Immune signatures in human PBMCs of idiotypic vaccine for HCV-related lymphoproliferative disorders
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RESEARCH
Open Access
Immune signatures in human PBMCs of idiotypic vaccine for HCV-related lymphoproliferative disorders Luigi Buonaguro1,9, Annacarmen Petrizzo1, Marialina Tornesello1, Maria Napolitano2, Debora Martorelli3, Giuseppe Castello2, Gerardo Beneduce4, Amalia De Renzo5, Oreste Perrella6, Luca Romagnoli7, Vitor Sousa7, Valli De Re8, Riccardo Dolcetti3, Franco M Buonaguro1*
Abstract Hepatitis C virus (HCV) is one of the major risk factors for chronic hepatitis, which may progress to cirrhosis and hepatocellular carcinoma, as well as for type II mixed cryoglobulinemia (MC), which may further evolve into an overt B-cell non-Hodgkin’s lymphoma (NHL). It has been previously shown that B-cell receptor (BCR) repertoire, expressed by clonal B-cells involved in type II MC as well as in HCV-associated NHL, is constrained to a limited number of variable heavy (VH)- and light (VL)chain genes. Among these, the VK3-20 light chain idiotype has been selected as a possible target for passive as well as active immunization strategy. In the present study, we describe the results of a multiparametric analysis of the innate and early adaptive immune response after ex vivo stimulation of human immune cells with the VK3-20 protein. This objective has been pursued by implementing high-throughput technologies such as multiparameter flow cytometry and multiplex analysis of cytokines and chemokines. Introduction Hepatitis C virus (HCV) is a Hepacivirus of the Flaviviridae family, mainly involved in hepatic disorders, including chronic hepatitis which may progress to cirrhosis in about 10-20% of cases and further to hepatocellular carcinoma in 1-5% of cirrhotic patients [1]. Subsequently, the virus has been implicated as one of the major risk factors for type II mixed cryoglobulinemia (MC), an autoimmune disease that may evolve into an overt B-cell non-Hodgkin’s lymphoma (NHL) in about 10% of MC patients [2-5]. Several studies have contributed to establish the causative role of HCV infection in the etiopathogenesis of MC, showing the presence of the viral RNA and/or anti-HCV antibodies in a range of 70 to 100% of MC [6-8]. Furthermore, the clinical evolution of MC is closely linked to the natural history of the underlying HCV chronic infection [9,10].
* Correspondence: [email protected] 1 Lab. of Molecular Biology and Viral Oncogenesis & AIDS Reference Center, Istituto Nazionale Tumori “Fond. G. Pascale”, Naples, Italy
The most accredited pathogenetic mechanism of MC during HCV chronic infection is the persistent immune stimulation sustained by viral proteins which, in turn, may result in production of cross-reactive autoantibodies, including cryoglobulins [11,12]. Chronic stimulation of the B-cell by HCV epitopes may produce the expansion of B-cell subpopulations with dominant genetic characteristics. In particular, the interaction between HCV E2 protein and CD81 molecule, an almost ubiquitous tetraspannin present on B-cell surface, has been shown and it may lead to a strong and sustained polyclonal stimulation of B-cell compa
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