Abstract
Mixed cryoglobulinemia is the most common extrahepatic disease manifestation of chronic hepatitis C virus (HCV) infection, where immunoglobulins precipitate at low temperatures and cause symptoms such as vasculitis, glomerulonephritis and arthralgia. HCV-associated cryoglobulinemia is also strongly linked with the development of B cell non-Hodgkin lymphoma. Abnormal B cell function in HCV infections can lead to the formation of HCV cryoglobulin complexes that usually comprise monoclonal rheumatoid factor and HCV-specific immune complexes. The aim of this study was to characterize the activation phenotype of B cells from patients with chronic HCV infection in comparison to healthy controls using flow cytometry. In addition, we determined how the activation status varies depending on the presence of cryoglobulinemia and advanced liver fibrosis. We found that only memory B cells, not naïve cells, were significantly activated in chronic HCV infection when compared with healthy controls. We also identified markers of memory B cell activation that were specific for HCV patients with cryoglobulinemia (CD86, CD71, HLA-DR) and advanced liver disease (CD86). Our results demonstrate that HCV infection has differential effects on B cells depending on the severity of hepatic and extrahepatic disease.
Highlights
170–200 million people around the world are infected with the hepatitis C virus (HCV). 70–80% of patients develop a chronic infection which can lead to liver fibrosis and cirrhosis and an increased risk for developing hepatocellular carcinoma (HCC) [1]
The specific goals of this study were to determine if B cells are activated in HCV patients compared to healthy controls, and whether activation was enhanced in patients with cryoglobulinemia or advanced liver disease
We found that patients with detectable cryoglobulins have elevated levels of memory B cell CD86, HLA-DR and CD71 compared to HCV patients without detectable cryoglobulins
Summary
170–200 million people around the world are infected with the hepatitis C virus (HCV). 70–80% of patients develop a chronic infection which can lead to liver fibrosis and cirrhosis and an increased risk for developing hepatocellular carcinoma (HCC) [1]. Extrahepatic manifestations occur in patients with chronic HCV infection including kidney and skin disease, with the most common extrahepatic manifestation being mixed cryoglobulinemia [2]. Type I cryoglobulins consist of monoclonal IgG or IgM antibodies and are not typically associated with HCV and are usually found in patients with lymphoid tumors. Type II cryoglobulins typically consist of monoclonal IgM with enriched rheumatoid factor activity and polyclonal IgG, whereas type III cryoglobulins differ in that all Igs are polyclonal. Both type II and type III are considered ‘mixed cryoglobulinemia’ and were initially discovered to be associated with HCV infection in 1991, shortly after the discovery of HCV in 1989 [4,5]. Patients with cryoglobulinemia have an increased incidence of liver cirrhosis with an odds ratio of 4.87 [6,11]
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