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

Santos, Manuela M.; Schilham, Marco W.; Rademakers, L. H. P. M.; Marx, Jean L.; Sousa, Maria de

doi:10.1084/jem.184.5.1975

Cited by 181 publications

(82 citation statements)

References 55 publications

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“…To our knowledge, this is the first demonstration of the impact of an HLA-A allele (HLA-A29) and a mutation in a non-classical MHC-class I gene located 4 Mb away (H63D) on lymphocyte numbers. The consistent finding of a phenotypic association between low lymphocyte numbers and high hepatic iron storage in HH patients (Porto et al 1997(Porto et al , 1998 and in lymphocyte-defective knockout mice (De Sousa et al 1994;Santos et al 1996Santos et al , 2000, led us to the present finding of significantly higher numbers of CD8 + T cells in HLA-A29 normal subjects carrying the H63D mutation. This observation may give us some insight into the mechanism whereby the lymphocytes could contribute to the regulation of iron metabolism.…”

Section: Discussionsupporting

confidence: 67%

Co-selection of the H63D mutation and the HLA-A29 allele: a new paradigm of linkage disequilibrium?

Cardoso¹,

Alves

Mascarenhas³

et al. 2002

Immunogenetics

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The major histocompatibility complex (MHC) shows a remarkable conservation of particular HLA antigens and haplotypes in linkage disequilibrium in most human populations, suggesting the existence of a convergent evolution. A recent example of such conservation is the association of particular HLA haplotypes with the HFE mutations. With the objective of exploring the significance of that association, the present paper offers an analysis of the linkage disequilibrium between HLA alleles or haplotypes and the HFE mutations in a Portuguese population. Allele and haplotype associations between HLA and HFE mutations were first reviewed in a population of 43 hemochromatosis families. The results confirmed the linkage disequilibrium of the HLA haplotype HLA-A3-B7 and the HLA-A29 allele, respectively, with the HFE mutations C282Y and H63D. In order to extend the study of the linkage disequilibrium between H63D and the HLA-A29-containing haplotypes in a normal, random population, an additional sample of 398 haplotypes was analyzed. The results reveal significant linkage disequilibrium between the H63D mutation and all HLA-A29-containing haplotypes, favoring the hypothesis of a co-selection of H63D and the HLA-A29 allele itself. An insight into the biological significance of this association is given by the finding of significantly higher CD8 + T-lymphocyte counts in subjects simultaneously carrying the H63D mutation and the HLA-A29 allele.

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Section: Discussionsupporting

confidence: 67%

Co-selection of the H63D mutation and the HLA-A29 allele: a new paradigm of linkage disequilibrium?

Cardoso¹,

Alves

Mascarenhas³

et al. 2002

Immunogenetics

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“…9-16; D. Roopenian, unpublished observations). This is not surprising because β 2 m controls many immunological and nonimmunological processes, including the development and function of CD8 T cells, natural T cells, conventional NK cells (17), and iron homeostasis (18). Whether autoimmune phenotypes are dependent on FcRn thus remains to be clearly delineated.…”

Section: Introductionmentioning

confidence: 99%

The MHC class I-like Fc receptor promotes humorally mediated autoimmune disease

Akilesh¹

2004

Journal of Clinical Investigation

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The MHC class I family-like Fc receptor, FcRn, is normally responsible for extending the life span of serum IgG Ab's, but whether this molecule contributes to autoimmune pathogenesis remains speculative. To determine directly whether this function contributes to humoral autoimmune disease, we examined whether a deficiency in the FcRn heavy chain influences autoimmune arthritis in the K/BxN mouse model. FcRn deficiency conferred either partial or complete protection in the arthritogenic serum transfer and the more aggressive genetically determined K/BxN autoimmune arthritis models. The protective effects of an FcRn deficiency could be overridden with excessive amounts of pathogenic IgG Ab's. The therapeutic saturation of FcRn by high-dose intravenous IgG (IVIg) also ameliorated arthritis, directly implicating FcRn blockade as a significant mechanism of IVIg's anti-inflammatory action. The results suggest that FcRn is a potential therapeutic target that links the initiation and effector phases of humoral autoimmune disease.

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“…The primary form called hereditary haemochromatosis (HH) is characterized by poorly controlled absorption of iron from the diet in spite of high iron stores in the body. This genetic condition is believed to be absent in the animal kingdom (Santos et al, 1996;Jones et al, 1997). However, an animal model (b 2-microglobulin knockout mice) that recapitulates all aspects of HH in man, including the pattern of iron absorption and iron distribution in the liver, was produced (Santos et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

“…This genetic condition is believed to be absent in the animal kingdom (Santos et al, 1996;Jones et al, 1997). However, an animal model (b 2-microglobulin knockout mice) that recapitulates all aspects of HH in man, including the pattern of iron absorption and iron distribution in the liver, was produced (Santos et al, 1996). In addition, iron storage disease similar to hereditary haemochromatosis has been reported for the Salers breed of cattle (House et al, 1994;Smith, 1997).…”

Section: Introductionmentioning

confidence: 99%

A comparative study of iron retention in mynahs, doves and rats

et al. 2001

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Iron retention was studied in rats (Rattus norvegicus), doves (Streptopelia d. decaocto) and two species of mynahs (Acridotheres t. tristis and Gracula r. religiosa) fed two different pelleted diets (88.5 and 567.9 mg Fe/kg diet). The doves and rats served as species that are not susceptible to iron storage, whereas the mynahs are known to develop iron overload frequently. The retention was calculated after measuring the uptake and elimination of a single dose of radioactive iron ( 59 Fe) using whole-body counting. It was hypothesized that the mynahs would retain more iron than the rats and doves, and that after dietary iron challenge the mynahs would downregulate iron retention less effectively. It is concluded that mynahs have much higher iron uptake and retention than doves, but a similar uptake to that in rats. The four studied species are able to downregulate iron retention, the doves being the most efficient. It is suggested that at least part of the susceptibility to iron overload in mynahs is related to a high iron absorption from the intestines regardless of body iron stores, which is comparable with the situation of hereditary haemochromatosis in man.

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

Cited by 181 publications

References 55 publications

Co-selection of the H63D mutation and the HLA-A29 allele: a new paradigm of linkage disequilibrium?

Co-selection of the H63D mutation and the HLA-A29 allele: a new paradigm of linkage disequilibrium?

The MHC class I-like Fc receptor promotes humorally mediated autoimmune disease

A comparative study of iron retention in mynahs, doves and rats

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