[Direct immune response against hepatic antigens in patients with alpha-1-antitrypsin deficiency]

We have investigated the possible role of cell-mediated immunity in the pathogenesis of liver disease associated with alpha 1-antitrypsin (AAT) deficiency in 16 children with PiZZ phenotype, who presented with liver disease in infancy. Peripheral blood lymphocytes from 13 patients were incubated with autologous hepatocytes in a microcytotoxicity assay. There was a clear trend for cytotoxicity to increase with age and thus significantly increased cytotoxicity was found in four cases older than 2 years, while intermediate values were recorded in three children between 6 months and 2 years and normal values in children younger than 6 months. Fractionation of PBL into T and non-T-enriched subsets showed that both were involved in the cytotoxic reaction. A purified liver membrane lipoprotein preparation (LSP) inhibited both T and non-T-cell cytotoxicity suggesting that LSP is a major target antigen in this system. Sensitization to LSP was also present in 2 of the 3 children studied using a recently developed T-lymphocyte migration inhibitory factor (T-LIF) test. Control experiments performed in infants with neonatal hepatitis syndrome, but with normal Pi phenotype showed consistently increased cytotoxicity values. Cell-mediated immune reactions directed against autologous hepatocytes develop late in the course of the liver disease associated with AAT deficiency. While this reaction cannot be involved in the pathogenesis of the initial liver lesion, it may contribute to perpetuation of liver damage.