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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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“It has been observed that the cell involved in iron overload with the greatest effect on immunity is the macrophage, and there is a close relationship between iron and the major cells of adaptive immunity, the T lymphocytes, since they are major players in recycling the iron from hemoglobin [20].”
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“The mammalian immune system is therefore a double-edged sword, that is, equipped with mechanisms to withhold iron from microbes, to resist direct attack by invading pathogens and prevent iron overload.((10)) Consequently, the immune system has protective functions against both infection and the potential toxic effects…”
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Iron deprivation restrains the differentiation and pathogenicity of T helper 17 cell
Li, L., Xia, Y., Yuan, S., Li, F., Xie, X., Luo, Y. M., Yang, X., & He, R. (2021) · Journal of Leukocyte Biology · doi:10.1002/jlb.3ma0821-015r · Cited by 28
Ige, A. O., Ongele, F. A., Adele, B. O., Emediong, I. E., Odetola, A. O., & Adewoye, E. O. (2019) · Pathophysiology · doi:10.1016/j.pathophys.2019.03.002 · Cited by 27
Ba, T., Zhao, D., Chen, Y., Zeng, C., Zhang, C., Niu, S., & Dai, H. (2022) · Nutrients · doi:10.3390/nu14214549 · Cited by 27
“Importantly, iron overload had the greatest effect on immunity [67].”
BackgroundTelser, J., Volani, C., Hilbe, R., Seifert, M., Brigo, N., Paglia, G., & Weiß, G. (2019) · Microbial Cell · doi:10.15698/mic2019.12.700 · Cited by 23
“Moreover, iron exerts subtle effects on cellular immune regulation by affecting the differentiation of lymphocytes [18] but also by impacting on macrophage anti-microbial immune effector mechanisms including the formation of oxy-”
BackgroundSafety Issues in Iron Treatment in CKD
Vaziri, N. D. (2016) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2016.02.005 · Cited by 23
“For example, iron overload has been shown to deplete helper CD4þ T lymphocytes and increase expansion of CD8þCD28- suppressor T cells.(52,53) Lymphocytes have a poor ability to sequester iron such that excess iron impairs proliferation and promotes apoptosis in these cells.”
BackgroundEstablishment of a novel ferroptosis-related lncRNA pair prognostic model in colon adenocarcinoma
Li, H., Liu, L., Huang, T., Jin, M. L., Zheng, Z., Zhang, H., Ye, M., & Liu, K. (2021) · Aging · doi:10.18632/aging.203599 · Cited by 23
“Intriguing evidence indicated that parenchymal iron overload is linked to genes classically associated with the immune system [55].”
BackgroundDo Laboratory Mouse Females that Lose Their Litters Behave Differently around Parturition?
Weber, E. M., Hultgren, J., Algers, B., & Olsson, I. A. S. (2016) · PLoS ONE · doi:10.1371/journal.pone.0161238 · Cited by 22
Hong, J. Y., Davaa, G., Yoo, H., Hong, K., & Hyun, J. K. (2020) · Cells · doi:10.3390/cells9051310 · Cited by 21
Hultman, P. A., & Pollard, K. M. (2014) · Elsevier eBooks · doi:10.1016/b978-0-444-59453-2.00019-6 · Cited by 19
Adaptive immunity and vaccination – iron in the spotlight
Preston, A. E., Drakesmith, H., & Frost, J. N. (2021) · Immunotherapy Advances · doi:10.1093/immadv/ltab007 · Cited by 21
Ma, C. K. K., Clancy, L. E., Deo, S. S., Blyth, E., Micklethwaite, K. P., & Gottlieb, D. J. (2016) · Cytotherapy · doi:10.1016/j.jcyt.2016.09.013 · Cited by 18
“HLA-A3positive HH patients have reduced percentages of CD8+ CD28+ T cells in peripheral blood [57], and functional studies have shown that CD8 T cells from such donors exhibit reduced cytotoxic activity compared with CD8 T cells from healthy controls [57,58].”
BackgroundSumida, K., Diskin, C. J., Molnar, M. Z., Potukuchi, P. K., Thomas, F., Lü, J., Rhee, C. M., Streja, E., Yamagata, K., Kalantar‐Zadeh, K., et al. (2017) · American Journal of Nephrology · doi:10.1159/000484356 · Cited by 18
Azcárate, I. G., Sánchez-Jaut, S., Marín-García, P., Linares, M., Pérez-Benavente, S., García-Sánchez, M., Uceda, J., Kamali, A. N., Morán-Jiménez, M.-J., Puyet, A., et al. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2017.09.027 · Cited by 12
“Not much research has addressed the interaction between iron loading and DCs function [67], and we have observed a preference of monocyte recruitment into spleens to differentiate into macrophages.”
BackgroundCiobanu, L. G., Sachdev, P. S., Trollor, J. N., Reppermund, S., Thalamuthu, A., Mather, K. A., Cohen‐Woods, S., Stacey, D., Toben, C. G., Schubert, K. O., et al. (2020) · Journal of Affective Disorders · doi:10.1016/j.jad.2020.02.001 · Cited by 16
Functional Consequences of Human Lymphocyte Cryopreservation
Faint, J., Tuncer, C., Garg, A., Adams, D., & Lalor, P. F. (2011) · Journal of Immunotherapy · doi:10.1097/cji.0b013e31822bc3d0 · Cited by 16
Resch, T., Ashraf, M., Ritschl, P. V., Ebner, S., Fabritius, C., Brunner, A., Schäfer, G., Regele, H. M., Günther, J., Weiß, G., et al. (2017) · The Journal of Heart and Lung Transplantation · doi:10.1016/j.healun.2017.03.004 · Cited by 15
Das, S., Saqib, M., Meng, R. C., Chittur, S. V., Guan, Z., Wan, F., & Sun, W. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2110166119 · Cited by 14
“As mentioned earlier (48), iron-overload tips the immunoregulatory balance of hosts unfavorably and impairs host immunity, which may favor the explosive proliferation of Δfur in HH mice.”
Graff, R. E., Cho, E., Lindström, S., Kraft, P. L., Willett, W. C., & Eliassen, A. H. (2014) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-13-0907 · Cited by 13
“Iron also suppresses host defenses, thereby permitting cancer cell proliferation, and acts as a nutrient for unrestricted tumor cell multiplication (8, 11-13).”
Wróblewska, A., Bernat, A., Woziwodzka, A., Markiewicz, J., Romanowski, T., Bielawski, K. P., Smiatacz, T., & Sikorska, K. (2016) · Clinical and Experimental Medicine · doi:10.1007/s10238-016-0423-4 · Cited by 14
“Deficiency in proteins of the adaptive immune response such as b-microglobulin or MHC class I leads to iron overload in mice [32].”
BackgroundIron and the Reticuloendothelial System
Weiß, G. (2011) · Humana Press eBooks · doi:10.1007/978-1-60327-485-2_11 · Cited by 13
Advances in Parasite Control in Africa: From Basic Science to Translation
Mutapi, F. (2012) · Journal of Parasitology Research · doi:10.1155/2012/158039 · Cited by 12
Grubwieser, P., Brigo, N., Seifert, M., Grander, M., Theurl, I., Nairz, M., Weiß, G., & Pfeifhofer‐Obermair, C. (2024) · BIO-PROTOCOL · doi:10.21769/bioprotoc.4929 · Cited by 14
“Appropriately, a state of systemic or cellular iron excess is associated with increased bacterial proliferation (Khan et al., 2007; Porto and De Sousa, 2007; Kao et al., 2016).”
BackgroundNasir, N. J. M., Heemskerk, H., Jenkins, J., Hamadee, N. H., Bunte, R. M., & Tucker‐Kellogg, L. (2023) · eLife · doi:10.7554/elife.85633 · Cited by 11
Hong-bin, S., Wan-jun, Y., Chen-hui, D., Yang, X., Shen-song, L., & Zhou, P. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.816460 · Cited by 12
The role of iron in immunity and inflammation: implications for the response to infection
Kuvibidila, S. R., Baliga, S. B., Chandra, L. C., & French, C. (2013) · Elsevier eBooks · doi:10.1533/9780857095749.2.193 · Cited by 11
Immune Function in Chronic Kidney Disease
Pahl, M. V., & Vaziri, N. D. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-411602-3.00024-x · Cited by 11
Su, J., Zhong, G., Qin, W., Zhou, L., Ye, J., Ye, Y., Chen, C., Liang, P., Zhao, W., Xiao, X., et al. (2024) · Discover Oncology · doi:10.1007/s12672-024-00969-3 · Cited by 10
“Decreased transferrin and its receptor may lead to reduced thymic cell numbers [68, 69].”
BackgroundHistopathological changes in myocardial tissue due to coronary venous hypertension
Akşıt, E., Büyük, B., & Oğuz, S. (2020) · Archives of Medical Science · doi:10.5114/aoms.2019.91472 · Cited by 10
“Reportedly, iron overload directly damages the tissue by oxidative stress and indirectly by leading to the primary activation of the autoimmune cascade [25].”
BackgroundInflammation-induced effects on iron-related proteins in splenic macrophages and the liver in mice
Sukumaran, A., Venkatraman, A., & Jacob, M. (2012) · Blood Cells Molecules and Diseases · doi:10.1016/j.bcmd.2012.03.002 · Cited by 10
Iron overload in HFE-related hemochromatosis severely impairs Vδ2+ γδ T-cell homeostasis
Erdoğdu, D., Becoku, I., Huber, V., Wang, Y., Eyrich, M. K., Hashimoto, H., Döring, M., Schulte, J. H., & Schilbach, K. (2025) · Blood · doi:10.1182/blood.2024025345 · Cited by 9
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Elevated Iron Indices in Preterm Infants: Association with Male Gender
Molloy, E. J., EL-Khuffash, A. F., Bieda, A., Jelinek, M., & Baley, J. E. (2008) · American Journal of Perinatology · doi:10.1055/s-0028-1090588 · Cited by 9
“Iron overload alters immune function.(25) Iron overload decreases antibody-mediated and mitogenstimulated phagocytosis by monocytes and macrophages, alters T-lymphocyte subsets, modifies lymphocyte distribution in different compartments of the immune system,(26) suppresses functions of the complement system, may cause…”
BackgroundIron in the inflammed gut: another pro-inflammatory hit?
Weiß, G. (2010) · Gut · doi:10.1136/gut.2010.229047 · Cited by 9
“The induction of experimental iron overload in rats resulted in a shift in the ratio between T-helper (CD4+) and T-suppressor/cytotoxic T cells (CD8+) with a relative expansion of the latter.(2) Moreover, T-helper (Th) subsets respond differently to iron perturbations with Th-1 cells being more sensitive to iron restr…”
BackgroundInfluentialSikorska, K., Romanowski, T., & Bielawski, K. P. (2014) · Biotechnologia · doi:10.5114/bta.2011.46517 · Cited by 8
Şıvgın, S., Baldane, S., Denız, K., Zararsız, G., Kaynar, L., Çetın, M., Ünal, A., & Eser, B. (2016) · Clinical Lymphoma Myeloma & Leukemia · doi:10.1016/j.clml.2016.02.005 · Cited by 8
“0 386 (210-5904) 28 (13-54) 1 922 (123-1565) 26 (12-83) 2 1689 (576-14,865) 49 (3-97) 3 2272 (1348-3869) 43.”
Foka, P., Dimitriadis, A., Karamichali, E., Kochlios, E., Eliadis, P., Valiakou, V., Koskinas, J. S., Mamalaki, A., & Georgopoulou, U. (2021) · Cells · doi:10.3390/cells10092251 · Cited by 10
“This may have serious connotations for viral elimination during early infection, since it has been suggested that the iron-mediated deregulation of innate immune responses may in turn affect adaptive immune responses, possibly on top of a more direct effect of iron-driven changes on T-lymphocytes [70].”
BackgroundGhaith, M. M., El‐Boshy, M., Almasmoum, H. A., Abdelghany, A. H., Azzeh, F. S., Almaimani, R. A., Idris, S., Ahmad, J., Mahbub, A. A., Basalamah, M. A., et al. (2022) · Journal of Trace Elements in Medicine and Biology · doi:10.1016/j.jtemb.2022.127085 · Cited by 8
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Use of Metal-Rich Slag as a Source of Grit and Its Effects on Pigeon Health and Fitness
Parker, G. H., & Kraak, G. V. D. (2018) · Journal of Environmental Science and Pollution Research · doi:10.30799/jespr.121.18040201 · Cited by 7
“Other fitness parameters, including assessment of the status and performance of the immunological system, as discussed by Porto and De Sousa [30] and Walker and Walker [31], were not examined but may represent a worthwhile direction for future studies.”
MethodÉléments-trace essentiels en nutrition humaine: chrome, sélénium, zinc et fer
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Hepatic Pathobiology of Iron Overload
Ruddell, R. G., & Ramm, G. A. (2011) · Humana Press eBooks · doi:10.1007/978-1-60327-485-2_18 · Cited by 7
Estevam, M., Appoloni, C. R., Malvezi, A. D., Tatakihara, V. L. H., Panis, C., Cecchini, R., Rizzo, L. V., & Pinge‐Filho, P. (2011) · FEMS Immunology & Medical Microbiology · doi:10.1111/j.1574-695x.2011.00917.x · Cited by 5
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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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