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Iron overload and immunity.
Open accessAbstract
Progress in the characterization of genes involved in the control of iron homeostasis in humans and in mice has improved the definition of iron overload and of the cells affected by it. The cell involved in iron overload with the greatest effect on immunity is the macrophage. Intriguing evidence has emerged, however, in the last 12 years indicating that parenchymal iron overload is linked to genes classically associated with the immune system. This review offers an update of the genes and proteins relevant to iron metabolism expressed in cells of the innate immune system, and addresses the question of how this system is affected in clinical situations of iron overload. The relationship between iron and the major cells of adaptive immunity, the T lymphocytes, will also be reviewed. Most studies addressing this last question in humans were performed in the clinical model of Hereditary Hemochromatosis. Data will also be reviewed demonstrating how the disruption of molecules essentially involved in adaptive immune responses result in the spontaneous development of iron overload and how they act as modifiers of iron overload.
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![Figure 1 A model illustration of the two topics addressed in this review: how innate immunity is affected and affects 'phagocytic' iron overload (Box A) and the evidence that defective immune system models, namely natural and experimental defects in MHC-class Ⅰ related genes (HFE, β 2-microglobulin and HLA) are associated with the spontaneous development of 'non-phagocytic' or parenchymal iron overload (Box B). A : Macrophages 'overwhelmed' by continuous iron overloading as seen in conditions of chronic transfusion and increased erythrophagocytosis are compromised in their function of surveillance of bacterial growth resulting in increased host susceptibility to infection. As part of the natural response to bacterial infection macrophages modulate the expression of a number of genes involved in the regulation of cellular iron metabolism. By activating the cytokine cascade they induce up-regulation of liver hepcidin synthesis with further increase in macrophage iron retention and perpetuation of this cycle; B : A 'non-phagocytic' or parenchymal iron overload is observed in hepatocytes of several defective immune system models associated with a relative iron deficiency in macrophages, recapitulating the findings observed in the human model of Hereditary Hemochromatosis. The mechanisms underlying the spontaneous development of iron overload in these models are not yet understood. Three possible (not mutually exclusive) mechanisms are represented in this figure: (1) the fact that both Hfe and β 2m knockout mouse models lack the liver hepcidin response to iron overload [90,97,98] may support the notion of a liver-derived, systemically induced iron overload. The involvement of liver hepcidin in the development of iron overload in mice deficient in the MHC-class Ⅰ molecules H2K b and D b (HLA) was never tested; (2) the iron overload seen in the β 2m -/-Rag1 -/-and Hfe -/-Rag1 -/-mouse models support the involvement of lymphocytes themselves as modifiers of the severe parenchymal iron overload phenotype seen in those mice [39] ; (3) finally, the recent demonstration of a strong link between the MHC-class Ⅰ region and the genetic transmission of low CD8+ T lymphocyte numbers in humans and the association of total lymphocyte numbers with a more severe iron overload phenotype in patients with Hereditary Hemochroma tosis [78,82,83] opens a new possibility that another, still unidentified MHC-class Ⅰ associated gene(s) may simultaneously regulate CD8+ T lymphocyte numbers and influence the development of parenchymal iron overload [84] .](/paper-figures/ae885087c1604df897d426e500b03ad0/iron-overload-and-immunity-figure-1.png)
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“Previous studies support the notion that optimal immunity operates within a range of physiological Fe concentrations [41].”
From Host Iron Withholding Demands Siderophore Utilization for Candida glabrata to Survive Macrophage Killing (2011) · cites this paper as [41]
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Metadata
- Authors
- Porto, G.
- Affiliations
- Instituto de Biologia Molecular e Celular (PT)
- Corresponding author
- Porto, Graça
- ORCID
- Porto, Graça
- Venue
- World Journal of Gastroenterology
- Publisher
- Baishideng Publishing Group Inc.
- Published
- 2007
- Volume
- 13
- Issue
- 35
- Pages
- 4707
- ISSN
- 1007-9327 (ISSN-L)
- PMC
- PMC4611192
- OpenAlex
- W2126983810
- Cited by
- 140
- References
- 107
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 6 · 2023: 4 · 2022: 5 · 2021: 8 · 2020: 6 · 2019: 9 · 2018: 7 · 2017: 8 · 2016: 10 · 2015: 6 · 2014: 6 · 2013: 10 · 2012: 5
- FWCI
- 1.40
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- World Journal of Gastroenterology (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Keywords
- iron overload, iron homeostasis, innate immunity, macrophages, T cells, adaptive immunity, hereditary hemochromatosis, iron metabolism genes
- MeSH terms
- Hemochromatosis Protein, Animals, Genes, MHC Class I, Homeostasis, Humans, Immunity, Innate, Iron, Membrane Proteins, Histocompatibility Antigens Class I, Iron Overload, Mice
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