Abstract
The HFE gene (OMIM 235200), most commonly associated with the genetic iron overload disorder Hemochromatosis, was identified by Feder et al. in 1996, as a major histocompatibilty complex (MHC) class I like gene, first designated human leukocyte antigen-H (HLA-H). This discovery was thus accomplished 20 years after the realization of the first link between the then “idiopathic” hemochromatosis and the human leukocyte antigens (HLA). The availability of a good genetic marker in subjects homozygous for the C282Y variant in HFE (hereditary Fe), the reliability in serum markers such as transferrin saturation and serum ferritin, plus the establishment of noninvasive methods for the estimation of hepatic iron overload, all transformed hemochromatosis into a unique age related disease where prevention became the major goal. We were challenged by the finding of iron overload in a 9-year-old boy homozygous for the C282Y HFE variant, with two brothers aged 11 and 5 also homozygous for the mutation. We report a 20 year follow-up during which the three boys were seen yearly with serial determinations of iron parameters and lymphocyte counts. This paper is divided in three sections: Learning, applying, and questioning. The result is the illustration of hemochromatosis as an age related disease in the transition from childhood to adult life and the confirmation of the inextricable link between iron overload and the cells of the immune system.
Highlights
The practice of vaccination and the use of antibiotics provoked a significant decrease of infectious disease in the spectrum of modern clinical practice
Under “learning”, we briefly review the evidence sustaining the importance of immunology in HFE-related hemochromatosis, starting by the improbable discovery of its link with human leukocyte antigens (HLA) to the discovery of the HFE gene as a major histocompatibilty complex (MHC) class I-like gene and its later association with selected immune defects
Evidence of the inextricable connection between iron homeostasis and the adaptive immune system recently gained a novel impulse with the demonstration that patients with a homozygous p.Tyr20His mutation in the transferrin receptor 1 (TfR1) have a combined immunodeficiency characterized by normal numbers but impaired function of T and B cells [34]
Summary
The practice of vaccination and the use of antibiotics provoked a significant decrease of infectious disease in the spectrum of modern clinical practice. That postulate was followed by a series of studies of immunological cell populations in patients with “idiopathic” hemochromatosis [8,9,14,15], preceding the finding by Feder et al in 1996 of the hemochromatosis gene as a novel MHC class I-like gene [16], closing a circle of 21 years from the improbable to the discovery.
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