Bet v 1 is the major allergen in birch pollen to which up to 95% of patients sensitized to birch respond. As a member of the pathogenesis-related PR 10 family, its natural function is implicated in plant defense, with a member of the PR10 family being reported to be upregulated under iron deficiency. As such, we assessed the function of Bet v 1 to sequester iron and its immunomodulatory properties on human immune cells. Binding of Bet v 1 to iron quercetin complexes FeQ2 was determined in docking calculations and by spectroscopy. Serum IgE-binding to Bet v 1 with (holoBet v1) and without ligands (apoBet v 1) were assessed by ELISA, blocking experiments and Western Blot. Crosslinking-capacity of apo/holoBet v 1 were assessed on human mast cells and Arylhydrocarbon receptor (AhR) activation with the human reporter cellline AZ-AHR. Human PBMCs were stimulated and assessed for labile iron and phenotypic changes by flow cytometry. Bet v 1 bound to FeQ2 strongly with calculated Kd values of 1 nm surpassing affinities to quercetin alone nearly by a factor of 1000. Binding to FeQ2 masked IgE epitopes and decreased IgE binding up to 80% and impaired degranulation of sensitized human mast cells. Bet v 1 facilitated the shuttling of quercetin, which activated the anti-inflammatory AhR pathway and increased the labile iron pool of human monocytic cells. The increase of labile iron was associated with an anti-inflammatory phenotype in CD14+monocytes and downregulation of HLADR. To summarize, we reveal for the first time that FeQ2 binding reduces the allergenicity of Bet v 1 due to ligand masking, but also actively contributes anti-inflammatory stimuli to human monocytes, thereby fostering tolerance. Nourishing immune cells with complex iron may thus represent a promising antigen-independent immunotherapeutic approach to improve efficacy in allergen immunotherapy.

Center for Plant Biotechnology and Genomics Biotechnology Department ETSIAAB CBGP Universidad Politécnica de Madrid 28040 Madrid Spain

Center of Pathophysiology Infectiology and Immunology Institute of Pathophysiology and Allergy Research Medical University of Vienna 1090 Vienna Austria

Comparative Medicine The Interuniversity Messerli Research Institute of the University of Veterinary Medicine Vienna Medical University Vienna and University of Vienna 1210 Vienna Austria

Department of Biosciences University of Salzburg 5020 Salzburg Austria

Department of Cell Biology and Genetics Faculty of Science Palacky University 78371 Olomouc Czech Republic

Division of Pharmacology Utrecht Institute for Pharmaceutical Sciences Faculty of Science Utrecht University 3584 CG Utrecht The Netherlands

Zobrazit více v PubMed

Jensen-Jarolim E., Pacios L., Bianchini R., Hofstetter G., Roth-Walter F. Structural similarities of human and mammalian lipocalins, and their function in innate immunity and allergy. Allergy. 2016;71:286–294. doi: 10.1111/all.12797. PubMed DOI PMC

Missaoui K., Gonzalez-Klein Z., Pazos-Castro D., Hernandez-Ramirez G., Garrido-Arandia M., Brini F., Diaz-Perales A., Tome-Amat J. Plant non-specific lipid transfer proteins: An overview. Plant Physiol. Biochem. 2022;171:115–127. doi: 10.1016/j.plaphy.2021.12.026. PubMed DOI

Shewry P.R., Beaudoin F., Jenkins J., Griffiths-Jones S., Mills E.N.C. Plant protein families and their relationships to food allergy. Biochem. Soc. Trans. 2002;30:906–910. doi: 10.1042/bst0300906. PubMed DOI

Iizuka T., Barre A., Rougé P., Charpin D., Scala E., Baudin B., Aizawa T., Sénéchal H., Poncet P. Gibberellin-regulated proteins: Emergent allergens. Front. Allergy. 2022;3:877553. doi: 10.3389/falgy.2022.877553. PubMed DOI PMC

Radauer C., Breiteneder H. Evolutionary biology of plant food allergens. J. Allergy Clin. Immunol. 2007;120:518–525. doi: 10.1016/j.jaci.2007.07.024. PubMed DOI

Roth-Walter F., Gomez-Casado C., Pacios L.F., Mothes-Luksch N., Roth G.A., Singer J., Diaz-Perales A., Jensen-Jarolim E. Bet v 1 from birch pollen is a lipocalin-like protein acting as allergen only when devoid of iron by promoting Th2 lymphocytes. J. Biol. Chem. 2014;289:17416–17421. doi: 10.1074/jbc.M114.567875. PubMed DOI PMC

Roth-Walter F., Schmutz R., Mothes-Luksch N., Lemell P., Zieglmayer P., Zieglmayer R., Jensen-Jarolim E. Clinical efficacy of sublingual immunotherapy is associated with restoration of steady-state serum lipocalin 2 after SLIT: A pilot study. World Allergy Organ. J. 2018;11:21. doi: 10.1186/s40413-018-0201-8. PubMed DOI PMC

Devireddy L.R., Gazin C., Zhu X., Green M.R. A Cell-Surface Receptor for Lipocalin 24p3 Selectively Mediates Apoptosis and Iron Uptake. Cell. 2005;123:1293–1305. doi: 10.1016/j.cell.2005.10.027. PubMed DOI

Meier J., Schnetz M., Beck S., Schmid T., Dominguez M., Kalinovic S., Daiber A., Brüne B., Jung M. Iron-Bound Lipocalin-2 Protects Renal Cell Carcinoma from Ferroptosis. Metabolites. 2021;11:329. doi: 10.3390/metabo11050329. PubMed DOI PMC

Mertens C., Kuchler L., Sola A., Guiteras R., Grein S., Brüne B., Von Knethen A., Jung M. Macrophage-Derived Iron-Bound Lipocalin-2 Correlates with Renal Recovery Markers Following Sepsis-Induced Kidney Damage. Int. J. Mol. Sci. 2020;21:7527. doi: 10.3390/ijms21207527. PubMed DOI PMC

Ali S., Ganai B.A., Kamili A.N., Bhat A.A., Mir Z.A., Bhat J.A., Tyagi A., Islam S.T., Mushtaq M., Yadav P., et al. Pathogenesis-related proteins and peptides as promising tools for engineering plants with multiple stress tolerance. Microbiol. Res. 2018;212–213:29–37. doi: 10.1016/j.micres.2018.04.008. PubMed DOI

Herlihy J.H., Long T.A., McDowell J.M. Iron homeostasis and plant immune responses: Recent insights and translational implications. J. Biol. Chem. 2020;295:13444–13457. doi: 10.1074/jbc.REV120.010856. PubMed DOI PMC

Trapet P.L., Verbon E.H., Bosma R.R., Voordendag K., Van Pelt J.A., Pieterse C.M.J. Mechanisms underlying iron deficiency-induced resistance against pathogens with different lifestyles. J. Exp. Bot. 2021;72:2231–2241. doi: 10.1093/jxb/eraa535. PubMed DOI

Shen C., Yang Y., Liu K., Zhang L., Guo H., Sun T., Wang H. Involvement of endogenous salicylic acid in iron-deficiency responses in Arabidopsis. J. Exp. Bot. 2016;67:4179–4193. doi: 10.1093/jxb/erw196. PubMed DOI

Aznar A., Chen N., Rigault M., Riache N., Joseph D., Desmaële D., Mouille G., Boutet S., Soubigou-Taconnat L., Renou J.-P., et al. Scavenging Iron: A Novel Mechanism of Plant Immunity Activation by Microbial Siderophores. Plant Physiol. 2014;164:2167–2183. doi: 10.1104/pp.113.233585. PubMed DOI PMC

Waters B.M., Amundsen K., Graef G. Gene Expression Profiling of Iron Deficiency Chlorosis Sensitive and Tolerant Soybean Indicates Key Roles for Phenylpropanoids under Alkalinity Stress. Front. Plant Sci. 2018;9:10. doi: 10.3389/fpls.2018.00010. PubMed DOI PMC

Fraser C.M., Chapple C. The Phenylpropanoid Pathway in Arabidopsis. Arab. Book. 2011;9:e0152. doi: 10.1199/tab.0152. PubMed DOI PMC

Wasli H., Jelali N., Saada M., Ksouri R., Cardoso S. Insights on the Adaptation of Foeniculum vulgare Mill to Iron Deficiency. Appl. Sci. 2021;11:7072. doi: 10.3390/app11157072. DOI

Verbon E.H., Trapet P.L., Stringlis I.A., Kruijs S., Bakker P.A., Pieterse C.M. Iron and Immunity. Annu. Rev. Phytopathol. 2017;55:355–375. doi: 10.1146/annurev-phyto-080516-035537. PubMed DOI

Liu G., Greenshields D.L., Sammynaiken R., Hirji R.N., Selvaraj G., Wei Y. Targeted alterations in iron homeostasis underlie plant defense responses. J. Cell Sci. 2007;120:596–605. doi: 10.1242/jcs.001362. PubMed DOI

Dellagi A., Segond D., Rigault M., Fagard M., Simon C., Saindrenan P., Expert D. Microbial Siderophores Exert a Subtle Role in Arabidopsis during Infection by Manipulating the Immune Response and the Iron Status. Plant Physiol. 2009;150:1687–1696. doi: 10.1104/pp.109.138636. PubMed DOI PMC

Klessig D.F., Durner J., Noad R., Navarre D.A., Wendehenne D., Kumar D., Zhou J.M., Shah J., Zhang S., Kachroo P., et al. Nitric oxide and salicylic acid signaling in plant defense. Proc. Natl. Acad. Sci. USA. 2000;97:8849–8855. doi: 10.1073/pnas.97.16.8849. PubMed DOI PMC

Sánchez-Sanuy F., Cuadra R.M., Okada K., Sacchi G.A., Campo S., San Segundo B. Iron treatment induces defense responses and disease resistance against Magnaporthe oryzae in rice. bioRxiv. 2021 doi: 10.1101/2021.12.09.471912. PubMed DOI

Seutter von Loetzen C., Hoffmann T., Hartl M.J., Schweimer K., Schwab W., Rösch P., Hartl-Spiegelhauer O. Secret of the major birch pollen allergen Bet v 1: Identification of the physiological ligand. Biochem. J. 2014;457:379–390. doi: 10.1042/BJ20130413. PubMed DOI

Ren J., Meng S., Lekka C.E., Kaxiras E. Complexation of Flavonoids with Iron: Structure and Optical Signatures. J. Phys. Chem. B. 2008;112:1845–1850. doi: 10.1021/jp076881e. PubMed DOI

Morel I., Lescoat G., Cogrel P., Sergent O., Pasdeloup N., Brissot P., Cillard P., Cillard J. Antioxidant and iron-chelating activities of the flavonoids catechin, quercetin and diosmetin on iron-loaded rat hepatocyte cultures. Biochem. Pharmacol. 1993;45:13–19. doi: 10.1016/0006-2952(93)90371-3. PubMed DOI

Kofler S., Asam C., Eckhard U., Wallner M., Ferreira F., Brandstetter H. Crystallographically Mapped Ligand Binding Differs in High and Low IgE Binding Isoforms of Birch Pollen Allergen Bet v 1. J. Mol. Biol. 2012;422:109–123. doi: 10.1016/j.jmb.2012.05.016. PubMed DOI PMC

Worda J.M., Lovell S., Richardson J., Richardson D.C. Asparagine and glutamine: Using hydrogen atom contacts in the choice of side-chain amide orientation. J. Mol. Biol. 1999;285:1735–1747. doi: 10.1006/jmbi.1998.2401. PubMed DOI

Morris G.M., Huey R., Lindstrom W., Sanner M.F., Belew R.K., Goodsell D.S., Olson A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem. 2009;30:2785–2791. doi: 10.1002/jcc.21256. PubMed DOI PMC

Trott O., Olson A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 2010;31:455–461. doi: 10.1002/jcc.21334. PubMed DOI PMC

Eberhardt J., Santos-Martins D., Tillack A.F., Forli S. AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings. J. Chem. Inf. Model. 2021;61:3891–3898. doi: 10.1021/acs.jcim.1c00203. PubMed DOI PMC

Carson M. Ribbons. Methods Enzymol. 1997;277:493–505. doi: 10.1016/0263-7855(94)80044-8. PubMed DOI

Pettersen E.F., Goddard T.D., Huang C.C., Couch G.S., Greenblatt D.M., Meng E.C., Ferrin T.E. UCSF Chimera?A visualization system for exploratory research and analysis. J. Comput. Chem. 2004;25:1605–1612. doi: 10.1002/jcc.20084. PubMed DOI

Guhsl E.E., Hofstetter G., Hemmer W., Ebner C., Vieths S., Vogel L., Breiteneder H., Radauer C. Vig r 6, the cytokinin-specific binding protein from mung bean (Vigna radiata) sprouts, cross-reacts with Bet v 1-related allergens and binds IgE from birch pollen allergic patients’ sera. Mol. Nutr. Food Res. 2014;58:625–634. doi: 10.1002/mnfr.201300153. PubMed DOI PMC

Erel O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin. Biochem. 2004;37:277–285. doi: 10.1016/j.clinbiochem.2003.11.015. PubMed DOI

Miller N.J., Rice-Evans C., Davies M.J., Gopinathan V., Milner A. A Novel Method for Measuring Antioxidant Capacity and its Application to Monitoring the Antioxidant Status in Premature Neonates. Clin. Sci. 1993;84:407–412. doi: 10.1042/cs0840407. PubMed DOI

Petje L., Jensen S.A., Szikora S., Sulzbacher M., Bartosik T., Pjevac P., Hausmann B., Hufnagl K., Untersmayr E., Fischer L., et al. Functional iron-deficiency in women with allergic rhinitis is associated with symptoms after nasal provocation and lack of iron-sequestering microbes. Allergy. 2021;76:2882–2886. doi: 10.1111/all.14960. PubMed DOI PMC

Bartosik T., Jensen S.A., Afify S.M., Bianchini R., Hufnagl K., Hofstetter G., Berger M., Bastl M., Berger U., Rivelles E., et al. Ameliorating Atopy by Compensating Micronutritional Deficiencies in Immune Cells: A Double-Blind Placebo-Controlled Pilot Study. J. Allergy Clin. Immunol. Pract. 2022;10:1889–1902.e9. doi: 10.1016/j.jaip.2022.02.028. PubMed DOI

Folkerts J., Redegeld F., Folkerts G., Blokhuis B., van den Berg M.P., de Bruijn M.J., van IJcken W.F., Junt T., Tam S.Y., Galli S.J., et al. Butyrate inhibits human mast cell activation via epigenetic regulation of FcepsilonRI-mediated signaling. Allergy. 2020;75:1966–1978. doi: 10.1111/all.14254. PubMed DOI PMC

Afify S.M., Regner A., Pacios L.F., Blokhuis B.R., Jensen S.A., Redegeld F.A., Pali-Schöll I., Hufnagl K., Bianchini R., Guethoff S., et al. Micronutritional supplementation with a holoBLG-based FSMP (food for special medical purposes)-lozenge alleviates allergic symptoms in BALB/c mice: Imitating the protective farm effect. Clin. Exp. Allergy. 2022;52:426–441. doi: 10.1111/cea.14050. PubMed DOI

Roth-Walter F., Afify S.M., Pacios L.F., Blokhuis B.R., Redegeld F., Regner A., Petje L.M., Fiocchi A., Untersmayr E., Dvorak Z., et al. Cow’s milk protein beta-lactoglobulin confers resilience against allergy by targeting complexed iron into immune cells. J. Allergy Clin. Immunol. 2021;147:321–334.e4. doi: 10.1016/j.jaci.2020.05.023. PubMed DOI

Luscher A., Gasser V., Bumann D., Mislin G.L., Schalk I.J., Köhler T. Plant-Derived Catechols Are Substrates of TonB-Dependent Transporters and Sensitize Pseudomonas aeruginosa to Siderophore-Drug Conjugates. mBio. 2022;13:e0149822. doi: 10.1128/mbio.01498-22. PubMed DOI PMC

Roth-Walter F. Iron-Deficiency in Atopic Diseases: Innate Immune Priming by Allergens and Siderophores. Front. Allergy. 2022;3:859922. doi: 10.3389/falgy.2022.859922. PubMed DOI PMC

Gieras A., Cejka P., Blatt K., Focke-Tejkl M., Linhart B., Flicker S., Stoecklinger A., Marth K., Drescher A., Thalhamer J., et al. Mapping of Conformational IgE Epitopes with Peptide-Specific Monoclonal Antibodies Reveals Simultaneous Binding of Different IgE Antibodies to a Surface Patch on the Major Birch Pollen Allergen, Bet v 1. J. Immunol. 2011;186:5333–5344. doi: 10.4049/jimmunol.1000804. PubMed DOI

Novotna A., Petr P., Dvorak Z. Novel Stably Transfected Gene Reporter Human Hepatoma Cell Line for Assessment of Aryl Hydrocarbon Receptor Transcriptional Activity: Construction and Characterization. Environ. Sci. Technol. 2011;45:10133–10139. doi: 10.1021/es2029334. PubMed DOI

Mengos A.E., Gastineau D.A., Gustafson M.P. The CD14(+)HLA-DR(lo/neg) Monocyte: An Immunosuppressive Phenotype That Restrains Responses to Cancer Immunotherapy. Front. Immunol. 2019;10:1147. doi: 10.3389/fimmu.2019.01147. PubMed DOI PMC

Wasuwanich P., Fan G., Burke B., Furst A.L. Metal-phenolic networks as tuneable spore coat mimetics. J. Mater. Chem. B. 2022;10:7600–7606. doi: 10.1039/D2TB00717G. PubMed DOI

Khan I.H., Javaid A. Biocontrol Aspergillus species together with plant biomass alter histochemical characteristics in diseased mungbean plants. Microsc. Res. Tech. 2022;85:2953–2964. doi: 10.1002/jemt.24145. PubMed DOI

Afify S.M., Pali-Schöll I., Hufnagl K., Hofstetter G., El-Bassuoni M.A.-R., Roth-Walter F., Jensen-Jarolim E. Bovine Holo-Beta-Lactoglobulin Cross-Protects Against Pollen Allergies in an Innate Manner in BALB/c Mice: Potential Model for the Farm Effect. Front. Immunol. 2021;12:611474. doi: 10.3389/fimmu.2021.611474. PubMed DOI PMC

Bergmann K.C., Raab J., Krause L., Becker S., Kugler S., Zuberbier T., Roth-Walter F., Jensen-Jarolim E., Kramer M.F., Graessel A. Long-term benefits of targeted micronutrition with the holoBLG lozenge in house dust mite allergic patients. Allergo J. Int. 2022. (accepted)

Bergmann K.-C., Graessel A., Raab J., Banghard W., Krause L., Becker S., Kugler S., Zuberbier T., Ott V.B., Kramer M.F., et al. Targeted micronutrition via holo-BLG based on the farm effect in house dust mite allergic rhinoconjunctivitis patients—First evaluation in a standardized allergen exposure chamber. Allergo J. Int. 2021;30:141–149. doi: 10.1007/s40629-021-00163-9. DOI

Lin L., Dai Y., Xia Y. An overview of aryl hydrocarbon receptor ligands in the Last two decades (2002–2022): A medicinal chemistry perspective. Eur. J. Med. Chem. 2022;244:114845. doi: 10.1016/j.ejmech.2022.114845. PubMed DOI

Koch S., Stroisch T.J., Vorac J., Herrmann N., Leib N., Schnautz S., Kirins H., Förster I., Weighardt H., Bieber T. AhR mediates an anti-inflammatory feedback mechanism in human Langerhans cells involving FcepsilonRI and IDO. Allergy. 2017;72:1686–1693. doi: 10.1111/all.13170. PubMed DOI

Roth-Walter F., Bergmayr C., Meitz S., Buchleitner S., Stremnitzer C., Fazekas-Singer J., Moskovskich A., Müller M.A., Roth G.A., Manzano-Szalai K., et al. Janus-faced Acrolein prevents allergy but accelerates tumor growth by promoting immunoregulatory Foxp3+ cells: Mouse model for passive respiratory exposure. Sci. Rep. 2017;7:45067. doi: 10.1038/srep45067. PubMed DOI PMC

Gandhi R., Kumar D., Burns E.J., Nadeau M., Dake B., Laroni A., Kozoriz D., Weiner H.L., Quintana F.J. Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell–like and Foxp3+ regulatory T cells. Nat. Immunol. 2010;11:846–853. doi: 10.1038/ni.1915. PubMed DOI PMC

Negishi T., Kato Y., Ooneda O., Mimura J., Takada T., Mochizuki H., Yamamoto M., Fujii-Kuriyama Y., Furusako S. Effects of aryl hydrocarbon receptor signaling on the modulation of TH1/TH2 balance. J. Immunol. 2005;175:7348–7356. doi: 10.4049/jimmunol.175.11.7348. PubMed DOI

Aguilera-Montilla N., Chamorro S., Nieto C., Sánchez-Cabo F., Dopazo A., Fernández-Salguero P.M., Rodríguez-Fernández J.L., Pello O.M., Andrés V., Cuenda A., et al. Aryl hydrocarbon receptor contributes to the MEK/ERK-dependent maintenance of the immature state of human dendritic cells. Blood. 2013;121:e108–e117. doi: 10.1182/blood-2012-07-445106. PubMed DOI

Agoro R., Taleb M., Quesniaux V.F.J., Mura C. Cell iron status influences macrophage polarization. PLoS ONE. 2018;13:e0196921. doi: 10.1371/journal.pone.0196921. PubMed DOI PMC

Carrasco-Marín E., Alvarez-Domínguez C., Lopez-Mato P., Martínez-Palencia R., Leyva-Cobian F., Carrasco-Marín E. Iron Salts and Iron-Containing Porphyrins Block Presentation of Protein Antigens by Macrophages to MHC Class II-Restricted T Cells. Cell Immunol. 1996;171:173–185. doi: 10.1006/cimm.1996.0192. PubMed DOI

Leung S., Holbrook A., King B., Lu H.-T., Evans V., Miyamoto N., Mallari C., Harvey S., Davey D., Ho E., et al. Differential Inhibition of Inducible T Cell Cytokine Secretion by Potent Iron Chelators. J. Biomol. Screensupp. 2005;10:157–167. doi: 10.1177/1087057104272295. PubMed DOI

Jason J., Archibald L.K., Nwanyanwu O.C., Bell M., Jensen R.J., Gunter E., Buchanan I., Larned J., Kazembe P.N., Dobbie H., et al. The effects of iron deficiency on lymphocyte cytokine production and activation: Preservation of hepatic iron but not at all cost. Clin. Exp. Immunol. 2001;126:466–473. doi: 10.1046/j.1365-2249.2001.01707.x. PubMed DOI PMC

Thorson J.A., Smith K.M., Gomez F., Naumann P.W., Kemp J.D. Role of iron in T cell activation: Th1 clones differ from TH2 clones in their sensitivity to inhibition of DNA synthesis caused by IGG mabs against the transferrin receptor and the iron chelator deferoxamine. Cell. Immunol. 1991;134:126–137. doi: 10.1016/0008-8749(91)90336-A. PubMed DOI

Drury K.E., Schaeffer M., Silverberg J.I. Association Between Atopic Disease and Anemia in US Children. JAMA Pediatr. 2016;170:29–34. doi: 10.1001/jamapediatrics.2015.3065. PubMed DOI

Rhew K., Brown J.D., Oh J.M. Atopic Disease and Anemia in Korean Patients: Cross-Sectional Study with Propensity Score Analysis. Int. J. Environ. Res. Public Health. 2020;17:1978. doi: 10.3390/ijerph17061978. PubMed DOI PMC

Rhew K., Oh J.M. Association between atopic disease and anemia in pediatrics: A cross-sectional study. BMC Pediatr. 2019;19:455. doi: 10.1186/s12887-019-1836-5. PubMed DOI PMC

Shaheen S.O., Gissler M., Devereux G., Erkkola M., Kinnunen T.I., Mcardle H., Sheikh A., Hemminki E., Nwaru B.I. Maternal iron supplementation in pregnancy and asthma in the offspring: Follow-up of a randomised trial in Finland. Eur. Respir. J. 2020;55:1902335. doi: 10.1183/13993003.02335-2019. PubMed DOI

Shaheen S.O., Macdonald-Wallis C., Lawlor D.A., Henderson A.J. Haemoglobin concentrations in pregnancy and respiratory and allergic outcomes in childhood: Birth cohort study. Clin. Exp. Allergy. 2017;47:1615–1624. doi: 10.1111/cea.13034. PubMed DOI PMC

Shaheen S., Newson R., Henderson A., Emmett P., Sherriff A., Cooke M. The ALSPAC Study Team Umbilical cord trace elements and minerals and risk of early childhood wheezing and eczema. Eur. Respir. J. 2004;24:292–297. doi: 10.1183/09031936.04.00117803. PubMed DOI

Nyakeriga A.M., Williams T.N., Marsh K., Wambua S., Perlmann H., Grandien A., Troye-Blomberg M. Cytokine mRNA Expression and Iron Status in Children Living in a Malaria Endemic Area. Scand. J. Immunol. 2005;61:370–375. doi: 10.1111/j.1365-3083.2005.01573.x. PubMed DOI

DeRosa A., Leftin A. The Iron Curtain: Macrophages at the Interface of Systemic and Microenvironmental Iron Metabolism and Immune Response in Cancer. Front. Immunol. 2021;12:614294. doi: 10.3389/fimmu.2021.614294. PubMed DOI PMC

Walter P.B., Knutson M.D., Paler-Martinez A., Lee S., Xu Y., Viteri F.E., Ames B.N. Iron deficiency and iron excess damage mitochondria and mitochondrial DNA in rats. Proc. Natl. Acad. Sci. USA. 2002;99:2264–2269. doi: 10.1073/pnas.261708798. PubMed DOI PMC

Barreto L.R., Barreto T., Melo S., Pungartnik C., Brendel M. Sensitivity of Yeast Mutants Deficient in Mitochondrial or Vacuolar ABC Transporters to Pathogenesis-Related Protein TcPR-10 of Theobroma cacao. Biology. 2018;7:35. doi: 10.3390/biology7020035. PubMed DOI PMC

Nutritional Provision of Iron Complexes by the Major Allergen Alt a 1 to Human Immune Cells Decreases Its Presentation