Clonality and specificity of cryoglobulins associated with HCV: Pathophysiological implications

Mario U. Mondelli, Irene Zorzoli, Antonella Cerino, Agostino Cividini, Morena Bissolati, Laura Segagni, Vittorio Perfetti, Ernesto Anesi, Pietro Garini, Giampaolo Merlini

Research output: Contribution to journalArticle

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Abstract

Background/Aims: Hepatitis C virus (HCV) infection plays a central role in the pathogenesis of mixed cryoglobulinemia through molecular mechanisms which remain to be elucidated. The aim of this study was to investigate the role of antibody responses to HCV in the pathogenesis of cryoglobulinemia through characterization of the anti-HCV specificity and immunochemical characteristics of the immunoglobulins involved in cryoprecipitation. Methods: Sera from 50 consecutive patients with chronic HCV infection (RNA positive) were screened for the presence of cryoglobulins. The two major components of cryoprecipitates, IgM rheumatoid factors and IgG, were separated by high performance liquid chromatography and analyzed for immunochemical composition by immunoblotting and antibody specificity by ELISA and immunoblotting using recombinant HCV proteins and synthetic peptides as antigens. Results: Cryoprecipitates were observed in 27 patients and characterized by immunofixation: 13 (48%) were classified as type II and 14 (52%) as type III. Monoclonal immunoglobulins were detected by immunoblotting in 20 cryoprecipitates: IgM in 14 samples and IgG in 14, with a clear preponderance of IgG3 (12/14). Specificity studies on sera and purified IgM and IgG fractions from cryoprecipitates revealed enrichment in cryoglobulins, predominantly polyclonal IgG1, reactive with the HCV structural proteins, whereas specificities for nonstructural viral proteins were relatively less represented compared to whole serum. No restricted pattern of fine specificity was observed. IgG3 subclass was apparently not involved in HCV nucleoprotein binding. Conclusions: Our findings do not support a direct link between monoclonal cryoglobulins and immune response to HCV. According to the proposed pathogenetic model, HCV infection can induce the formation of cryoprecipitable rheumatoid factors, sustain their production, and eventually lead to monoclonal B-cell expansion through several cooperative mechanisms.

Original languageEnglish
Pages (from-to)879-886
Number of pages8
JournalJournal of Hepatology
Volume29
Issue number6
DOIs
Publication statusPublished - Dec 1998

Fingerprint

Cryoglobulins
Hepacivirus
Immunoglobulin G
Virus Diseases
Immunoblotting
Immunoglobulin M
Cryoglobulinemia
Rheumatoid Factor
Immunoglobulins
Viral Nonstructural Proteins
Serum
Viral Structural Proteins
Virus Attachment
Antibody Specificity
Chronic Hepatitis C
Antibody Formation
B-Lymphocytes
Enzyme-Linked Immunosorbent Assay
High Pressure Liquid Chromatography
RNA

Keywords

  • Clonality
  • Cryoglobulins
  • Hepatitis C virus
  • IgG subclasses
  • Immune response
  • Peptides

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Clonality and specificity of cryoglobulins associated with HCV : Pathophysiological implications. / Mondelli, Mario U.; Zorzoli, Irene; Cerino, Antonella; Cividini, Agostino; Bissolati, Morena; Segagni, Laura; Perfetti, Vittorio; Anesi, Ernesto; Garini, Pietro; Merlini, Giampaolo.

In: Journal of Hepatology, Vol. 29, No. 6, 12.1998, p. 879-886.

Research output: Contribution to journalArticle

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abstract = "Background/Aims: Hepatitis C virus (HCV) infection plays a central role in the pathogenesis of mixed cryoglobulinemia through molecular mechanisms which remain to be elucidated. The aim of this study was to investigate the role of antibody responses to HCV in the pathogenesis of cryoglobulinemia through characterization of the anti-HCV specificity and immunochemical characteristics of the immunoglobulins involved in cryoprecipitation. Methods: Sera from 50 consecutive patients with chronic HCV infection (RNA positive) were screened for the presence of cryoglobulins. The two major components of cryoprecipitates, IgM rheumatoid factors and IgG, were separated by high performance liquid chromatography and analyzed for immunochemical composition by immunoblotting and antibody specificity by ELISA and immunoblotting using recombinant HCV proteins and synthetic peptides as antigens. Results: Cryoprecipitates were observed in 27 patients and characterized by immunofixation: 13 (48{\%}) were classified as type II and 14 (52{\%}) as type III. Monoclonal immunoglobulins were detected by immunoblotting in 20 cryoprecipitates: IgM in 14 samples and IgG in 14, with a clear preponderance of IgG3 (12/14). Specificity studies on sera and purified IgM and IgG fractions from cryoprecipitates revealed enrichment in cryoglobulins, predominantly polyclonal IgG1, reactive with the HCV structural proteins, whereas specificities for nonstructural viral proteins were relatively less represented compared to whole serum. No restricted pattern of fine specificity was observed. IgG3 subclass was apparently not involved in HCV nucleoprotein binding. Conclusions: Our findings do not support a direct link between monoclonal cryoglobulins and immune response to HCV. According to the proposed pathogenetic model, HCV infection can induce the formation of cryoprecipitable rheumatoid factors, sustain their production, and eventually lead to monoclonal B-cell expansion through several cooperative mechanisms.",
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T1 - Clonality and specificity of cryoglobulins associated with HCV

T2 - Pathophysiological implications

AU - Mondelli, Mario U.

AU - Zorzoli, Irene

AU - Cerino, Antonella

AU - Cividini, Agostino

AU - Bissolati, Morena

AU - Segagni, Laura

AU - Perfetti, Vittorio

AU - Anesi, Ernesto

AU - Garini, Pietro

AU - Merlini, Giampaolo

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