Suspected and unsuspected factors in the multifaceted immunopathology of viral hepatitis

Abstract

In the past decade, our knowledge of the mechanisms producing disease during acute and chronic infections with hepatitis B (HBV) and C (HCV) viruses has solidified the fact that the immune response induced by these viruses plays dominant roles. It is becoming increasingly clear that HBV and HCV can subvert the host immune system to survive, and the viral persistence can also induce autoimmune manifestations that complicate the clinical setting and may contraindicate therapies that indiscriminately augment immune effector mechanisms [1]. The liver is considered as an “immunological organ”, with innate immune functions and cells [2] that aid in the recognition of HBV and HCV antigens, leading to the production of type I interferons (I-IFN) and inflammatory cytokines that inhibit the viral replication [3]. This is potentially beneficial in clearing viral infections, but may also initiate liver fibrosis, increasing the risk of cirrhosis and the subsequent risk of hepatocellular carcinoma (HCC) [4]. In the case of HBV, chronic liver disease afflicts approximately 300– 400 million people worldwide, despite the availability of a safe and effective vaccine [5]. HCV infects up to 170 million persons worldwide and the development of cirrhosis is associated with an annual incidence of HCC of 3–5 % [6, 7]. Currently, HCV infection, resulting in cirrhosis and/or HCC, is the leading indication for orthotopic liver transplantation in developed countries [6, 7]. To provide a comprehensive view of the newest information regarding HBV and HCV infections, the articles presented in this special issue of Seminars in Immunopathology focus on the most controversial immunopathological aspects associated with both infections. These articles provide new evidence of the link between the immune response and virus survival within hepatocytes, elucidate occult infections and the risk of recurrent hepatitis in liver transplanted patients, and describe the autoimmunity associated with chronic HBV and HCV infections. The contributions to this special issue prove a deeper understanding of the mechanisms by which hepatitis and its complications are caused by the viruses themselves as well as by inflammation and immunological mechanisms that culminate in chronic liver damage. For pragmatic purposes, we have arbitrarily subdivided the themes discussed in this issue between suspected and unsuspected factors involved in the pathogenesis (Table 1). One limitation in the study of HBVand HCV infections is the lack of understanding in the replication strategies used by these viruses to persist in infected liver cells. Dandri et al. describe the most recent experimental models developed for the study of HBV, that are surrogates because HBV infection occurs naturally only in human beings and chimpanzee, which limits potential studies due to obvious practical and ethical problems. These numerous in vitro systems and animal models (i.e. murine, duck, woodchuck and tree shrew) have provided a better insight into the progress of HBV infection, and have been helpful in understanding the immunopathogenesis and testing of new therapeutic strategies. It is important to highlight the role of the innate immune system in response to viral hepatitis, and in fact This article is a contribution to the special issue on Immunopathology of Viral Hepatitis _ Guest Editors: C. Selmi and J. M. Vierling C. Selmi :A. Ceribelli Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center, Milan, Italy