We present a strategy to characterize specific antigen/autoantibody systems using polyclonal sera from patients as a probe and crude antigenic preparations such as mitoplasts. Sera from patients with primary biliary cirrhosis (PBC) are characterized by at least one of two specific subtypes of antimitochondrial antibodies (AMA), anti-p48 or anti-p62. Immunoblotting of such sera with mitoplast preparations derived from human, rat and rabbit livers revealed three proteins of approximately 27, 48 and 68 kDa as target antigens. On the basis of the molecular weight of these antigens we were able to purify them by elution from preparative SDS gels. Immunization of NZB mice with the high molecular weight component (the 68 kDa antigen from human liver mitoplasts) elicited a monoclonal antibody. The 68 kDa protein was then isolated by affinity chromatography and may well represent the prime target antigen of anti-p62 antimitochondrial antibodies. This experimental approach could be applied to protein target antigens of other autoantibodies.

Animals↗

PubMed1988

[Effect of various roentgen contrast media on pancreatic and liver enzymes in ERCP].

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Adult↗

PubMed1988

Reactivation of chronic type B hepatitis: the effect on expression of serum HBV-DNA and pre-S encoded proteins.

Hepatitis B markers were studied in seven patients with reactivated liver disease. Reactivation of chronic type B hepatitis, as indicated by the reappearance of hepatitis B e antigen (HBeAg) in the serum, was characterised by the appearance of hepatitis B virus-DNA (HBV-DNA) in the serum. The expression of pre-S 1 encoded protein remained unchanged in five of seven patients, and poly-HSA as a marker for pre-S 2 encoded protein remained detectable in six of seven patients before and after reactivation of chronic hepatitis. The level of serum HBV-DNA correlated well with the level of liver enzymes, which rose from normal to various levels after reactivation of the liver disease. The data suggest that inflammatory activity of the liver disease is not related to the expression of pre-S encoded protein but to viral replication. Possibly pre-C and C-gene encoded antigens, which are produced together with viral nucleic acid and expressed on the surface of HBV-infected liver cells, play the key role in liver damage believed to be mediated by cytotoxic T cells.

Adolescent↗

PubMed1988

Immunochemical characterization of anti-acetylcholine receptor antibodies in primary biliary cirrhosis.

Although the presence of anti-mitochondrial antibodies is the main characteristic of primary biliary cirrhosis (PBC), other autoantibodies have been described in this disease. This study employs immunoblot methods to test whether the sera of PBC patients also contain antibodies directed against nicotinic acetylcholine receptors (AChR). We show that the majority of patients' sera indeed react with AChR just as sera of myasthenic patients do. In contrast, however, these anti-AChR antibodies do not lead to significant clinical symptoms of myasthenia. In all cases studied, PBC sera recognized a protein with the molecular weight of the alpha-chain of acetylcholine receptor (40 kDa). In addition, with both liver mitochondria and AChR-rich membranes as antigens, PBC sera reacted with proteins with apparent molecular weights around 68 kDa and the same pI values. This protein is not present in purified AChR preparations. These data suggest structural, if not functional, relationships between membrane components of liver mitochondria and muscle endplates.

Autoantibodies↗

PubMed1988

IgG subclass distribution of autoantibodies to glomerular basement membrane in Goodpasture's syndrome compared to other autoantibodies.

The IgG subclass distribution of autoantibodies to glomerular basement membrane (anti-GBM antibodies) was investigated and compared to the distribution of liver-kidney microsomal (LKM) autoantibodies in chronic active hepatitis, to antimitochondrial autoantibodies (AMA) in primary biliary cirrhosis, and to the subclass distribution of total serum IgG within a healthy population. Solid phase assays for the demonstration of these autoantibodies were performed with four mouse monoclonal antibodies specific for each human subclass to provide quantitative data for the autoantibodies. In addition, the subclass distribution of total IgG in these sera was analyzed. IgG1 accounted for 75% of the total antibody activity in anti-GBM antibodies. In LKM antibodies a more homogeneous distribution was observed between the different subclasses with a relative high proportion of IgG4 autoantibodies (21.2%). In AMA a high proportion of IgG3 subclass autoantibodies was found (anti-p-48 = 28.7%, anti-p-62 = 29.9%). In these patients a high proportion of IgG3 (23 vs. 27.2%) could also be demonstrated in the subclass distribution of total IgG, whereas in patients with anti-GBM antibodies and LKM antibodies the subclass distribution of total IgG was comparable to a population of healthy volunteers. We conclude that the subclass distribution in anti-GBM antibodies differs from the distribution in other autoimmune diseases and from a healthy population and that these differences may be of pathogenetic relevance.

Anti-Glomerular Basement Membrane Disease↗

PubMed1988

Expression of Pre-S-encoded proteins in sera of individuals chronically infected with hepatitis D virus.

The sera of 16 individuals chronically infected with the hepatitis D virus were analyzed for hepatitis B virus (HBV) markers. The majority of these patients had a non-replicative form of viral type B hepatitis as indicated by negative tests for HBeAg and HBV-DNA. Pre-S-encoded proteins were detected in 13/16 sera. Sera that were negative for polymerized serum albumin did also not contain pre-S1-encoded proteins. The presence of pre-S-encoded proteins is probably predominantly associated with 22-nm HBsAg forms present in large amounts in sera of individuals with chronic type D hepatitis.

Chronic Disease↗

PubMed1988

[Detection of pre-S gene products in HBsAg carriers and in hepatitis B vaccines].

The immunogenicity and efficacy of different commercially available vaccines against hepatitis B virus (HBV) has been demonstrated in a number of controlled vaccination trials throughout the world. However, the significance of pre-S proteins in hepatitis B vaccines is still controversially discussed. Therefore, a radioimmunoassay (RIA) was developed to detect pre-S proteins in HBsAg-carriers as well as in different hepatitis B vaccines. This study confirmed the high amount of pre-S proteins as well as poly-albumin receptors in purified Dane particles and sera of patients with acute hepatitis B. The currently available plasma derived vaccine H-B-Vax and the recombinant hepatitis B vaccines Gen H-B-Vax and Engerix B yielded negative results in pre-S- and poly-albumin-receptor-RIAs. The plasma derived vaccine Hevac B Pasteur included pre-S encoded proteins. Future vaccination trials in man have to evaluate the role of pre-S antigens and antibodies in the pathogenesis and the protection of hepatitis B infection including recombinant pre-S vaccines which are under development.

Carrier State↗

PubMed1988

[ERCP: which contrast medium is suitable?].

To evaluate, wether a new non-ionic contrast medium decreases the complication rate of endoscopic retrograde cholangiopancreaticography (ERCP), we performed a prospective randomized study in 46 indoor patients with suspected pancreatic or bile duct related disease. The low-osmolar low-viscosity non-ionic Iopromid (Ultravist, n = 15), the low-viscosity high-osmolar Ioglicinate (Rayvist, n = 18), and the conventional dissociable high-viscosity Ioxaglinate (Heaxbrix, n = 13), each presenting a iodine content of 300-320 mg/ml were compared. All three contrast solutions gave excellent imaging of pancreatic and bile ducts. No complications, particularly no pancreatitis were observed. Hexabrix caused significant elevations of gamma-GT from 126 U/l to 178 U/l and mof lipase from 144 U/l to 418 U/l (p less than 0.01), respectively. Following Rayvist or Ultravist injections, no significant changes of the leucocytes, SGOT, SGPT, gamma-GT, AP, lipase and amylase were observed. We conclude that ERCP performed by skilled investigators is a low risk procedure. Selection of suitable contrast media may diminish hepatotoxic and pancreatotoxic side effects. According to our results, we recommend low-viscosity contrast media (Rayvist, Ultravist). The presumed benefit of the non-ionic solution (Ultravist) could not be demonstrated.

Adult↗

PubMed1988

[The diagnostic value of immunologic findings in the differentiation of chronic liver diseases].

Various types of virus induced and non-virus induced chronic active hepatitis (CAH) as well as chronic non-suppurative destructive cholangitis (PBC) and primary sclerosing cholangitis have to be distinguished. Classical autoimmune type "lupoid" CAH is characterized by antinuclear antibodies (ANA), liver membrane antibodies (LMA) and smooth muscle antibodies (SMA). A second subgroup of autoimmune type CAH is characterized by anti liver kidney-microsomal antibodies (LKM) which are directed against a specific cytochrome p-450 isoenzyme. A third subgroup of autoimmune type CAH is identified by auto-antibodies to a soluble cytoplasmic liver antigen (SLA). Autoimmune type CAH profits from immuno-suppressive therapy, i.e. corticosteroids alone or in combination with azathioprin. Chronic hepatitis B virus infection is nowadays treated with Interferon when HBV-DNA is detectable in serum, duration of liver disease is less than 5 years and superinfection with HDV and HIV can be excluded. PBC is diagnosed through the detection of antimitochondrial antibodies (AMA) and its PBC specific subtypes anti p 62 (M2) and anti p 48. Aetiology and pathogenesis of PBC are still unknown. Liver transplantation is an established therapy for endstage PBC. This is also true for primary sclerosing cholangitis (PSC).

Antigens, Viral↗

PubMed1988

Does the immune response play a role in the pathogenesis of chronic liver disease?

The pathogenesis and perpetuation of hepatocellular injury in chronic inflammatory liver disease is still unclear. Several pieces of circumstantial evidence point to the importance of antigen-specific immune responses. In chronic hepatitis B virus infection, the hepatitis B virus nucleoprotein appears to be a major target antigen for both helper and cytotoxic T lymphocytes. In autoimmune chronic active hepatitis, several autoantibodies have been identified that are associated with different disease subgroups and that may be helpful to distinguish this form of chronic active hepatitis from that caused by non-A, non-B agents. In primary biliary cirrhosis, antimitochondrial antibodies are almost invariably present and have now been characterized at the molecular level.

Antibody Formation↗

PubMed1987

[Heterogeneity of autoimmune chronic active hepatitis. Differentiation of SLA-autoantibody positive chronic active hepatitis].

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Autoantibodies↗

PubMed1987

Characterisation of a new subgroup of autoimmune chronic active hepatitis by autoantibodies against a soluble liver antigen.

Autoantibodies against a soluble liver antigen (SLA) were detected in 23 patients with HBsAg-negative chronic active hepatitis (CAH) but not in 502 patients with various other hepatic and non-hepatic disorders or 165 healthy blood donors. Anti-SLA-positive serum samples were negative for antinuclear and liver-kidney-microsomal antibodies, markers of two subgroups of autoimmune-type CAH, 6 anti-SLA-positive patients were negative for all autoantibodies sought. Most of the anti-SLA-positive patients were young women (2 men, 21 women; mean age 37 years) with hypergammaglobulinaemia (mean 3.2 g/l, range 1.8-5.3 g/l); 18 of the 23 patients had received immunosuppressive treatment and all responded well. Anti-SLA titres declined during therapy, corresponding to disease activity. Anti-SLA cannot be detected by immunofluorescence. SLA is not organ-specific or species-specific, but the highest concentrations were found in liver and kidney. Anti-SLA autoantibodies characterise a third subgroup of autoimmune-type CAH and will allow a better differentiation of HBsAg-negative CAH which has therapeutic consequences.

Adolescent↗