ALY ALY MICE - A UNIQUE MODEL OF BILIARY DISEASE/

An autosomal recessive murine mutation, coined ''aly/aly'' or ''alymph oplasia,'' was recently reported. Homozygotes for aly are defective in both humoral and cell-mediated immune function and have diffuse lymph oid cell infiltration of various tissues, particularly around the cond uit ducts of the pancreas and salivary glands. In pilot studies in our laboratories, aly/aly mice were found to have peculiar biliary tract lesions, which were analyzed histologically and immunohistochemically in the present study. The livers of aly/aly mice older than 8 weeks co nsistently showed a variable lymphoid cell infiltration with lymph fol licle formation in portal tracts; intrahepatic biliary epithelial cell s showed various types of damage including pseudopyloric gland metapla sia and proliferative changes. In addition, the extrahepatic bile duct and intrahepatic large bile duct were found to contain an acidophilic substance in their epithelial cytoplasm, In the lumen and occasionall y in the cytoplasm of these bile ducts, acidophilic crystals were also seen. Ultrastructurally, the intracytoplasmic acidophilic substances consisted of membrane-bound intracytoplasmic inclusions with homogeneo us electron density, likely derived from rough endoplasmic reticulum ( ER). Immunohistochemically, the cytoplasmic acidophilic substances wer e simultaneously positive for cystatin C, gastrin, serotonin, and soma tostatin. In contrast, the acidophilic crystals did not react with any of these antibodies, These findings suggest that the intracytoplasmic acidophilic substances may contain a precursor of the peptide hormone s, possibly because of defective secretion or intracellular transport. We believe that the aly/aly mouse is a useful model for the analysis of biliary metabolic events, and for studies of the interaction of the immune system and biliary destruction.