HCV-NS3 and IgG-Fc crossreactive IgM in patients with type II mixed cryoglobulinemia and B-cell clonal proliferations.
We demonstrate that in three cases of MC (two with immunocytoma), the IgM-RF+ component of their cryoprecipitated represents the circulating counterpart of the B-cell receptor (BCR) of the monoclonal overexpanded B-cell population. These IgMs were isolated and used to demonstrate a crossreactivity against both hepatitis C virus (HCV) NS3 antigen and the Fc portion of IgG. Epitopes were identified in a fraction of exemplary samples by using epitope excision approach (NS(31250-1334) and IgG Fc(345-355)). The same phenomenon of crossreactivity has been shown to occur in vivo after immunization of a mouse with the NS3(1251-1270) peptide. To verify if the same reaction was also present in MC samples characterized by an oligo/polyclonal B-cell proliferation, IgM crossreactivity was tested in 14 additional samples. Five out of the 14 were reactive against HCV NS3 and 11 out of 14 were reactive against IgG-Fc peptide. The data support the role of HCV NS3 antigen in a subset of patients with MC, whereas the high frequency of the IgG-Fc epitope suggests that these B cells originate from precursors strongly selected for auto-IgG specificity. We suggest that engagement of specific BCRs by NS3 (or NS3-immunocomplex) antigen could explain the prevalence of IgM cryoglobulins in these patients.
De Re
V
V
Division of Experimental Oncology I, Centro di Riferimento Oncologico, IRCCS-National Cancer Institute, Aviano, Pordenone, Italy. vdere@cro.it
Sansonno
D
D
Simula
M P
MP
Caggiari
L
L
Gasparotto
D
D
Fabris
M
M
Tucci
F A
FA
Racanelli
V
V
Talamini
R
R
Campagnolo
M
M
Geremia
S
S
Dammacco
F
F
De Vita
S
S
D002999:Clone Cells; D003449:Cryoglobulinemia / Q000145:classification* / Q000175:diagnosis / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000276:immunology*; D007075:Immunoglobulin M / Q000187:drug effects / Q000276:immunology*; D016393:Lymphoma, B-Cell / Q000276:immunology*; D008958:Models, Molecular; D010446:Peptide Fragments / Q000276:immunology; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D012217:Rheumatoid Factor / Q000187:drug effects / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000276:immunology* / Q000494:pharmacology; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000939:Epitopes; D007141:Immunoglobulin Fc Fragments; D007075:Immunoglobulin M; D010446:Peptide Fragments; D011947:Receptors, Antigen, B-Cell; D012217:Rheumatoid Factor; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases