Virus-driven autoimmunity and lymphoproliferation: the example of HCV infection

Abstract

HCV chronic infection is characterized by possible development of both hepatic and extrahepatic manifestations. The infection by this both hepatotropic and lymphotropic virus is responsible for polyoligoclonal B-lymphocyte expansion, leading to several immune-mediated disorders. Mixed cryoglobulinemia syndrome that in some cases may evolve to frank B-cell non-Hodgkin’s lymphoma is the prototype of HCV-driven autoimmune and lymphoproliferative disorders. The HCV oncogenic potential has been suggested by several clinicoepidemiological and laboratory studies; it includes hepatocellular carcinoma, B-cell non-Hodgkin’s lymphoma and papillary thyroid cancer. The definition HCV syndrome refers to the complex of HCV-driven diseases; these latter are characterized by heterogeneous geographical distribution, suggesting a role of other important genetic and/or environmental cofactors. The natural history of HCV syndrome is the result of a multifactorial and multistep pathogenetic process, which may evolve from mild manifestations to systemic autoimmune disorders, and less frequently to malignant neoplasias. The present updated review analyzes the clinical and pathogenetic aspects of the main HCV-associated diseases.

Keywords:

• autoimmunity
• B-cell NHL
• cancer
• cryoglobulinemia
• cryoglobulinemic vasculitis
• diabetes
• hepatitis C virus
• lymphoma
• mixed cryoglobulinemia
• thyroid

Financial & competing interests disclosure

L Gragnani is supported by a 2014 fellowship ‘Fondazione Umberto Veronesi.’ The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• The complex of HCV-associated disorders, the HCV syndrome, represents a good model of virus-driven autoimmunity and lymphoproliferation in humans.

• The pathogenetic role of HCV infection is clearly defined for some extrahepatic conditions such mixed cryoglobulinemia syndrome and B-cell non-Hodgkin’s lymphomas.

• In addition, epidemiological studies showed that the strength of association between HCV infection and different diseases largely varies among patient populations from different countries.

• Clinical and laboratory studies suggested that the HCV-driven autoimmune and lymphoproliferative disorders are the consequence of a multifactorial and multistep pathogenetic process.

• It is possible to hypothesize that HCV per se is not sufficient to trigger/maintain the immune system alterations observed in HCV-infected individuals; other genetic-epigenetic and/or environmental cofactors might be involved to different extents in the pathogenesis of HCV-associated conditions.

• The treatment of HCV-driven extrahepatic diseases should take into account the coexistence in the same individual of contrasting biological disorders, namely, viral infection and autoimmune and neoplastic alterations.

• Mixed cryoglobulinemia represents the prototype of this complex condition that can be treated at three different levels: HCV eradication with antiviral drugs, pathogenetic therapies by means of immunomodulating drugs (mainly anti-CD20 monoclonal antibodies) and symptomatic/pathogenetic treatments (steroids, plasma-exchange, etc.).

• At present, only the viral eradication seems to be able to persistently improve or cure mixed cryoglobulinemia syndrome in a consistent percentage of patients.

Notes

^†HCV is the etiological agent or it is detectable in the majority of patients.

^‡HCV is detectable in a significant proportion of patients compared to the general population, its potential role is supported by pathogenetic studies.

^§A role of HCV infection has been suggested by cohort studies.

^¶A role of HCV infection has been suggested by some anecdotal observations.