CHOLANGIOPATHY AND TUMORS OF THE PANCREAS, LIVER, AND BILIARY TREE INBOYS WITH X-LINKED IMMUNODEFICIENCY WITH HYPER-IGM

We report an association between X-linked immunodeficiency with hyper- IgM (XHIM) and carcinomas affecting the liver, pancreas, biliary free, and associated neuroedodermal endocrine cells. The tumors were fatal in eight of nine cases and in most instances were preceded by chronic cholangiopathy and/or cirrhosis. An additional group of subjects with XHIM had chronic inflammation of the liver or bile ducts but no malign ancy. Many patients with XHIM were infected with cryptosporidia. CD40 is normally expressed on regenerating or inflammed bile duct epthelium . A CD40(+) hepatocellular carcinoma cell line, HepG2, susceptible to cryptosporidia and CMV infection became resistant when cell surface CD 40 was cross-linked by a CD40 ligand fusion protein. Apoptosis was tri ggered in HepG2 cells if protein synthesis was blocked by cycloheximid e or a the cells were infected by cryptosporidia. Ligation of CD40 on biliary epithelium may contribute to defense against infection by intr acellular pathogens. We propose that the CD40 ligand mutations that ca use XHIM deprive the biliary epithelium of one line of defense against intracellular pathogens and that malignant transformation in the bili ary free follows chronic infection or inflammation. The resulting tumo rs may then progress without check by an effective immune response, Pa tients with XHIM who have abnormal liver function tests should be cons idered at increased risk for cholangiopathy or malignancy.