Experimental hemochromatosis due to MHC class IHFE deficiency: Immune status and iron metabolism

The puzzling linkage between genetic hemochromatosis and histocompatibility loci became even more so when the gene involved, HFE, was identified. Inde ed, within the well defined, mainly peptide-binding, MHC class I family of molecules, HFE seems to perform an unusual yet essential function. As yet, our understanding of HFE function in iron homeostasis is only partial; an e ven more open question is its possible role in the immune system. To advanc e on both of these avenues, we report the deletion of HFE alpha 1 and alpha 2 putative ligand binding domains in vivo. HFE-deficient animals were anal yzed for a comprehensive set of metabolic and immune parameters. Faithfully mimicking human hemochromatosis, mice homozygous for this deletion develop iron overload, characterized by a higher plasma iron content and a raised transferrin saturation as well as an elevated hepatic iron load. The primar y defect could, indeed, be traced to an augmented duodenal iron absorption. In parallel, measurement of the gut mucosal iron content as well as iron r egulatory proteins allows a more informed evaluation of various hypotheses regarding the precise role of HFE in iron homeostasis. Finally, an extensiv e phenotyping of primary and secondary lymphoid organs including the gut pr ovides no compelling evidence for an obvious immune-linked function for HFE .