through inhibition of FC gammaIIR in HCV(+) cryoglobulinemic patients.
Persistent HCV infection may be associated with extrahepatic manifestations such as type II mixed cryoglobulinemia (II-MC), a clonal B cell proliferative disorder. In persistent HCV infection without II-MC, an increase in serum immunoglobulins (Ig) is commonly observed. This increase is polyclonal and is determined primarily by increased levels of IgG which include both HCV-specific and nonspecific antibodies. Nonetheless, memory CD27(+) B cells do not accumulate. This paradoxical phenomenon depends on heightened sensitivity of memory B cells to BCR-independent noncognate T cell help, which speeds up their terminal differentiation into antibody-secreting cells and makes them more prone to apoptosis. In persistent HCV infection with II-MC, serum Ig elevation is also a general occurrence, and characteristically includes IgM antibodies with rheumatoid factor activity, which are essential for the development of circulating, cryoprecipitable immune complexes. Hypergammaglobulinemia is sustained by a peripheral expansion of IgM(+)k(+)IgD(low/neg)CD21(low)CD27(+) B cells. These cells exhibit marked V(H), J(H), and V(K) gene segment usage restriction, indicating that a limited number of antigens drive their proliferation through BCR interaction. Recently, two epitopes, one of the human IgG and the second of the HCV(NS3) protein, had been identified and demonstrated able to link the BCR exposed on II-MC subjects. Based on the above findings, we propose a model whereby BCR binding the IgM/IgG/HCV(NS3) immune complexes deprives Fc gammaIIR of its natural ligand. This takes the brake off RF(+)CD27(+) B cell proliferation and promotes their selective accumulation, which is otherwise prevented by increased apoptosis susceptibility in persistent HCV infection without II-MC.
De Re
Valli
V
Experimental and Clinical Pharmacology Unit, DOMERT, Molecular Oncology and Translational Research Department, Centro di Riferimento Oncologico, IRCCS, National Cancer Institute, Aviano (PN), Italy. vdere@cro.it
Pavan
Alessandro
A
Sansonno
Silvia
S
Sansonno
Domenico
D
Racanelli
Vito
V
D018941:Antigens, CD19 / Q000378:metabolism; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D002999:Clone Cells / Q000166:cytology / Q000378:metabolism; D003449:Cryoglobulinemia / Q000097:blood* / Q000150:complications; D006526:Hepatitis C / Q000150:complications*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018613:Microscopy, Confocal; D008954:Models, Biological; D017452:Receptors, IgG / Q000276:immunology / Q000378:metabolism*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism
D018941:Antigens, CD19; C080571:Fc gamma receptor IIB; D017452:Receptors, IgG; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7