Species cross-reactivity of anti-LSP antibodies in acute viral hepatitis.

Previous reports have suggested that circulating antibodies reacting with species cross-reactive determinants in the liver-specific membrane lipoprotein (LSP) complex are rare in acute viral hepatitis (AVH) and that their high frequency in chronic active hepatitis (CAH) indicates a fundamental change in antigen specificity of anti-LSP autoantibodies associated with progression to chronic liver disease. In the present study, sera from 20 patients with uncomplicated AVH (10 with virus A and 10 with virus B infection) were examined by radioimmunoassay for antibodies reacting with human, rabbit and rat LSP. All 20 patients were found to be seropositive for antibodies against all 3 LSP preparations. Titres of anti-human and anti-rat LSP were significantly higher (p less than 0.001) than those of anti-rabbit LSP but a strong linear correlation (p less than 0.005) was found between titres of antibodies against the 3 LSP preparations. Cross-inhibition experiments with sera from 10 patients (5 with AVH-A and 5 with AVH-B) failed to reveal any major differences in antigen specificity between anti-rabbit and anti-rat LSP in 8 but results with the remaining 2 patients suggested that their anti-LSP antibodies were not reacting with the same antigens in the 2 LSP preparations. The results indicate that antibodies reacting with species cross-reactive LSP determinants are a normal occurrence in AVH and suggest that, if anti-LSP antibodies are involved in progression to (and/or development of) CAH, this is more likely to be related to a defect in the control of autoreactivity than to inherent differences in target antigen specificities of these autoantibodies in acute and chronic liver diseases, although the latter possibility cannot be totally excluded.

Anti-LSP antibodies in acute liver disease.

Sera from 71 patients with acute liver injury have been tested for antibodies to hepatocyte membrane lipoprotein complex (LSP) using a sensitive radioimmunoassay. Two main patterns of anti-LSP response were seen. In the first, seen in patients with type A and B viral hepatitis, anti-LSP antibodies were detectable at presentation, with the highest titres two to 10 days before the peak in serum aminotransferases and, in the hepatitis B patients, when viral DNA polymerase concentrations were still high, indicating active viral replication. These findings are consistent with the anti-LSP response being consequent on an interaction between T cells and neoantigens on the liver cell surface. A similar pattern was found in halothane hepatitis where immune responses to a halothane-altered liver membrane antigen are present early in the course of the disease. In the second type of response, exemplified by cases with paracetamol-induced hepatic necrosis, anti-LSP was only occasionally detectable at presentation, although present in very low titre later in the clinical course. This may be due to the release of altered antigen at the time of hepatocellular injury. The same pattern was found in a selected group of patients with uncomplicated acute alcoholic hepatitis, suggesting that in both these groups of patients the liver damage may have been due to a direct toxic effect on liver cells.

Autoimmunity to a liver membrane lipoprotein and liver damage in alcoholic liver disease.

Antibodies reacting with a liver membrane lipoprotein (LSP) have been detected by radioimmunoassay in the sera of 15 (27%) of 55 patients with alcohol-related liver lesions. There was a close association between the presence of the anti-LSP antibody and the findings on liver biopsy of a lymphocytic infiltrate in the portal tracts together with piecemeal necrosis of periportal hepatocytes. These histological features are characteristically found in the autoimmune disorder of chronic active hepatitis, in which anti-LSP antibodies are almost invariably present. It is suggested that in these cases of alcoholic liver disease there is loss of tolerance, and continued production of anti-LSP could promote periportal inflammation and accelerate the progression to cirrhosis. In the cases of acute alcoholic hepatitis without periportal inflammation studied, anti-LSP was not detected demonstrating that production of this autoantibody is not simply secondary to liver damage.

Antibodies to a human liver membrane lipoprotein (LSP) in primary biliary cirrhosis.

Antibodies reacting with a human liver-specific membrane lipoprotein (LSP) have been detected using a sensitive and specific radioimmunoassay in 19 (51%) of 37 patients with primary biliary cirrhosis. The anti-LSP antibodies were found only in the later stages of the disease as judged by histological criteria, being present in 73% of those in stage IV, 44% of those in stage III, and none of those in stage I or II. Although there was no relationship between percentage binding and standard liver function tests, there was a close correlation between percentage binding of 125I-LSP by serum and the extent of piecemeal necrosis of periportal hepatocytes on liver biopsy. The timing of the anti-LSP response makes it very unlikely that it is involved in the pathogenesis of the early bile duct damage but the results of this and other studies suggest that antibodies to this hepatocyte membrane lipoprotein may be an important cause of periportal liver cell necrosis in both primary biliary cirrhosis and chronic active hepatitis and could be one of the factors determining progression to cirrhosis in both these conditions.