G. Hess

Hepatic expression patterns of the large and middle hepatitis B virus surface proteins in viremic and nonviremic chronic hepatitis B

The envelope of hepatitis B virus consists of large, middle, and small hepatitis B surface proteins. Recent data from in vitro studies suggest that intracellular expression and distribution of the three polypeptides may be variable. These observations in artificial expression systems prompted this analysis of the occurrence and distribution of the three hepatitis B surface proteins in the liver tissue of substantial viremic (hepatitis B virus DNA- and hepatitis B e antigen-positive) and low-viremic or nonviremic (hepatitis B virus DNA-negative, anti-hepatitis B e antigen-positive) carriers by specific monoclonal antibodies against large, middle, and small proteins. Patients with an active form of viral replication showed a prevalence of middle and small hepatitis B surface proteins in the liver. In nonviremic carriers, the large hepatitis B surface protein was the predominant intrahepatic antigen, a finding that was confirmed at the ultrastructural level by staining of the entire filaments of the viral envelope material in ground glass hepatocytes. The present data are thus consistent with observations in hepatitis B virus-transgenic mice and in transfected cell systems, suggesting that the different patterns of the envelope proteins in the liver may be due to different processing at the translational level.

Pre-S encoded surface proteins in relation to the major viral surface antigen in acute hepatitis B virus infection.

The role of pre-S encoded viral surface proteins in acute hepatitis B virus infection is still poorly understood. Binding sites for polymerized human serum albumin have been found to be encoded by the pre-s2 region of the hepatitis B virus genome. Recently, murine monoclonal antibodies against pre-s1 and pre-s2 encoded hepatitis B virus gene products were generated and used for their specific detection in serum. In sera from patients with acute hepatitis B, pre-s1 and pre-s2 antigen occurred in 16 of 20 and 15 of 20 patients, respectively. In the initial stage of the disease, pre-S gene products correlated with binding sites for polymerized human serum albumin, but not with hepatitis B surface antigen. Subsequently, pre-s1 and pre-s2 antigens were cleared from the serum of patients with acute hepatitis B before binding sites for polymerized human serum albumin and hepatitis B surface antigen. Possibly, the early clearance of pre-S markers can be of prognostic value in acute hepatitis B. The mechanisms of the early clearance of the pre-S antigens in acute hepatitis B remain to be elucidated. However, elimination by immunologic mechanisms appears likely.

Antiviral effect of prolonged intermittent lymphoblastoid alpha interferon treatment in chronic hepatitis B.

In a European multicentre study 40 patients with HBeAg positive chronic hepatitis B virus (HBV) infection were treated with 5 mega units of lymphoblastoid alpha-interferon daily according to the following regimen: a four week primer course, four weeks of rest and a second course lasting 16 to 30 weeks. After 52 weeks of follow up, a response (HBeAg seroconversion and HBV-DNA negativity) was observed in 22 patients (55%). HBsAg seroconversion occurred in five patients (12.5%). One patient exhibited a relapse for serum HBeAg and HBV-DNA after cessation of treatment. According to a response prediction model, the observed response rate was not related to the selection of patients likely to respond. The initial interferon course induced a reduction of the serum HBV-DNA and HBeAg levels of 87% and 18%, respectively, leading to a significantly lower level of viral replication activity at the start of the second longterm course compared with baseline. After 24 weeks of follow up (week 16 of the second course), 19 (48%) patients exhibited a response, 13 (32%) a partial response (HBeAg < 50% of initial level or HBV-DNA negative) and 8 (20%) no response. For eight of the 13 partial responders treatment was stopped at week 24 and viral replication rebounded to pretreatment values. In the last five partial responders prolongation of therapy up to week 38 led to a definite response and HBsAg seroconversion in three of the five patients. The results of this study suggest that a short primer course and prolongation of therapy may help to enhance the response rate of alpha-interferon therapy for chronic hepatitis type B.

In vivo and in vitro induction of natural killer cells by cloned human tumor necrosis factor

SummaryThe natural killer (NK) cell activity of mice in the peritoneal cavity is very low or undetectable and testing peritoneal NK cells is a useful model for studying the influence of activating substances upon local injection. Injection of tumor necrosis factor (TNF) at doses of 10–200 ng caused a marked activation of NK cell activity which was maximal after 24 h and declined rapidly on day 2. A similar effect was observed when interferons alpha and beta were injected, and there were additive results when interferon was injected together with TNF. The NK cell nature of the effector cells activated by TNF was substantiated by the finding that previous injection with anti-asialo GM 1 antibody prevented activation. Interferon could not be detected in the peritoneal wash fluid after injection of TNF suggesting interferon-independent activation. In further experiments after i.p. injection of TNF peritoneal exudate cells (PECs) only killed YAC-1 targets in a 4-h assay. There was no additional killing in an 18-h assay towards neither YAC-1 cells or P815 cells, suggesting that macrophages were not involved. Furthermore TNF was also active in vitro by activating NK cells in isolated human peripheral blood cells. However in the PECs stimulated in vitro no significant induction of cytotoxic capacities by TNF was measured. Our data suggest that the action of TNF is not restricted to the lysis of tumor cells but can also induce immunological properties in the host defense against virus infections and neoplasms.

Intravenous luteinizing hormone-releasing hormone has no effect on serum N-terminal pro-brain natriuretic peptide in children and adolescents

Background:  Little is known about the acute effects of i.v. luteinizing hormone‐releasing hormone (LHRH) on the heart function, therefore the aim of the present study was to measure N‐terminal pro‐brain natriuretic peptide (N‐BNP) in children, who underwent a diagnostic work up for short stature or delayed puberty.

Kooperative prospektive Studie „Akute Virushepatitis“ (DFG)

Motiv fur die 1972 begonnene prospektive DFG-Studie „Akute Virushepatitis“ war ursprunglich die Abklarung der diagnostischen und prognostischen Bedeutung des ersten HBV-Markers, des Australia-Antigen (= HBsAg). Insbesondere sollte die Spatprognose von HBsAg-positiver und-negativer Hepatitis verglichen werden. 1976 konnte ich an gleicher Stelle in einem ersten Zwischenbericht [1] mitteilen, das sich ein Jahr nach akuter HBsAg-positiver Virushepatitis mit 8,5% ebenso haufig gesicherte chronische Verlaufe fanden wie nach HBsAg-negativer Hepatitis (8,6%). Bereits damals wurde vermutet und heute ist erwiesen, das sich die HBsAg-negative Gruppe aus A-, Non-A, Non-B- und einem kleinen Anteil von HBsAg-negativen B-Hepatitiden zusammensetzt. Aufgrund der Planung der Studie mit Anlage einer Serumbank und der weiteren Entwicklung der Virusserologie mit der Moglichkeit zur Differenzierung von Hepatitis A und — vorerst per exclusionem — Non-A, Non-B sind heute Aussagen zu erweiterten Fragestellungen moglich: 1. Abgrenzung von Virushepatitiden unterschiedlicher atiologie: A; B; Non-A, Non-B. 2. Haufigkeit der Entwicklung einer chronischen Hepatitis in Abhangigkeit von der atiologie. 3. Die Bedeutung virusserologischer Parameter der Hepatitis B fur die fruhe Prognosestellung. 4. Besonderheiten des Krankheitsverlaufes bei akuter Virus-Hepatitis unterschiedlicher Atiologie.

Prospektive kooperative Studie „Klinisch gesunde HBsAg-Träger“ (DFG)

Motiv fur die 1972 begonnene kooperative DFG-Studie „Klinisch gesunde HBsAg-Trager“ war die damals ganz ungewisse Prognose dieses Personenkreises, die in Korrelation zu virusserologischen Parametern durch eine prospektive Verlaufsbeobachtung untersucht werden sollte.

Vergleich von Serummarkern zum quantitativen Nachweis von Dane-Partikeln

Das Dane-Partikel besteht aus einem spharischen 27-nm-Hepatitis B-core-Antigen (HBcAg) und einer HBsAg-Hulle und stellt nur einen geringen Anteil aller im Serum zirkulierender HBsAg-Partikel dar [1]. Eine Subpopulation von Dane-Partikeln enthalt eine zirkulare doppelstrangige DNS mit einstrangigen Abschnitten und eine DNS-Polymerase, diese Dane-Partikelsubpopulation wird als das komplette Hepatitis B-Virus angesehen [2]. In der DNS-Polymerasereaktion werden die einstrangigen DNS-Abschnitte durch die endogene DNS-Polymerase komplettiert [2]. Die vorliegende Arbeit vergleicht die Hohe der DNS-Polymera- seaktivitat mit dem quantitativen Nachweis von HBeAg (Hepatitis B-e-Antigen), HBsAg und anti-HBc und beschreibt deren Bedeutung als Dane-Partikelmar- ker.

Untersuchungen zur Ätiologie der HBsAg-negativen chronischen Hepatitis

Wahrend die Atiologie der Hepatitis-B-surface-Antigen (HBsAg)-positiven chronischen Hepatitis heute weitgehend geklart erscheint, ist die Atiologie der HBsAg-negativen chronischen Hepatitis noch unklar. Durch die Beschreibung eines Lebermembranautoantikorpers (LMA) kann innerhalb der Gruppe der HBsAg-negativen chronischen Hepatitiden eine autoimmune Form der chronischen Hepatitis abgetrennt werden. Neben Medikamenten kommen das Hepatitis-B-Virus (HBV), das Hepatitis-A-Virus (HAV) und die Erreger der Non-A/non-B-Virushepatitis atiologisch fur die Entwicklung der HBsAg-negativen chronischen Hepatitis in Frage. In der vorliegenden Arbeit wurden bei 37 Patienten mit HbsAg-negativer chronischer Hepatitis Autoimmunphanomene und HBV und HAV-Marker bestimmt.

Gleichzeitiges Vorkommen von Hepatitis-B-surface-Antigen (HBsAg) und Antikörper gegen HBsAg (Anti-HBs) verschiedenen Subtyps im Serum. (Serologische und fluoreszenzhistologische Untersuchungen)

Uber das gleichzeitige Vorkommen von HBsAg und Anti-HBs im Serum liegen bisher keine Untersuchungen vor. Wir berichten uber 10 Patienten, bei denen gleichzeitig HBsAg und Anti-HBs im Serum nachgewiesen werden konnte. Bei 4 Patienten wurde eine Leberpunktion mit fluoreszenzhistologischer Untersuchung des Biopsiematerials durchgefuhrt.