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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.
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Submitted December 3, 2004
Accepted April 1, 2005
HFE crosstalks with the MHC class I antigen presentation pathway
Sergio F De Almeida, Isabel F Carvalho, Carla S Cardoso, Joao V Cordeiro, Jorge E Azevedo, Jacques Neefjes, and Maria De Sousa*
Iron Genes and the Immune System, Institute for Molecular and Cell Biology (IBMC) and ICBAS, Oporto, Portugal
UniLiPe, IBMC and ICBAS, Oporto, Portugal
Department of Tumor and Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
* Corresponding author; email: mdesousa{at}ibmc.up.pt.
HFE is a protein known to be involved in iron metabolism yet, besides its homology with major histocompatibility complex (MHC) class I molecules, it has not been described as having an immunological function. Here we report that peripheral blood mononuclear cells (PBMC) from Hereditary Hemochromatosis (HH) patients carrying the C282Y mutation in HFE have reduced cell surface expression of MHC class I due to enhanced endocytosis rate of MHC class I molecules caused by premature peptide and  2m dissociation. This faster turnover also leads to increased expression levels of cell surface free class I HC in mutant PBMC. 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 crosstalk 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 immunological defects in HH patients.
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