Culprits identified in Hep B liver damage

26 December 2001 10:30 GMT

by Julie Clayton, BioMedNet News

http://news.bmn.com/news/story?day=011227&story=1

                                         Injecting antibodies to two rogue chemokines implicated in the chronic disease phase of Hepatitis B infection, which follows the initial acute response, blocks much of the secondary inflammation in the liver, claim US immunologists.

The antibodies, aimed at the signaling molecules known as IP10 and Mig, reduced the severity of liver damage in mice by blocking the second wave of inflammation, according to unpublished data from Luca Guidotti associate professor of experimental pathology at the Scripps Institute for Research in La Jolla, California.

Hepatitis B virus (HBV) causes cytotoxic T lymphocytes (CTLs) to target infected hepatocytes, and this response was originally thought responsible for subsequent liver damage. However, the CTLs also release interferon-gamma (IFNg), a cytokine that triggers liver cells to release IP10 and Mig. And it now appears that these chemokines attract a whole array of lymphocytes that inadvertently destroy the liver.

"Eventually you can think of an in vivo therapeutic kind of approach where you boost whatever CTLs are left in the patient, and block recruitment of the bad guys", said Guidotti at a pre-Christmas meeting of the British Society for Immunology in Harrogate.

            About 350 million people worldwide are infected with HBV, and around one million victims die each year. The virus travels through the blood to the liver, then invades and replicates inside hepatocytes. Following an initial acute phase of disease, most patients continue to harbor the virus. Later chronic developments can eventually destroy the liver altogether, or cause cancer.

            Researchers originally postulated that CTLs caused most of the liver destruction as they targeted infected cells. But, five years ago, Guidotti and his colleagues began a series of new observations.

They transfected liver cells in mice and found that CTLs specific for

                       HBV kill only a small proportion of infected cells. The CTLs also

                       release soluble cytokines, particularly IFNg, which "cure" the

                       majority of other infected liver cells by triggering intracellular

                       signals that interfere with viral replication.

                       In this way, the immune system tries to control infection without

                       causing widescale destruction.

                       Then, two years ago, the team found in a chimp model of HBV

                       infection, that there was a time lag between clearing virus from the

                       blood and liver, and severe inflammation, or hepatitis. This was due

                       to a second influx of a mixture of white cells, including more CTLs,

                       CD4 "helper" T cells, dendritic cells, macrophages and neutrophils.

                       "For each antigen-specific cell there are between 1000 and 10,000

                       antigen-non-specific cells. Those cells, most likely, are causing

                       most of the damage," by releasing enzymes, free radicals and

                       blocking the circulation of oxygen and nutrients, according to

                       Guidotti.

                       Some hepatocytes remain infected, however, and continue

                       stimulating a chronic influx of CTLs.

                       Similar events are likely to be occurring in human HBV infection,

                       accepts Antonio Bertoletti, senior lecturer in the Institute of

                       Hepatology at University College London.

                       "If we look in the liver of patients that have very low inflammation,

                       the frequency of antigen-specific cells is quite high," he told

                       BioMedNet News. "If we look at the patients with very high

                       inflammation, the antigen-specific cells are very few, suggesting

                       that there is a high recruitment of non-antigen-specific cells."

                       Within an hour of the first CTLs arriving, the two chemokines are

                       "massively induced," said Guidotti, and injecting antibodies aimed

                       at them stops much of the permanent damage, he adds.

                       Picture caption and credit:

                       Transmission electron micrograph of hepatitis B virions. CDC/Dr.

                       Erskine Palmer.

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                       Overview of the pathogenesis, prophylaxis and therapeusis of viral hepatitis B, with focus on

                       reduction to practical applications [Review]

                       Maurice R. Hilleman

                       Vaccine, 2001, 19:15-16:1837 - 1848

                            Manuscript received 19 September 2000 Accepted 21 September 2000;

                            Abstract

                            Hepatitis B is the most important of several hepatitis viruses of man because of the

                            number of cases of the disease and the frequent occurrence of persistent infection

                            that may lead to cirrhosis and cancer of the liver. The pathology of hepatitis B

                            infection results mainly from the self-destructive cytotoxic T cell response of the

                            host. This may be modulated by soluble pre-core e antigen of the virus that induces

                            immune tolerance and by cytokines elaborated by cytotoxic T cells, which suppress

                            viral replication in the infected cell. Pathogenesis of the disease is markedly

                            influenced by viral mutations. Persistent hepatitis B virus infection may be controlled

                            in a minority of patients by passive -interferon therapy, and in a majority of

                            patients by the nucleoside lamivudine until resistance develops. The best means to

                            control the disease is by prevention through application of the highly effective

                            vaccine prepared using surface antigen of the virus. It is anticipated that the

                            gradually increasing application of the vaccine throughout the world may lead to

                            elimination of hepatitis B as an important medical problem. This paper is intended to

                            provide a cursory overview of the contemporary knowledge relating to pathogenesis,

                            prophylaxis and therapeusis of human hepatitis B.

                       X protein of hepatitis B virus modulates cytokine and growth factor related signal transduction

                       pathways during the course of viral infections and hepatocarcinogenesis [Survey]

                       Jingyu Diao, Robert Garces and Christopher D. Richardson

                       Cytokine and Growth Factor Reviews, 2001, 12:2-3:189 - 205

                            Abstract

                            Hepatitis B virus produces chronic infections of the liver leading to cirrhosis and

                            hepatocellular carcinoma. The X protein of hepatitis B virus (HBx) is a

                            multifunctional protein that can interact with p53 but can also influence a variety of

                            signal transduction pathways within the cell. In most instances this small viral

                            protein favors cell survival and probably initiates hepatocarcinogenesis. HBx

                            upregulates the activity of a number of transcription factors including NF-B, AP-1,

                            CREB, and TBP. However, the majority of HBx is localized to the cytoplasm where it

                            interacts with and stimulates protein kinases such as protein kinase C, Janus

                            kinase/STAT, IKK, PI-3-K, stress-activated protein kinase/Jun N-terminal kinase,

                            and protein kinase B/Akt. This small viral protein can localize to the mitochondrion.

                            HBx may act as an adaptor or kinase activator to influence signal transduction

                            pathways. This review will attempt to analyze the involvement of HBx in signal

                            transduction pathways during hepatitis B viral infections and hepatocellular carinoma

                            development.