scholarly journals Adaptive Response of Iron Absorption to Anemia, Increased Erythropoiesis, Iron Deficiency, and Iron Loading in β2-Microglobulin Knockout Mice

Blood ◽  
1998 ◽  
Vol 91 (8) ◽  
pp. 3059-3065 ◽  
Author(s):  
Manuela Santos ◽  
Hans Clevers ◽  
Maria de Sousa ◽  
J.J.M. Marx

Recently, a novel gene of the major histocompatibility complex (MHC) class I family, HFE (HLA-H), has been found to be mutated in a large proportion of hereditary hemochromatosis (HH) patients. Further support for a causative role of HFE in this disease comes from the observation that β2-microglobulin knockout (β2m−/−) mice, that fail to express MHC class I products, develop iron overload. We have now used this animal model of HH to examine the capacity to adapt iron absorption in response to altered iron metabolism in the absence of β2m-dependent molecule(s). Mucosal uptake, mucosal transfer and retention of iron were measured in control and β2m−/−mice with altered iron metabolism. Mucosal uptake of Fe(III), but not of Fe(II), by the mutant mice was significantly higher when compared with B6 control mice. Mucosal transfer in the β2m−/−mice was higher, independent of the iron form tested. No significant differences were found in iron absorption between control and β2m−/− mice when anemia was induced either by repetitive bleeding or by hemolysis through phenylhydrazine treatment. However, iron absorption in mice made anemic by dietary deprivation of iron was significantly higher in the mutant mice. Furthermore, the β2m−/− mice manifested an impaired capacity to downmodulate iron absorption when dietary or parenterally iron-loaded. The expression of the defect in iron absorption in the β2m−/− mice is quantitative, with iron absorption being excessively high for the size of body iron stores. The higher iron absorption capacity in the β2m−/− mice may involve the initial step of ferric mucosal uptake and the subsequent step of mucosal transfer of iron to the plasma.

1995 ◽  
Vol 7 (6) ◽  
pp. 975-984 ◽  
Author(s):  
Hans-Gustaf Ljunggren ◽  
Luc Van Kaer ◽  
Marc S. Sabatine ◽  
Hugh Auchincloss ◽  
Susumu Tonegawa ◽  
...  

Hematology ◽  
2014 ◽  
Vol 2014 (1) ◽  
pp. 216-221 ◽  
Author(s):  
Carla Casu ◽  
Stefano Rivella

Abstract Excess iron deposition in vital organs is the main cause of morbidity and mortality in patients affected by β-thalassemia and hereditary hemochromatosis. In both disorders, inappropriately low levels of the liver hormone hepcidin are responsible for the increased iron absorption, leading to toxic iron accumulation in many organs. Several studies have shown that targeting iron absorption could be beneficial in reducing or preventing iron overload in these 2 disorders, with promising preclinical data. New approaches target Tmprss6, the main suppressor of hepcidin expression, or use minihepcidins, small peptide hepcidin agonists. Additional strategies in β-thalassemia are showing beneficial effects in ameliorating ineffective erythropoiesis and anemia. Due to the suppressive nature of the erythropoiesis on hepcidin expression, these approaches are also showing beneficial effects on iron metabolism. The goal of this review is to discuss the major factors controlling iron metabolism and erythropoiesis and to discuss potential novel therapeutic approaches to reduce or prevent iron overload in these 2 disorders and ameliorate anemia in β-thalassemia.


1996 ◽  
Vol 54 (1) ◽  
pp. 31-35 ◽  
Author(s):  
Ussama M. Abdel-Motal ◽  
Jan Dahmén ◽  
Tianmin Liu ◽  
Hans-Gustaf Ljunggren ◽  
Mikael Jondal

Immunity ◽  
1998 ◽  
Vol 9 (4) ◽  
pp. 531-541 ◽  
Author(s):  
Sam J.P Gobin ◽  
Ad Peijnenburg ◽  
Marja van Eggermond ◽  
Marlijn van Zutphen ◽  
Rian van den Berg ◽  
...  

Blood ◽  
2007 ◽  
Vol 109 (10) ◽  
pp. 4511-4517 ◽  
Author(s):  
Maja Vujic Spasic ◽  
Judit Kiss ◽  
Thomas Herrmann ◽  
Regina Kessler ◽  
Jens Stolte ◽  
...  

Abstract Mutations in the Hfe gene result in hereditary hemochromatosis (HH), a disorder characterized by increased duodenal iron absorption and tissue iron overload. Identification of a direct interaction between Hfe and transferrin receptor 1 in duodenal cells led to the hypothesis that the lack of functional Hfe in the duodenum affects TfR1-mediated serosal uptake of iron and misprogramming of the iron absorptive cells. Contrasting this view, Hfe deficiency causes inappropriately low expression of the hepatic iron hormone hepcidin, which causes increased duodenal iron absorption. We specifically ablated Hfe expression in mouse enterocytes using Cre/LoxP technology. Mice with efficient deletion of Hfe in crypt- and villi-enterocytes maintain physiologic iron metabolism with wild-type unsaturated iron binding capacity, hepatic iron levels, and hepcidin mRNA expression. Furthermore, the expression of genes encoding the major intestinal iron transporters is unchanged in duodenal Hfe-deficient mice. Our data demonstrate that intestinal Hfe is dispensable for the physiologic control of systemic iron homeostasis under steady state conditions. These findings exclude a primary role for duodenal Hfe in the pathogenesis of HH and support the model according to which Hfe is required for appropriate expression of the “iron hormone” hepcidin which then controls intestinal iron absorption.


Blood ◽  
2007 ◽  
Vol 110 (8) ◽  
pp. 3028-3035 ◽  
Author(s):  
Jing Yang ◽  
Xiang Zhang ◽  
Ji Wang ◽  
Jianfei Qian ◽  
Liang Zhang ◽  
...  

Abstract We recently showed that monoclonal antibodies (mAbs) against β2-microglobulin (β2M) have a remarkably strong apoptotic effect on myeloma cells. The mAbs induced apoptosis by recruiting major histocompatibility complex (MHC) class I to lipid rafts, activated c-Jun N-terminal kinase (JNK), and inhibited phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal–regulated kinase (ERK) pathways. Growth and survival cytokines such as interleukin-6 (IL-6) and insulin-like growth factor-I (IGF-I), which could protect myeloma cells from dexamethasone-induced apoptosis, did not affect mAb-mediated cell death. This study was undertaken to elucidate the mechanisms underlying anti-β2M mAb–induced PI3K/Akt and ERK inhibition and the inability of IL-6 and IGF-I to protect myeloma cells from mAb-induced apoptosis. We focused on lipid rafts and confirmed that these membrane microdomains are required for IL-6 and IGF-I signaling. By recruiting MHC class I into lipid rafts, anti-β2M mAbs excluded IL-6 and IGF-I receptors and their substrates from the rafts. The mAbs not only redistributed the receptors in cell membrane, but also abrogated IL-6– or IGF-I–mediated Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3), PI3K/Akt, and Ras/Raf/ERK pathway signaling, which are otherwise constitutively activated in myeloma cells. Thus, this study further defines the tumoricidal mechanism of the mAbs and provides strong evidence to support the potential of these mAbs as therapeutic agents for myeloma.


2005 ◽  
Vol 174 (2) ◽  
pp. 925-933 ◽  
Author(s):  
Sophie Tourdot ◽  
Mohamed Nejmeddine ◽  
Simon J. Powis ◽  
Keith G. Gould

1998 ◽  
Vol 150 (2) ◽  
pp. 282-295 ◽  
Author(s):  
Hans Lindå ◽  
Henrik Hammarberg ◽  
Staffan Cullheim ◽  
Agneta Levinovitz ◽  
Mohsen Khademi ◽  
...  

Immunity ◽  
2000 ◽  
Vol 13 (2) ◽  
pp. 213-222 ◽  
Author(s):  
Andres G Grandea ◽  
Tatiana N Golovina ◽  
Sara E Hamilton ◽  
Venkataraman Sriram ◽  
Thomas Spies ◽  
...  

Blood ◽  
2005 ◽  
Vol 106 (3) ◽  
pp. 971-977 ◽  
Author(s):  
Sérgio F. de Almeida ◽  
Isabel F. Carvalho ◽  
Carla S. Cardoso ◽  
João V. Cordeiro ◽  
Jorge E. Azevedo ◽  
...  

AbstractHFE 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 β2-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.


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