Experimental hemochromatosis due to MHC class I HFE deficiency: Immune status and iron metabolism

Hereditary hemochromatosis (HH) is a disorder of iron metabolism in which enhanced iron absorption of dietary iron causes increased iron accumulation in the liver, heart, and pancreas. Most individuals with HH are homozygous for a C282Y mutation in the HFE gene. The function of HFE protein is unknown, but it is hypothesized that it acts in association with ␤2-microglobulin and transferrin receptor 1 to regulate iron uptake from plasma transferrin by the duodenum, the proposed mechanism by which body iron levels are sensed. The aim of this study was to test this hypothesis by comparing clearance of transferrin-bound iron in Hfe knockout (KO) mice with that observed in C57BL͞6 control mice. The mice were fed either an iron-deficient, control, or iron-loaded diet for 6 weeks to alter body iron status. The mice then were injected i.v. with 59 Fe-transferrin, and blood samples were taken over 2 h to determine the plasma 59 Fe turnover. After 2 h, the mice were killed and the amount of radioactivity in the duodenum, liver, and kidney was measured. In both Hfe KO and C57BL͞6 mice, plasma iron turnover and iron uptake from plasma transferrin by the duodenum, liver, and kidney correlated positively with plasma iron concentration. However, duodenal iron uptake from plasma transferrin was decreased in the Hfe KO mice compared with the control mice. Despite this difference in duodenal uptake, the Hfe KO mice showed no decrease in iron uptake by the liver and kidney or alteration in the plasma iron turnover when compared with C57BL͞6 mice. These data support the hypothesis that HFE regulates duodenal uptake of transferrin-bound iron from plasma, and that this mechanism of sensing body iron status, as reflected in plasma iron levels, is impaired in HH.

Section: Discussionmentioning

confidence: 90%

Iron uptake from plasma transferrin by the duodenum is impaired in the Hfe knockout mouse

Trinder

Olynyk

Sly

et al. 2002

“…In HH patients, it is postulated that HFE mutations result in the impairment of HFE function in duodenal crypt cells (46,47). In the mouse models of HH, loss of HFE function results both from the C282Y mutation or knockout mutations in the HFE gene and from deficiency of ␤ 2 M as in the ␤ 2 M-knockout mouse (11)(12)(13)(14)(15). In fact, the discovery that ␤ 2 M-deficient mice show an HH phenotype was the initial piece of evidence associating MHC class I-type proteins in iron homeostasis and in HH (11,12).…”

Section: Discussionmentioning

confidence: 99%

“…Another interesting question is whether mutant HFEs will behave like HFE expressed in the absence of ␤ 2 M in CHO and TRVb-1 cells. Because HFE knockout and C282Y mutant mice behave phenotypically like ␤ 2 M-deficient mice, i.e., both have the murine HH phenotype, one would predict that they would (11)(12)(13)(14)(15). By analogy with the role of HFE-␤ 2 M in modulating uptake of Tf-Fe by CHO and TRVb-1 cells, we suggest: (i) that HFE-␤ 2 M normally plays a role in facilitating uptake of Tf-bound iron by duodenal crypt cells and macrophages; (ii) that HFE mutations that impair this function in HH patients contribute to dysregulation of iron absorption, because this uptake process by duodenal crypt cells is key to sensing the level of Tf-bound iron in capillaries surrounding crypt cells of the duodenum where iron absorption is controlled (48,50,51); and (iii) this impairment of Tf-bound iron uptake leads the duodenal crypt cells to be iron poor (47)(48)(49)52), even in the face of body iron excess, and to program cells differentiating into mature villus cells to absorb excess iron in HH.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Regulation of transferrin-mediated iron uptake by HFE, the protein defective in hereditary hemochromatosis

Waheed

Grubb

Zhou

et al. 2002

124

The protein defective in hereditary hemochromatosis, called HFE, is similar to MHC class I-type proteins and associates with ␤2-microglobulin (␤2M). Its association with ␤2M was previously shown to be necessary for its stability, normal intracellular processing, and cell surface expression in transfected COS cells. Here we use stably transfected Chinese hamster ovary cell lines expressing both HFE and ␤ 2 M or HFE alone to study the effects of ␤ 2 M on the stability and maturation of the HFE protein and on the role of HFE in transferrin receptor 1 (TfR1)-mediated iron uptake. In agreement with prior studies on other cell lines, we found that overexpression of HFE, without overexpressing ␤2M, resulted in a decrease in TfR1-dependent iron uptake and in lower iron levels in the cells, as evidenced by ferritin and TfR1 levels measured at steady state. However, overexpression of both HFE and ␤2M had the reverse effect and resulted in an increase in TfR1-dependent iron uptake and increased iron levels in the cells. The HFE-␤2M complex did not affect the affinity of TfR1 for transferrin or the internalization rate of transferrin-bound TfR1. Instead, HFE-␤2M enhanced the rate of recycling of TfR1 and resulted in an increase in the steady-state level of TfR1 at the cell surface of stably transfected cells. We propose that Chinese hamster ovary cells provide a model to explain the effect of the HFE-␤2M complex in duodenal crypt cells, where the HFE-␤2M complex appears to facilitate the uptake of transferrin-bound iron to sense the level of body iron stores. Impairment of this process in duodenal crypt cells leads them to be iron poor and to signal the differentiating enterocytes to take up iron excessively after they mature into villus cells in the duodenum of hereditary hemochromatosis patients.H ereditary hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism, characterized by excessive absorption of dietary iron in the small intestine. The excess iron is stored in the parenchymal cells of major tissues, primarily the liver, pancreas, heart, pituitary, and joints, eventually leading to severe tissue damage (1-3). The pathogenesis of HH is thought to involve a defect in the mechanism controlling iron absorption in the small intestine (4).The gene defective in hemochromatosis, HFE, encodes an MHC class I-type protein (5). In multiple population studies, 85-90% of HH patients of northern European ancestry were found to be homozygous for the C282Y mutation in HFE. About 5% are compound heterozygotes for C282Y and a second mutation, H63D (5-10). Even earlier, the observation that ␤ 2 -microglobulin (␤ 2 M)-deficient mice develop progressive iron overload similar to that seen in HH patients suggested the involvement of an MHC class I protein in HH (11, 12). Confirmation that mutations in HFE cause HH was provided by observations of mice with targeted disruption of the HFE gene. These HFE knockout mice showed high transferrin saturation and an increase in iron storage in hepatocytes (13-15).The C282Y mutati...

“…Mice deficient in ␤ 2 M and mice deficient in Hfe or engineered to express the disease-associated C282Y HFE mutation demonstrate systemic iron overload with iron deposition in liver parenchymal cells (11)(12)(13)(14)(15)(16). The B2m null (Ϫ) mutation has been highly back-crossed onto an array of inbred mouse strain backgrounds (17)(18)(19).…”

mentioning

confidence: 99%

Naturally variant autosomal and sex-linked loci determine the severity of iron overload in β₂-microglobulin-deficient mice

Sproule

Jazwinska

Britton

et al. 2001

Hereditary hemochromatosis (HH) is a common chronic human genetic disorder whose hallmark is systemic iron overload. Homozygosity for a mutation in the MHC class I heavy chain paralogue gene HFE has been found to be a primary cause of HH. However, many individuals homozygous for the defective allele of HFE do not develop iron overload, raising the possibility that genetic variation in modifier loci contributes to the HH phenotype. Mice deficient in the product of the ␤2-microglobulin (␤2M) class I light chain fail to express HFE and other MHC class I family proteins, and they have been found to manifest many characteristics of the HH phenotype. To determine whether natural genetic variation plays a role in controlling iron overload, we performed classical genetic analysis of the iron-loading phenotype in ␤2M-deficient mice in the context of different genetic backgrounds. Strain background was found to be a major determinant in iron loading. Sex played a role that was less than that of strain background but still significant. Resistance and susceptibility to iron overload segregated as complex genetic traits in F1 and back-cross progeny. These results suggest the existence of naturally variant autosomal and Y chromosome-linked modifier loci that, in the context of mice genetically predisposed by virtue of a ␤2M deficiency, can profoundly influence the severity of iron loading. These results thus provide a genetic explanation for some of the variability of the HH phenotype.