Murine tissue distribution of an antigen recognized by an antibody against the hemochromatosis gene product, HFE, and the role of HFE in intestinal immunology and diabetes

Hereditary hemochromatosis (HH) is an autosomal recessive, primary iron overload disorder caused by mutation of the HLA-associated Hfe gene. Patients with HH constantly absorb iron from their diet, regardless of serum iron levels. Formalin-fixed paraffin-embedded tissue sections from multiple mouse organs were used to determine the tissue distribution of an antigen recognized by an anti-HFE antibody developed in the laboratory. The anti-HFE antibody recognizes an antigen expressed in epithelial cells of the gallbladder, digestive tract, kidney, and lung; and cells of hemopoietic origin, including B cells and macrophages but excluding red blood cells (RBC). Antigen expression is limited to cells that express MHC class II molecules, possibly because of posttranslational regulation of HFE.;To examine the role played by intraepithelial lymphocytes (IELs) in dietary iron absorption, hemochromatotic and normal mice were analyzed under various dietary iron conditions as well as after infection with S. ryphimurium . IELs respond either to HFE or intracellular iron levels of small intestine crypt epithelial cells. This response is manifested by changes in the ratio of IELs expressing an alphabeta T cell receptor (TCR) to IELs expressing a gammadelta TCR. Mutation of HFE may increase susceptibility to S. typhimurium infection when an underlying hematological abnormality is present. The mechanism of increased susceptibility may involve inappropriately increased gammadelta IEL levels. Increasing dietary iron concentrations leads to increased production of tumor necrosis factor (TNF) by small intestine IELs. The level of TNF production may affect iron deposition in villus epithelial cells. Mutation of HFE affects TNF production, thereby affecting iron deposition in villus cells. How HFE mutation affects TNF production varies between different genetic backgrounds. Removal of dietary iron for prolonged periods increases TNF production independent of HFE.;To examine whether HFE plays a direct role in induction of diabetes, or whether diabetes in HH patients is induced by high levels of iron, pancreas from normal and hemochromatotic mice of ten weeks of age were examined. Mutation of HFE does not play a direct role in induction of diabetes.