The CD8+ T-lymphocyte profile as a modifier of iron overload in HFE hemochromatosis: An update of clinical and immunological data from 70 C282Y homozygous subjects

Cruz, Eugénia; Melo, Graça; Lacerda, Rosa; Almeida, Susana; Porto, Graça

doi:10.1016/j.bcmd.2006.04.004

Cited by 33 publications

(41 citation statements)

References 31 publications

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“…Few studies even reported thalassemia patients with low CD8 percentage (Cunningham-Rundles et al, 2000;Consolini et al, 2001). A study conducted by Cruz et al (2006) reported a negative correlation between CD8+ T-lymphocytes and iron stores in HFE homozygous hemochromatosis male patients; this correlation was not found in our patient population. These contradictory results could be due to clinical heterogeneity among patients.…”

Section: Discussioncontrasting

confidence: 74%

Investigation of the distribution of lymphocyte subsets and zinc levels in multitransfused β‐thalassemia major patients

Al-Awadhi

AlFadhli

Al-Khaldi

et al. 2010

Int J Lab Hematology

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Homozygous beta-thalassemia is a common genetic disorder in the Arabian Peninsula and an important cause of morbidity in Kuwait. The anemia is so severe that chronic blood transfusions, and the resulting iron overload, cause a shift in immunoregulatory balances and a deficiency in zinc. It was reported that individual immunological profile of CD8+ T-lymphocytes may have a modifying effect on the severity of iron overload in HFE homozygous hemochromatosis patients, with low numbers being negatively correlated with the total amount of body iron stores. This has not been tested in thalassemia major patients. This study was designed to utilize flow cytometric immunophenotyping to characterize effects of regular blood transfusion, and high serum ferritin levels because of irregular use of iron chelation therapy on T lymphocytes (CD2, CD3, CD4 and CD8), B lymphocytes (CD19) and natural killer cells (CD56) and zinc levels in the blood of patients with thalassemia major (n = 49) and healthy normal controls (n = 60) in Kuwait. None of the patients had active infections. T-cell markers' percentage levels were comparable between patients and controls (P > 0.05), while B cell marker (CD19) was significantly higher in patients (P = 0.007). Patients had lower percentage levels of CD56 cells (P = 0.007) and normal serum zinc. All patients had high serum ferritin levels with no significant correlation to CD8+ T lymphocytes (P > 0.05). High iron stores did not have an effect on T lymphocytes' profile, with normal zinc levels perhaps related to non compliance with chelation therapy. The high B cell marker may be indicative of stimulation of antibody producing cells as a result of regular blood transfusions.

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Section: Discussioncontrasting

confidence: 74%

Investigation of the distribution of lymphocyte subsets and zinc levels in multitransfused β‐thalassemia major patients

Al-Awadhi

AlFadhli

Al-Khaldi

et al. 2010

Int J Lab Hematology

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“…The variation in phenotypes of patients with the HFE mutation has led to the hypothesis that there are HFE modifiers, including iron importers (37)(38)(39). Interestingly, the survival of Slc11a2 Ϫ/Ϫ mice that lack DMT1 is significantly improved when HFE alleles were inactivated.…”

Section: Discussionmentioning

confidence: 99%

The Hereditary Hemochromatosis Protein, HFE, Inhibits Iron Uptake via Down-regulation of Zip14 in HepG2 Cells

Gao

Zhao

Knutson

et al. 2008

Journal of Biological Chemistry

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Lack of functional hereditary hemochromatosis protein, HFE, causes iron overload predominantly in hepatocytes, the major site of HFE expression in the liver. In this study, we investigated the role of HFE in the regulation of both transferrin-bound iron (TBI) and non-transferrin-bound iron (NTBI) uptake in HepG2 cells, a human hepatoma cell line. Expression of HFE decreased both TBI and NTBI uptake. It also resulted in a decrease in the protein levels of Zip14 with no evident change in the mRNA level of Zip14. Zip14 (Slc39a14) Iron absorbed from the intestine is transported directly to the liver, a key organ involved in iron homeostasis. Hepatocytes, making up about 80% of the liver in volume, play an important role in maintaining iron homeostasis and iron sensing. They take up both transferrin-bound iron (TBI) 2 and nontransferrin-bound iron (NTBI). NTBI uptake requires both reduction by ferric reductase and transport by a ferrous transporter. Steap3 is the candidate reductase in the liver (1, 2), and DMT1 (divalent metal transporter 1) and Zip14 (Zrtand Irt-like protein 14) are candidate transporters. DMT1 was the first iron transporter identified and is ubiquitously expressed (3, 4). Zip14, a member of the SLC39A metal ion transporter family, initially identified as zinc transporter (5, 6), was recently reported to be abundantly expressed in hepatocytes and involved in NTBI uptake (7). Patients with hereditary hemochromatosis have significant levels of NTBI in their serum (8,9).Mutation of a single base pair in the hereditary hemochromatosis gene (HFE) causes iron overload in the liver, heart, pancreas, and parathyroid and pituitary glands, leading to multiorgan dysfunction (10, 11). This mutation results in a substitution of tyrosine for cysteine in the hereditary hemochromatosis protein, HFE, which disrupts a disulfide bond required for proper folding, preventing it from binding to ␤ 2 -microglobulin and trafficking to the cell surface (12). The importance of functional HFE in iron metabolism is also supported by the evidence that hepatocytes from Hfe Ϫ/Ϫ knock-out mice can take up more NTBI (9) and have an 8-fold higher iron accumulation in the liver than wild-type mice (13).Several mechanisms have been proposed by which HFE regulates iron metabolism. HFE competes with transferrin (Tf) for binding to TfR1 (transferrin receptor 1), lowering iron uptake into cells (14 -16). Alternately, Tf binding to TfR1 releases HFE to bind to TfR2 in hepatocytes to increase hepcidin transcription (17). Hepcidin is a hormone secreted by the liver that negatively regulates dietary iron uptake by the intestine. HFE can also lower NTBI uptake in isolated primary mouse hepatocytes (9) and in Chinese hamster ovary cells lacking endogenous TfR1 (18). Thus, the mechanism by which HFE regulates iron metabolism still remains elusive.In the present study, the regulation of both TBI and NTBI uptake by HFE was studied in HepG2 cells, a human hepatoma cell line. We found that expression of HFE decreased both TBI and NTBI uptake. Expre...

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“…26 Further, the CD8 ϩ T lymphocyte profile has also been identified as a modifier of iron stores but this effect is not seen in females. 27 Given these findings, it is tempting to speculate on the presence of further modifying genes on chromosome 6 that have a sex-specific effect on iron loading and are associated with a locus controlling T-cell numbers. Of interest, recent reports suggest that this potential sex-linked For personal use only.…”

Section: Sexmentioning

confidence: 99%

Environmental and genetic modifiers of the progression to fibrosis and cirrhosis in hemochromatosis

Wood

Powell

Ramm

2008

Blood

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The CD8+ T-lymphocyte profile as a modifier of iron overload in HFE hemochromatosis: An update of clinical and immunological data from 70 C282Y homozygous subjects

Cited by 33 publications

References 31 publications

Investigation of the distribution of lymphocyte subsets and zinc levels in multitransfused β‐thalassemia major patients

Investigation of the distribution of lymphocyte subsets and zinc levels in multitransfused β‐thalassemia major patients

The Hereditary Hemochromatosis Protein, HFE, Inhibits Iron Uptake via Down-regulation of Zip14 in HepG2 Cells

Environmental and genetic modifiers of the progression to fibrosis and cirrhosis in hemochromatosis

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