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Blood, 1 August 2005, Vol. 106, No. 3, pp. 971-977. Prepublished online as a Blood First Edition Paper on April 19, 2005; DOI 10.1182/blood-2004-12-4640.
IMMUNOBIOLOGY HFE cross-talks with the MHC class I antigen presentation pathwayFrom the Iron Genes and Immune System Lab, the Organelle Biogenesis and Function Group, Institute for Molecular and Cell Biology (IBMC) and Abel Salazar Institute for the Biomedical Sciences (ICBAS), Oporto, Portugal; and the Department of Tumor and Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
HFE is a protein known to be involved in iron metabolism; yet, other than its homology with major histocompatibility complex (MHC) class I molecules, it has not been described as having an immunologic function. Here we report that peripheral blood mononuclear cells (PBMCs) from patients with hereditary hemochromatosis (HH) carrying the C282Y mutation in HFE have reduced cell-surface expression of MHC class I due to an enhanced endocytosis rate of MHC class I molecules caused by premature peptide and
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| Copyright © 2005 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
2-microglobulin dissociation. This faster turnover also leads to increased expression levels of cell-surface free class I heavy chains in mutant PBMCs. Biochemical analysis indicates an earlier peptide loading and endoplasmic reticulum maturation of MHC class I molecules in C282Y mutant cells. Thermostability assays further showed that in HFE mutants the MHC class I peptide loading gives rise to low-stability heterotrimers that dissociate prematurely during its intracellular traffic. The present results suggest the existence of an intriguing cross-talk between a particular HFE mutation and the classical MHC class I route. These findings constitute the first description of peptide presentation pathway abnormalities linked to HFE and provide additional evidence for the occurrence of immunologic defects in patients with HH. 
