Peripheral lymphocytes and intracellular cytokines in C282Y homozygous hemochromatosis patients

Gavarini, Fabio; Zarantonello, M; Mocellin, Cristina; Bonara, Paola; Corengia, Chiara; Fargion, Silvia; Fiorelli, G.

doi:10.1016/s0168-8278(02)00276-3

Cited by 22 publications

(12 citation statements)

References 33 publications

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“…Nonetheless, this finding is unlikely to be clinically important. Indeed, previous studies have reported such abnormalities of immunity associated with C282Y homozygous patients, suggesting an imbalance in the immune state of C282Y homozygous patients with HH (44–46).…”

Section: Discussionmentioning

confidence: 91%

Elevated MCP‐1 serum levels are associated with the H63D mutation and not the C282Y mutation in hereditary hemochromatosis

et al. 2007

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Monocyte chemoattractant protein-1 (MCP-1) is a major lymphocyte and inflammatory chemokine associated with persistent inflammatory states. Several abnormalities in the immune status of patients with hereditary hemochromatosis (HH) have been reported, suggesting an imbalance in their immune function. This may include persistent production of, or exposure to, inflammatory cytokines contributing to the pathogenesis of this disorder. The aim of this study was to assess MCP-1 levels in patients with HH and correlate these results with HFE status and iron indexes. One hundred and thirty-nine subjects diagnosed with HH (C282Y homozygotes = 87, C282Y/H63D = 26 heterozygotes, H63D homozygotes = 26), 27 healthy control subjects with no HFE mutation (N/N), and 18 normal subjects heterozygous for the H63D mutation served as age- and sex-matched controls. Ferritin and transferrin saturation and the presence of HFE mutation status were correlated with MCP-1 levels. Full white blood cell count analysis was also performed. We found a strongly significant decrease in MCP-1 protein levels in the C282Y homozygotes compared with the H63D homozygotes (P = 0.0009) and C282Y/H63D heterozygotes (P = 0.002). Similarly, MCP-1 protein levels in the C282Y homozygotes were decreased compared with the healthy controls (P = 0.00076). Furthermore, MCP-1 serum levels were elevated in H63D patients compared with the healthy controls (P = 0.0008). This study suggests for the first time that a differential expression of MCP-1 protein in patients with HH is associated with the specific HFE genetic component for iron overload. Therefore, these findings offer a possible explanation in the variable clinical spectrum of pathogenesis in patients with HH through abnormalities of an imbalance in the immune states of patients with HH.

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Section: Discussionmentioning

confidence: 91%

Elevated MCP‐1 serum levels are associated with the H63D mutation and not the C282Y mutation in hereditary hemochromatosis

et al. 2007

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“…More recently, Fabio et al (56) confirmed the early finding of a decrease in CD8+ CD28+ cells and the finding of low total lymphocyte counts in C282Y homozygous asymptomatic patients. The same authors reported low numbers of NK cells.…”

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confidence: 75%

“…In addition to the abnormalities in numbers, an increased production was observed by T cells of the following cytokines: IFN‐γ, TNF, IL‐2, IL‐4, IL‐5, IL‐10, and IL‐13. Statistically significant increases in IL‐4, IL‐5 and IL‐10 production by the CD3+ CD8+ subset were found (56).…”

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confidence: 99%

HFE, the MHC and hemochromatosis: Paradigm for an extended function for MHC class I

Cardoso¹,

Sousa²

2003

Tissue Antigens

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HFE was discovered as the hereditary hemochromatosis (HH) gene. It is located on chromosome 6 (6p21.3), 4Mb telomeric to the HLA-A locus, and its product has a structure similar to MHC class I molecules. HFE encodes two frequent mutations: C282Y and H63D. One of these (C282Y) is present in a large proportion of Caucasian HH patients. HFE has a tissue distribution compatible with a role in iron absorption (intestine), recycling (macrophages) and transport to the fetus (placenta).

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“…Selective abnormalities in CD8 + T lymphocytes have been consistently described in HH patients. These include a defective p56-lck kinase activity, decreased cytotoxic activity, a decreased number of CD8 + T cells expressing the CD28 molecule, abnormalities in the T cell receptor repertoire and cytokine production [11][12][13][14]. In addition, studies of double knockout mice indicate that the iron load in HfeÀ/À mice is higher when crossed to h2mÀ/À [15] or to Rag1À/À [16].…”

Section: Introductionmentioning

confidence: 99%

Low serum transferrin levels in HFE C282Y homozygous subjects are associated with low CD8+ T lymphocyte numbers

Macedo

Cruz

Lacerda

et al. 2005

Blood Cells, Molecules, and Diseases

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Hereditary hemochromatosis (HH) is a genetic iron overload disease, in the majority of cases associated with homozygosity for the C282Y mutation of the HFE gene. In spite of this genetic homogeneity, there is a great clinical heterogeneity among HH patients. Low CD8 + lymphocyte numbers have been associated with a more severe expression of iron overload in HH patients, and in experimental models of iron overload. HH patients present low serum transferrin levels. Transferrin is an indispensable resource for lymphopoiesis. Lymphocyte homeostasis follows general ecology rules of population dynamics that involve competition for limiting resources. In the present study, we questioned whether transferrin levels could be associated with the anomalies seen previously in lymphocyte subset numbers in HH patients. Transferrin levels, total and subset T lymphocyte counts were done in 426 apparently healthy subjects genotyped for HFE. All HFE C282Y carriers presented significantly lower serum transferrin levels than the wild type group, a difference that could not be explained solely by the degree of iron overload. Significant differences were also seen in transferrin levels between males and females, with females presenting higher average serum Transferrin levels. In the population of subjects with Transferrin levels lower than 248 mg/dl, a positive correlation was seen between the peripheral CD8 + lymphocyte numbers and serum transferrin levels (R 2 = 2.41; r = 0.16; P = 0.018). To test the possible limiting resource effect of transferrin, the correlation between transferrin levels and CD8 + lymphocyte numbers was scrutinized in 34 HH patients, homozygous for the C282Y mutation. In the homozygous males, where the lowest average transferrin levels were seen, another highly significant correlation was observed between Transferrin levels and CD8 + numbers. This correlation points to a possible role of transferrin as a limiting resource for MHC class I dependent lymphocyte proliferation, an effect that was not observed in C282Y homozygous female patients. D

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Peripheral lymphocytes and intracellular cytokines in C282Y homozygous hemochromatosis patients

Cited by 22 publications

References 33 publications

Elevated MCP‐1 serum levels are associated with the H63D mutation and not the C282Y mutation in hereditary hemochromatosis

Elevated MCP‐1 serum levels are associated with the H63D mutation and not the C282Y mutation in hereditary hemochromatosis

HFE, the MHC and hemochromatosis: Paradigm for an extended function for MHC class I

Low serum transferrin levels in HFE C282Y homozygous subjects are associated with low CD8+ T lymphocyte numbers

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