Defective iron homeostasis in beta 2-microglobulin knockout mice recapitulates hereditary hemochromatosis in man

Previously, hepatic iron overload resembling that in hereditary hemachromatosis (HH) has been found in beta 2-microglobulin knockout (beta 2m-/-) mice. We have now characterized iron metabolism in beta 2m- /- mice. The mutant mice fail to limit the transfer of iron from mucosal cells into the plasma. Transferrin saturation is abnormally high. Pathologic iron depositions occur predominantly in liver parenchymal cells. Reconstitution with normal hematopoietic cells redistributes the iron from parenchymal to Kupffer cells, but does not correct the mucosal defect. We conclude that (a) iron metabolism is defective in the gut mucosa as well as the liver of beta 2m-/- mice; and (b) a beta 2m-dependent gene product is involved in iron homeostasis. Recently, a novel gene of the major histocompatibility complex class I family, HLA-H, has been found to be mutated in a large proportion of HH patients. Our data provide functional support for the proposed causative role of HLA-H mutations in HH.

• Publication year

  1996

• Venue

  Journal of Experimental Medicine

• Publication date

  1996-11-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1084/JEM.184.5.1975PMID 8920884PMCID 2192883
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Mucosal uptake, mucosal transfer and retention of iron, measured by whole-body counting.

  2009cited by this paper
• Absence of macrophage and presence of plasmacellular iron storage in the terminal duodenum of patients with hereditary haemochromatosis

  2005cited by this paper
• beta2 knockout mice develop parenchymal iron overload: A putative role for class I genes of the major histocompatibility complex in iron metabolism.

  1996influential reference
• A novel MHC class I–like gene is mutated in patients with hereditary haemochromatosis

  1996cited by this paper
• The effects of dietary iron on initiation and promotion in chemical hepatocarcinogenesis

  1995cited by this paper
• Iron overload in African Americans.

  1995cited by this paper
• Surface expression of β2‐microglobulin‐associated thymus‐leukemia antigen is independent of TAP2

  1995cited by this paper
• Nonclassical behavior of the thymus leukemia antigen: peptide transporter-independent expression of a nonclassical class I molecule

  1995cited by this paper
• Haemochromatosis as a window into the study of the immunological system: A novel correlation between CD8+ lymphocytes and iron overload

  1994cited by this paper
• Genetics of haemochromatosis.

  1994cited by this paper
• Iron overload in beta 2-microglobulin-deficient mice.

  1994cited by this paper
• Clinical spectrum and management of haemochromatosis.

  1994cited by this paper
• Effect of chronic iron overload on procollagen gene expression

  1993cited by this paper
• Site of principal metabolic defect in idiopathic haemochromatosis: insights from transplantation of an affected organ.

  1993cited by this paper
• Animal models in liver research: iron overload.

  1993cited by this paper
• Chronic feeding of carbonyl-iron and TMH-ferrocene in rats. Comparison of two iron-overload models with different iron absorption.

  1993cited by this paper
• TAP1 mutant mice are deficient in antigen presentation, surface class I molecules, and CD4-8+ T cells.

  1992influential reference
• Ham-2 corrects the class I antigen-processing defect in RMA-S cells

  1992cited by this paper
• Regulation of transferrin, transferrin receptor, and ferritin genes in human duodenum.

  1992cited by this paper
• Transplantation of a donor liver with haemochromatosis: evidence against an inherited intrahepatic defect.

  1991cited by this paper
• Rejection of class I MHC-deficient haemopoietic cells by irradiated MHC-matched mice

  1991cited by this paper
• Restored expression of major histocompatibility class I molecules by gene transfer of a putative peptide transporter

  1991cited by this paper
• Linkage of faulty major histocompatibility complex class I to autoimmune diabetes.

  1991cited by this paper
• Long-term survival analysis in hereditary hemochromatosis.

  1991cited by this paper
• Regulation of intestinal iron absorption and mucosal iron kinetics in hereditary hemochromatosis.

  1991cited by this paper
• CD8 is needed for development of cytotoxic T cells but not helper T cells.

  1991cited by this paper
• Transport protein genes in the murine MHC: possible implications for antigen processing.

  1990cited by this paper
• Human leukocyte antigen F (HLA-F). An expressed HLA gene composed of a class I coding sequence linked to a novel transcribed repetitive element

  1990cited by this paper
• Normal development of mice deficient in beta 2M, MHC class I proteins, and CD8+ T cells.

  1990cited by this paper
• Liver transplantation in idiopathic hemochromatosis.

  1990cited by this paper
• Differential expression of transferrin receptor in duodenal mucosa in iron overload. Evidence for a site-specific defect in genetic hemochromatosis.

  1990cited by this paper
• β2-Microglobulin deficient mice lack CD4−8+ cytolytic T cells

  1990cited by this paper
• Hereditary haemochromatosis.

  1989cited by this paper
• Hereditary hemochromatosis: pathogenesis and clinical features of a common disease.

  1989cited by this paper
• Immunohistochemical evidence for a lack of ferritin in duodenal absorptive epithelial cells in idiopathic hemochromatosis.

  1989cited by this paper
• Model of reticuloendothelial iron metabolism in humans: abnormal behavior in idiopathic hemochromatosis and in inflammation.

  1989cited by this paper
• Reticuloendothelial iron stores and hereditary hemochromatosis: a paradox.

  1989cited by this paper
• Ferritin release by mononuclear cells in hereditary hemochromatosis.

  1989cited by this paper
• Duodenal iron proteins in idiopathic hemochromatosis.

  1989cited by this paper
• HLA-E. A novel HLA class I gene expressed in resting T lymphocytes.

  1988cited by this paper
• A human major histocompatibility complex class I gene that encodes a protein with a shortened cytoplasmic segment.

  1987cited by this paper
• Ultrastructural observations in the carbonyl iron-fed rat, an animal model for hemochromatosis

  1987cited by this paper
• Transferrin receptors in the human gastrointestinal tract

  1986cited by this paper
• Transferrin receptors in the human gastrointestinal tract. Relationship to body iron stores.

  1986cited by this paper
• Value of hepatic iron measurements in early hemochromatosis and determination of the critical iron level associated with fibrosis

  1986cited by this paper
• Cohort study of internal malignancy in genetic hemochromatosis and other chronic nonalcoholic liver diseases.

  1985cited by this paper
• Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis.

  1985cited by this paper
• Genetic and phenotypic expression of hemochromatosis in Canadians.

  1983cited by this paper
• Hereditary hemochromatosis. Analysis of laboratory expression of the disease by genotype in 18 pedigrees.

  1982cited by this paper
• Major histocompatibility antigens: the human (HLA-A, -B, -C) and murine (H-2K, H-2D) class I molecules.

  1981cited by this paper
• Iron absorption and iron overload.

  1981cited by this paper
• Primary structural: analysis of the transplantation antigens of the murine H-2 major histocompatibility complex.

  1981cited by this paper
• Genetic mapping of the hemochromatosis locus on chromosome six.

  1980cited by this paper
• In vitro studies of duodenal iron uptake in patients with primary and secondary iron storage disease.

  1980cited by this paper
• Idiopathic hemochromatosis. Demonstration of recessive transmission and early detection by family HLA typing.

  1977cited by this paper
• Patterns of iron storage in dietary iron overload and idiopathic hemochromatosis.

  1976cited by this paper
• Long term results of venesection therapy in idiopathic haemochromatosis.

  1976cited by this paper
• Hemochromatosis. Pathophysiologic and genetic considerations.

  1975cited by this paper
• Distribution of storage iron as body stores expand in patients with hemochromatosis.

  1975cited by this paper
• Iron absorption in normal subjects and patients with idiopathic haemochromatosis: relationship with serum ferritin concentration.

  1975cited by this paper
• Effects of cyclic starvation-feeding and of splenectomy on the development of hemosiderosis in rat livers.

  1974cited by this paper
• A simple rapid polychrome stain for epoxy-embedded tissue.

  1973cited by this paper
• Liver biopsy in diagnosis of hemochromatosis.

  1968cited by this paper
• Iron Absorption in Idiopathic Haemochromatosis before, during, and after Venesection Therapy

  1966cited by this paper
• EXPERIMENTAL HEMOCHROMATOSIS IN RATS.

  1965cited by this paper
• ABSORPTION AND EXCRETION OF IRON

  1945cited by this paper

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  2015cites this paper
• The neonatal Fc receptor, FcRn, as a target for drug delivery and therapy.

  2015cites this paper
• Lymphocytes in hemochromatosis: a genomic and functional approach

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  2014cites this paper
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  2014cites this paper
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  2014cites this paper
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  2013cites this paper
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  2013cites this paper
• Pharmacokinetics and Delivery of Proteins Modified with FcRn Binding Ligands

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  2013cites this paper
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  2012cites this paper
• Transplantation d'hépatocytes génétiquement modifiés : régénération hépatique et moyens d'amélioration de la prise de greffe hépatocytaire

  2012cites this paper
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• The non-conventional MHC class I MR1 molecule controls infection by Klebsiella pneumoniae in mice.

  2011cites this paper
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• World J Gastroenterol

  2010cites this paper
• Hepcidin messenger RNA expression in human lymphocytes

  2010cites this paper
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  2009cites this paper
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• Iron metabolism in the anemia of chronic disease.

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  2008cites this paper
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  2008cites this paper
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• Ceruloplasmin expression by human peripheral blood lymphocytes: a new link between immunity and iron metabolism.

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• The Regulation of Cellular Iron Metabolism

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• Iron overload and immunity.

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• Hereditary hemochromatosis results in decreased iron acquisition and growth by Mycobacterium tuberculosis within human macrophages

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  2006cites this paper
• Cloning and sequence analysis of the beta2-microglobulin transcript from flounder, Paralichthys olivaceous.

  2006cites this paper
• Distinct requirements for Hfe in basal and induced hepcidin levels in iron overload and inflammation.

  2006cites this paper
• Iron Imports. VI. HFE and regulation of intestinal iron absorption.

  2006cites this paper
• Comparative study between Hfe‐/‐ and β2m‐/‐ mice: progression with age of iron status and liver pathology

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• Accelerated transferrin degradation in HFE-deficient mice is associated with increased transferrin saturation.

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  2005cites this paper
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  2005cites this paper
• Iron in mammals: pathophysiological mechanisms of overload and deficiency in relation to disease

  2005cites this paper
• Modulation of gene expression by dietary iron

  2005cites this paper
• Pathophysiology of Hereditary Hemochromatosis

  2005cites this paper
• Pathophysiology of hereditary hemochromatosis.

  2005cites this paper
• The fate of iron in the organism and its regulatory pathways.

  2005cites this paper
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  2005cites this paper
• The role of hereditary hemochromatosis in aseptic loosening following primary total hip arthroplasty

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• Pathogenesis of hereditary hemochromatosis.

  2004cites this paper
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  2004cites this paper
• The MHC class I-like Fc receptor promotes humorally mediated autoimmune disease.

  2004cites this paper
• Hereditary hemochromatosis : with a special emphasis on HFE genotyping

  2004cites this paper
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  2004cites this paper
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  2004cites this paper
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  2003cites this paper
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  2003cites this paper
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