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Endocrine, Metabolic & Immune Disorders - Drug Targets


ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

Review Article

The Role of the Status of Selected Micronutrients in Shaping the Immune Function

Author(s): Ibrahim Elmadfa and Alexa L. Meyer*

Volume 19, Issue 8, 2019

Page: [1100 - 1115] Pages: 16

DOI: 10.2174/1871530319666190529101816


Objective: This narrative review gives an overview on the essential role of adequate nutrition to an optimally functioning immune defence. Micronutrients act as regulators of the immune response, with the focus of this review on the immunomodulatory effects of the trace elements iron, zinc and selenium, and the vitamins A, D, E, C, B6 and B12 and folic acid.

Results: Iron deficiency especially impairs the Th1 cell-borne cellular immunity. T lymphocytes are also most affected by a deficiency of zinc, needed for their maturation and the balance between the different T cell subpopulations and acting as a redox signal in the regulation of many enzymes. Selenium is also involved in redox reactions as the glutathione peroxidases and other redox enzymes are selenoproteins. Selenium status has shown special effects on cellular immunity and resistance to viral infections.

Vitamin A in the form of retinoic acid induces a humoral Th2 cell response via antigen-presenting cells and is involved in maintaining intestinal immune defence and tolerance through its nuclear receptor RAR and via kinase signalling cascades. Immune tolerance is particularly promoted by vitamin D acting through dendritic cells to stimulate the differentiation of regulatory T cells. Vitamin E has antiinflammatory effects and stimulates naïve T cells especially in the elderly. Besides its antioxidative properties, vitamin C has effects on cell signalling and epigenetic regulation. The B vitamins are required for cytotoxic cellular immunity and modulate T cell responses.

Conclusion: A diverse diet and regular exposure to sunlight are the best sources for a balanced nutrient supply to maintain an optimal immune defence.

Keywords: Immunonutrition, micronutrients, trace elements, vitamins, immune regulation, immune tolerance, inflammation.

Graphical Abstract
Chaplin, D.D. Overview of the immune response. J. Allergy Clin. Immunol., 2010, 125(2)(Suppl. 2), S3-S23.
[] [PMID: 20176265]
Katona, P.; Katona-Apte, J. The interaction between nutrition and infection. Clin. Infect. Dis., 2008, 46(10), 1582-1588.
[] [PMID: 18419494]
Ibrahim, M.K.; Zambruni, M.; Melby, C.L.; Melby, P.C. Im-pact of childhood malnutrition on host defense and infection. Clin. Microbiol. Rev., 2017, 30(4), 919-971.
[] [PMID: 28768707]
Kimmons, J.E.; Blanck, H.M.; Tohill, B.C.; Zhang, J.; Khan, L.K. Associations between body mass index and the prevalence of low micronutrient levels among US adults. MedGenMed, 2006, 8(4), 59.
[PMID: 17415336]
Astrup, A.; Bügel, S. Overfed but undernourished: recognizing nutritional inadequacies/deficiencies in patients with overweight or obesity. Int. J. Obes., 2019, 43(2), 219-232.
[] [PMID: 29980762]
Muthayya, S.; Rah, J.H.; Sugimoto, J.D.; Roos, F.F.; Kraemer, K.; Black, R.E. The global hidden hunger indices and maps: an advocacy tool for action. PLoS One, 2013, 8(6)e67860
[] [PMID: 23776712]
Fenech, M. The Genome Health Clinic and Genome Health Nutrigenomics concepts: diagnosis and nutritional treatment of genome and epigenome damage on an individual basis. Mutagenesis, 2005, 20(4), 255-269.
[] [PMID: 15956042]
Huskisson, E.; Maggini, S.; Ruf, M. The role of vitamins and minerals in energy metabolism and well-being. J. Int. Med. Res., 2007, 35(3), 277-289.
[] [PMID: 17593855]
Savina, A.; Amigorena, S. Phagocytosis and antigen presentation in dendritic cells. Immunol. Rev., 2007, 219, 143-156.
[] [PMID: 17850487]
Turner, M.D.; Nedjai, B.; Hurst, T.; Pennington, D.J. Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease. Biochim. Biophys. Acta, 2014, 1843(11), 2563-2582.
[] [PMID: 24892271]
Švajger, U.; Rožman, P. Induction of tolerogenic dendritic cells by endogenous biomolecules: An update. Front. Immunol., 2018, 9, 2482.
[] [PMID: 30416505]
Commins, S.P.; Borish, L.; Steinke, J.W. Immunologic messenger molecules: cytokines, interferons, and chemokines. J. Allergy Clin. Immunol., 2010, 125(2)(Suppl. 2), S53-S72.
[] [PMID: 19932918]
Hirahara, K.; Nakayama, T. CD4+ T-cell subsets in inflammatory diseases: beyond the Th1/Th2 paradigm. Int. Immunol., 2016, 28(4), 163-171.
[] [PMID: 26874355]
Bonilla, F.A.; Oettgen, H.C. Adaptive immunity. J. Allergy Clin. Immunol., 2010, 125(2)(Suppl. 2), S33-S40.
[] [PMID: 20061006]
Guglani, L.; Khader, S.A. Th17 cytokines in mucosal immunity and inflammation. Curr. Opin. HIV AIDS, 2010, 5(2), 120-127.
[] [PMID: 20543588]
Worley, L.; Tangye, S.G.; Ma, C.S. What can primary immunodeficiencies teach us about Th9 cell differentiation and function? Immunol. Cell Biol., 2019, 97(4), 380-388.
[] [PMID: 30357921]
Cosmi, L.; Maggi, L.; Santarlasci, V.; Liotta, F.; Annunziato, F. T helper cells plasticity in inflammation. Cytometry A, 2014, 85(1), 36-42.
[] [PMID: 24009159]
Sakaguchi, S.; Yamaguchi, T.; Nomura, T.; Ono, M. Regulatory T cells and immune tolerance. Cell, 2008, 133(5), 775-787.
[] [PMID: 18510923]
Hadaschik, E.N.; Enk, A.H. TGF-β1-induced regulatory T cells. Hum. Immunol., 2015, 76(8), 561-564.
[] [PMID: 26116540]
Peterson, R.A. Regulatory T-cells: diverse phenotypes integral to immune homeostasis and suppression. Toxicol. Pathol., 2012, 40(2), 186-204.
[] [PMID: 22222887]
Zeng, H.; Zhang, R.; Jin, B.; Chen, L. Type 1 regulatory T cells: a new mechanism of peripheral immune tolerance. Cell. Mol. Immunol., 2015, 12(5), 566-571.
[] [PMID: 26051475]
Weiss, G.; Ganz, T.; Goodnough, L.T. Anemia of inflammation. Blood, 2019, 133(1), 40-50.
[] [PMID: 30401705]
Mullick, S.; Rusia, U.; Sikka, M.; Faridi, M.A. Impact of iron deficiency anaemia on T lymphocytes & their subsets in children. Indian J. Med. Res., 2006, 124(6), 647-654.
[PMID: 17287552]
Aly, S.S.; Fayed, H.M.; Ismail, A.M.; Abdel Hakeem, G.L. Assessment of peripheral blood lymphocyte subsets in children with iron deficiency anemia. BMC Pediatr., 2018, 18(1), 49.
[] [PMID: 29433459]
Attia, M.A.; Essa, S.A.; Nosair, N.A.; Amin, A.M.; El-Agamy, O.A. Effect of iron deficiency anemia and its treatment on cell mediated immunity. Indian J. Hematol. Blood Transfus., 2009, 25(2), 70-77.
[] [PMID: 23100979]
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(1), 126-137.
[] [PMID: 1826464]
Drury, K.E.; Schaeffer, M.; Silverberg, J.I. Association be-tween atopic disease and anemia in US children. JAMA Pediatr., 2016, 170(1), 29-34.
[] [PMID: 26619045]
Bédard, A.; Lewis, S.J.; Burgess, S.; Henderson, A.J.; Shaheen, S.O. Maternal iron status during pregnancy and respiratory and atopic outcomes in the offspring: a Mendelian randomisation study. BMJ Open Respir. Res., 2018, 5(1)e000275
[] [PMID: 29636978]
Corna, G.; Campana, L.; Pignatti, E.; Castiglioni, A.; Tagliafico, E.; Bosurgi, L.; Campanella, A.; Brunelli, S.; Manfredi, A.A.; Apostoli, P.; Silvestri, L.; Camaschella, C.; Rovere-Querini, P. Polarization dictates iron handling by inflammatory and alternatively activated macrophages. Haematologica, 2010, 95(11), 1814-1822.
[] [PMID: 20511666]
Yeoh, B.S.; Aguilera Olvera, R.; Singh, V.; Xiao, X.; Kennett, M.J.; Joe, B.; Lambert, J.D.; Vijay-Kumar, M. Epigallocatechin-3-gallate inhibition of myeloperoxidase and its counter-regulation by dietary iron and lipocalin 2 in murine model of gut inflammation. Am. J. Pathol., 2016, 186(4), 912-926.
[] [PMID: 26968114]
Ward, R.J.; Crichton, R.R.; Taylor, D.L.; Della Corte, L.; Srai, S.K.; Dexter, D.T. Iron and the immune system. J. Neural Transm. (Vienna), 2011, 118(3), 315-328.
[] [PMID: 20878427]
Li, G.; Pone, E.J.; Tran, D.C.; Patel, P.J.; Dao, L.; Xu, Z.; Casali, P. Iron inhibits activation-induced cytidine deaminase enzymatic activity and modulates immunoglobulin class switch DNA recombination. J. Biol. Chem., 2012, 287(25), 21520-21529.
[] [PMID: 22556412]
Bach, J.; Bardenne, M.; Pleau, J.; Rosa, J. Biochemical characterisation of a serum thymic factor. Nature, 1977, 266(5597), 55-57.
[] [PMID: 300146]
Andreini, C.; Banci, L.; Bertini, I.; Rosato, A. Counting the zinc-proteins encoded in the human genome. J. Proteome Res., 2006, 5(1), 196-201.
[] [PMID: 16396512]
Maret, W. Zinc coordination environments in proteins as redox sensors and signal transducers. Antioxid. Redox Signal., 2006, 8(9-10), 1419-1441.
[] [PMID: 16987000]
Haase, H.; Rink, L. Multiple impacts of zinc on immune function. Metallomics, 2014, 6(7), 1175-1180.
[] [PMID: 24531756]
Bonaventura, P.; Benedetti, G.; Albarède, F.; Miossec, P. Zinc and its role in immunity and inflammation. Autoimmun. Rev., 2015, 14(4), 277-285.
[] [PMID: 25462582]
Hasan, R.; Rink, L.; Haase, H. Chelation of free Zn2+ impairs chemotaxis, phagocytosis, oxidative burst, degranulation, and cytokine production by neutrophil granulocytes. Biol. Trace Elem. Res., 2016, 171(1), 79-88.
[] [PMID: 26400651]
Mayer, L.S.; Uciechowski, P.; Meyer, S.; Schwerdtle, T.; Rink, L.; Haase, H. Differential impact of zinc deficiency on phagocytosis, oxidative burst, and production of pro-inflammatory cytokines by human monocytes. Metallomics, 2014, 6(7), 1288-1295.
[] [PMID: 24823619]
Wessels, I.; Maywald, M.; Rink, L. Zinc as a gatekeeper of immune function. Nutrients, 2017, 9(12), 1286.
[] [PMID: 29186856]
Haase, H.; Rink, L. Functional significance of zinc-related signaling pathways in immune cells. Annu. Rev. Nutr., 2009, 29, 133-152.
[] [PMID: 19400701]
International Zinc Nutrition Consultative Group (IZiNCG) (Hotz C, Brown KH, eds.).; Assessment of the risk of zinc deficiency in populations and options for its control. Food Nutr. Bull. , 2004; 25, pp. s91-s204.
Hunt, J.R.; Matthys, L.A.; Johnson, L.K. Zinc absorption, mineral balance, and blood lipids in women consuming controlled lactoovovegetarian and omnivorous diets for 8 wk. Am. J. Clin. Nutr., 1998, 67(3), 421-430.
[] [PMID: 9497185]
King, J.C. Zinc: an essential but elusive nutrient. Am. J. Clin. Nutr., 2011, 94(2)(Suppl.), 679S-684S.
[] [PMID: 21715515]
Hatfield, D.L.; Tsuji, P.A.; Carlson, B.A.; Gladyshev, V.N. Selenium and selenocysteine: roles in cancer, health, and development. Trends Biochem. Sci., 2014, 39(3), 112-120.
[] [PMID: 24485058]
Hoffmann, P.R. Mechanisms by which selenium influences immune responses. Arch. Immunol. Ther. Exp. (Warsz.), 2007, 55(5), 289-297.
[] [PMID: 18219759]
Hoffmann, F.W.; Hashimoto, A.C.; Shafer, L.A.; Dow, S.; Berry, M.J.; Hoffmann, P.R. Dietary selenium modulates activation and differentiation of CD4+ T cells in mice through a mechanism involving cellular free thiols. J. Nutr., 2010, 140(6), 1155-1161.
[] [PMID: 20375261]
Hoffmann, P.R.; Jourdan-Le Saux, C.; Hoffmann, F.W.; Chang, P.S.; Bollt, O.; He, Q.; Tam, E.K.; Berry, M.J. A role for dietary selenium and selenoproteins in allergic airway inflammation. J. Immunol., 2007, 179(5), 3258-3267.
[] [PMID: 17709542]
Sun, Z.; Xu, Z.; Wang, D.; Yao, H.; Li, S. Selenium deficiency inhibits differentiation and immune function and imbalances the Th1/Th2 of dendritic cells. Metallomics, 2018, 10(5), 759-767.
[] [PMID: 29766201]
Huang, Z.; Rose, A.H.; Hoffmann, P.R. The role of selenium in inflammation and immunity: from molecular mechanisms to therapeutic opportunities. Antioxid. Redox Signal., 2012, 16(7), 705-743.
[] [PMID: 21955027]
Verma, S.; Hoffmann, F.W.; Kumar, M.; Huang, Z.; Roe, K.; Nguyen-Wu, E.; Hashimoto, A.S.; Hoffmann, P.R. Selenoprotein K knockout mice exhibit deficient calcium flux in immune cells and impaired immune responses. J. Immunol., 2011, 186(4), 2127-2137.
[] [PMID: 21220695]
Norton, R.L.; Fredericks, G.J.; Huang, Z.; Fay, J.D.; Hoffmann, F.W.; Hoffmann, P.R. Selenoprotein K regulation of palmitoylation and calpain cleavage of ASAP2 is required for efficient FcγR-mediated phagocytosis. J. Leukoc. Biol., 2017, 101(2), 439-448.
[] [PMID: 27601625]
Peterlik, M. Vitamin D insufficiency and chronic diseases: hype and reality. Food Funct., 2012, 3(8), 784-794.
[] [PMID: 22695493]
Stoffaneller, R.; Morse, N.L. A review of dietary selenium intake and selenium status in Europe and the Middle East. Nutrients, 2015, 7(3), 1494-1537.
[] [PMID: 25734564]
Dos Reis, A.R.; El-Ramady, H.; Santos, E.F. Overview of selenium deficiency and toxicity worldwide: Affected areas, seleniumrelated health issues, and case studies. Selenium in plants. Molecular, physiological, ecological and evolution-ary aspects, 1st ed; Pilon-Smits, E.A.H.; Winkel, L.H.E.; Lin, Z.Q., Eds.. Springer: Berlin, 2017, pp. 209-230.
Craven, N.M.; Griffiths, C.E. Topical retinoids and cutaneous biology. Clin. Exp. Dermatol., 1996, 21(1), 1-10.
[] [PMID: 8689759]
McCullough, F.S.; Northrop-Clewes, C.A.; Thurnham, D.I. The effect of vitamin A on epithelial integrity. Proc. Nutr. Soc., 1999, 58(2), 289-293.
[] [PMID: 10466169]
McGrane, M.M. Vitamin A regulation of gene expression: molecular mechanism of a prototype gene. J. Nutr. Biochem., 2007, 18(8), 497-508.
[] [PMID: 17320364]
Evans, R.M.; Mangelsdorf, D.J. Nuclear Receptors, RXR, and the Big Bang. Cell, 2014, 157(1), 255-266.
[] [PMID: 24679540]
di Masi, A.; Leboffe, L.; De Marinis, E.; Pagano, F.; Cicconi, L.; Rochette-Egly, C.; Lo-Coco, F.; Ascenzi, P.; Nervi, C. Retinoic acid receptors: from molecular mechanisms to cancer therapy. Mol. Aspects Med., 2015, 41, 1-115.
[] [PMID: 25543955]
Dawson, M.I.; Xia, Z. The retinoid X receptors and their ligands. Biochim. Biophys. Acta, 2012, 1821(1), 21-56.
[] [PMID: 22020178]
de Lera, A.R.; Krezel, W.; Rühl, R. An endogenous mammali-an Retinoid X Receptor ligand, at last! ChemMedChem, 2016, 11(10), 1027-1037.
[] [PMID: 27151148]
Iwata, M.; Eshima, Y.; Kagechika, H. Retinoic acids exert direct effects on T cells to suppress Th1 development and enhance Th2 development via retinoic acid receptors. Int. Immunol., 2003, 15(8), 1017-1025.
[] [PMID: 12882839]
Dawson, H.D.; Collins, G.; Pyle, R.; Key, M.; Weeraratna, A.; Deep-Dixit, V.; Nadal, C.N.; Taub, D.D. Direct and indirect effects of retinoic acid on human Th2 cytokine and chemokine expression by human T lymphocytes. BMC Immunol., 2006, 7, 27.
[] [PMID: 17118196]
Ma, Y.; Chen, Q.; Ross, A.C. Retinoic acid and polyriboinosinic:polyribocytidylic acid stimulate robust anti-tetanus antibody production while differentially regulating type 1/type 2 cytokines and lymphocyte populations. J. Immunol., 2005, 174(12), 7961-7969.
[] [PMID: 15944302]
Park, J.J.; Omiya, R.; Matsumura, Y.; Sakoda, Y.; Kuramasu, A.; Augustine, M.M.; Yao, S.; Tsushima, F.; Narazaki, H.; Anand, S.; Liu, Y.; Strome, S.E.; Chen, L.; Tamada, K. B7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance. Blood, 2010, 116(8), 1291-1298.
[] [PMID: 20472828]
Hoag, K.A.; Nashold, F.E.; Goverman, J.; Hayes, C.E. Retinoic acid enhances the T helper 2 cell development that is essential for robust antibody responses through its action on antigen-presenting cells. J. Nutr., 2002, 132(12), 3736-3739.
[] [PMID: 12468615]
Raverdeau, M.; Mills, K.H. Modulation of T cell and innate immune responses by retinoic Acid. J. Immunol., 2014, 192(7), 2953-2958.
[] [PMID: 24659788]
Iwata, M.; Hirakiyama, A.; Eshima, Y.; Kagechika, H.; Kato, C.; Song, S.Y. Retinoic acid imprints gut-homing specificity on T cells. Immunity, 2004, 21(4), 527-538.
[] [PMID: 15485630]
Cassani, B.; Villablanca, E.J.; De Calisto, J.; Wang, S.; Mora, J.R. Vitamin A and immune regulation: role of retinoic acid in gut-associated dendritic cell education, immune protection and tolerance. Mol. Aspects Med., 2012, 33(1), 63-76.
[] [PMID: 22120429]
Minucci, S.; Leid, M.; Toyama, R.; Saint-Jeannet, J.P.; Peterson, V.J.; Horn, V.; Ishmael, J.E.; Bhattacharyya, N.; Dey, A.; Dawid, I.B.; Ozato, K. Retinoid X receptor (RXR) within the RXR-retinoic acid receptor heterodimer binds its ligand and enhances retinoid-dependent gene expression. Mol. Cell. Biol., 1997, 17(2), 644-655.
[] [PMID: 9001218]
Dzhagalov, I.; Chambon, P.; He, Y.W. Regulation of CD8+ T lymphocyte effector function and macrophage inflammatory cytokine production by retinoic acid receptor γ. J. Immunol., 2007, 178(4), 2113-2121.
[] [PMID: 17277115]
Kirchmeyer, M.; Koufany, M.; Sebillaud, S.; Netter, P.; Jouzeau, J.Y.; Bianchi, A. All-trans retinoic acid suppresses interleukin-6 expression in interleukin-1-stimulated synovial fibroblasts by inhibition of ERK1/2 pathway independently of RAR activation. Arthritis Res. Ther., 2008, 10(6), R141.
[] [PMID: 19068145]
World Health Organization. Global prevalence of vitamin A deficiency in populations at risk 1995–2005. WHO Global Database on Vitamin A Deficiency; World Health Organiza-tion: Geneva, 2009.
Hewison, M. Vitamin D and immune function: an overview. Proc. Nutr. Soc., 2012, 71(1), 50-61.
[] [PMID: 21849106]
Pike, J.W.; Christakos, S. Biology and mechanisms of action of the vitamin D hormone. Endocrinol. Metab. Clin. North Am., 2017, 46(4), 815-843.
[] [PMID: 29080638]
Penna, G.; Amuchastegui, S.; Giarratana, N.; Daniel, K.C.; Vulcano, M.; Sozzani, S.; Adorini, L. 1,25-Dihydroxyvitamin D3 selectively modulates tolerogenic properties in myeloid but not plasmacytoid dendritic cells. J. Immunol., 2007, 178(1), 145-153.
[] [PMID: 17182549]
Ferreira, G.B.; Gysemans, C.A.; Demengeot, J.; da Cunha, J.P.; Vanherwegen, A.S.; Overbergh, L.; Van Belle, T.L.; Pauwels, F.; Verstuyf, A.; Korf, H.; Mathieu, C. 1,25-Dihydroxyvitamin D3 promotes tolerogenic dendritic cells with functional migratory properties in NOD mice. J. Immunol., 2014, 192(9), 4210-4220.
[] [PMID: 24663679]
Ferreira, G.B.; Vanherwegen, A.S.; Eelen, G.; Gutiérrez, A.C.F.; Van Lommel, L.; Marchal, K.; Verlinden, L.; Verstuyf, A.; Nogueira, T.; Georgiadou, M.; Schuit, F.; Eizirik, D.L.; Gysemans, C.; Carmeliet, P.; Overbergh, L.; Mathieu, C. Vitamin D3 induces tolerance in human dendritic cells by activation of intracellular metabolic pathways. Cell Rep., 2015, 10(5), 711-725.
[] [PMID: 25660022]
Sloka, S.; Silva, C.; Wang, J.; Yong, V.W. Predominance of Th2 polarization by vitamin D through a STAT6-dependent mechanism. J. Neuroinflammation, 2011, 8, 56.
[] [PMID: 21605467]
Altieri, B.; Muscogiuri, G.; Barrea, L.; Mathieu, C.; Vallone, C.V.; Mascitelli, L.; Bizzaro, G.; Altieri, V.M.; Tirabassi, G.; Balercia, G.; Savastano, S.; Bizzaro, N.; Ronchi, C.L.; Colao, A.; Pontecorvi, A.; Della Casa, S. Does vitamin D play a role in autoimmune endocrine disorders? A proof of concept. Rev. Endocr. Metab. Disord., 2017, 18(3), 335-346.
[] [PMID: 28070798]
Ghareghani, M.; Reiter, R.J.; Zibara, K.; Farhadi, N. Latitude, vitamin D, melatonin, and gut microbiota act in concert to ini-tiate multiple sclerosis: A new mechanistic pathway. Front. Immunol., 2018, 9, 2484.
[] [PMID: 30459766]
Holmes, E.A.; Rodney Harris, R.M.; Lucas, R.M. Low sun exposure and vitamin D deficiency as risk factors for in-flammatory bowel disease, with a focus on childhood onset. Photochem. Photobiol., 2019, 95(1), 105-118.
[] [PMID: 30155900]
Holick, M.F. The vitamin D deficiency pandemic: Approaches for diagnosis, treatment and prevention. Rev. Endocr. Metab. Disord., 2017, 18(2), 153-165.
[] [PMID: 28516265]
EFSA Panel on Dietetic Products, Nutrition, and Allergies (NDA). Scientific Opinion on Dietary Reference Values for vitamin E as α-tocopherol. European Food Safety Authority, Parma, Italy. EFSA J., 2015, 13(7), 4149.
Knight, J.A. Review: Free radicals, antioxidants, and the immune system. Ann. Clin. Lab. Sci., 2000, 30(2), 145-158.
[PMID: 10807157]
Lewis, E.D.; Meydani, S.N.; Wu, D. Regulatory role of vitamin E in the immune system and inflammation. IUBMB Life, 2019, 71(4), 487-494.
[] [PMID: 30501009]
Wu, D.; Meydani, S.N. Mechanism of age-associated up-regulation in macrophage PGE2 synthesis. Brain Behav. Immun., 2004, 18(6), 487-494.
[] [PMID: 15331118]
Beharka, A.A.; Wu, D.; Serafini, M.; Meydani, S.N. Mechanism of vitamin E inhibition of cyclooxygenase activity in macrophages from old mice: role of peroxynitrite. Free Radic. Biol. Med., 2002, 32(6), 503-511.
[] [PMID: 11958951]
Marko, M.G.; Ahmed, T.; Bunnell, S.C.; Wu, D.; Chung, H.; Huber, B.T.; Meydani, S.N. Age-associated decline in effective immune synapse formation of CD4(+) T cells is reversed by vitamin E supplementation. J. Immunol., 2007, 178(3), 1443-1449.
[] [PMID: 17237392]
Molano, A.; Meydani, S.N. Vitamin E, signalosomes and gene expression in T cells. Mol. Aspects Med., 2012, 33(1), 55-62.
[] [PMID: 22138304]
Salinthone, S.; Kerns, A.R.; Tsang, V.; Carr, D.W. α-Tocopherol (vitamin E) stimulates cyclic AMP production in human peripheral mononuclear cells and alters immune function. Mol. Immunol., 2013, 53(3), 173-178.
[] [PMID: 22947771]
Han, S.N.; Pang, E.; Zingg, J.M.; Meydani, S.N.; Meydani, M.; Azzi, A. Differential effects of natural and synthetic vitamin E on gene transcription in murine T lymphocytes. Arch. Biochem. Biophys., 2010, 495(1), 49-55.
[] [PMID: 20026030]
Ricciarelli, R.; Tasinato, A.; Clément, S.; Ozer, N.K.; Boscoboinik, D.; Azzi, A. alpha-Tocopherol specifically inactivates cellular protein kinase C alpha by changing its phosphorylation state. Biochem. J., 1998, 334(Pt 1), 243-249.
[] [PMID: 9693126]
Egger, T.; Schuligoi, R.; Wintersperger, A.; Amann, R.; Malle, E.; Sattler, W. Vitamin E (alpha-tocopherol) attenuates cyclo-oxygenase 2 transcription and synthesis in immortalized murine BV-2 microglia. Biochem. J., 2003, 370(Pt 2), 459-467.
[] [PMID: 12429020]
Müller, L.; Theile, K.; Böhm, V. In vitro antioxidant activity of tocopherols and tocotrienols and comparison of vitamin E concentration and lipophilic antioxidant capacity in human plasma. Mol. Nutr. Food Res., 2010, 54(5), 731-742.
[] [PMID: 20333724]
Aggarwal, B.B.; Sundaram, C.; Prasad, S.; Kannappan, R. Tocotrienols, the vitamin E of the 21st century: its potential against cancer and other chronic diseases. Biochem. Pharmacol., 2010, 80(11), 1613-1631.
[] [PMID: 20696139]
Reiter, E.; Jiang, Q.; Christen, S. Anti-inflammatory properties of α- and γ-tocopherol. Mol. Aspects Med., 2007, 28(5-6), 668-691.
[] [PMID: 17316780]
Wilankar, C.; Sharma, D.; Checker, R.; Khan, N.M.; Patwardhan, R.; Patil, A.; Sandur, S.K.; Devasagayam, T.P. Role of immunoregulatory transcription factors in differential immunomodulatory effects of tocotrienols. Free Radic. Biol. Med., 2011, 51(1), 129-143.
[] [PMID: 21536125]
Wang, Y.; Jiang, Q. γ-Tocotrienol inhibits lipopolysaccharide-induced interlukin-6 and granulocyte colony-stimulating factor by suppressing C/EBPβ and NF-κB in macrophages. J. Nutr. Biochem., 2013, 24(6), 1146-1152.
[] [PMID: 23246159]
Wang, Y.; Park, N.Y.; Jang, Y.; Ma, A.; Jiang, Q. Vitamin E γ-tocotrienol inhibits cytokine-stimulated NF-κB activation by induction of anti-inflammatory A20 via stress adaptive re-sponse due to modulation of sphingolipids. J. Immunol., 2015, 195(1), 126-133.
[] [PMID: 26002975]
Yang, C.; Jiang, Q. Vitamin E δ-tocotrienol inhibits TNF-α-stimulated NF-κB activation by up-regulation of anti-inflammatory A20 via modulation of sphingolipid including elevation of intracellular dihydroceramides. J. Nutr. Biochem., 2019, 64, 101-109.
[] [PMID: 30471562]
Evans, R.M.; Currie, L.; Campbell, A. The distribution of ascorbic acid between various cellular components of blood, in normal individuals, and its relation to the plasma concentration. Br. J. Nutr., 1982, 47(3), 473-482.
[] [PMID: 7082619]
Omaye, S.T.; Schaus, E.E.; Kutnink, M.A.; Hawkes, W.C. Measurement of vitamin C in blood components by high-performance liquid chromatography. Implication in assessing vitamin C status. Ann. N. Y. Acad. Sci., 1987, 498, 389-401.
[] [PMID: 3304068]
Corpe, C.P.; Lee, J.H.; Kwon, O.; Eck, P.; Narayanan, J.; Kirk, K.L.; Levine, M. 6-Bromo-6-deoxy-L-ascorbic acid: an ascorbate analog specific for Na+-dependent vitamin C transporter but not glucose transporter pathways. J. Biol. Chem., 2005, 280(7), 5211-5220.
[] [PMID: 15590689]
Nualart, F.J.; Rivas, C.I.; Montecinos, V.P.; Godoy, A.S.; Guaiquil, V.H.; Golde, D.W.; Vera, J.C. Recycling of vitamin C by a bystander effect. J. Biol. Chem., 2003, 278(12), 10128-10133.
[] [PMID: 12435736]
Carr, A.C.; Maggini, S. Vitamin C and immune function. Nutrients, 2017, 9(11), 1211.
[] [PMID: 29099763]
Goetzl, E.J.; Wasserman, S.I.; Gigli, I.; Austen, K.F. Enhancement of random migration and chemotactic response of human leukocytes by ascorbic acid. J. Clin. Invest., 1974, 53(3), 813-818.
[] [PMID: 4273024]
Anderson, R.; Theron, A. Effects of ascorbate on leucocytes: Part III. In vitro and in vivo stimulation of abnormal neutrophil motility by ascorbate. S. Afr. Med. J., 1979, 56(11), 429-433.
[PMID: 550365]
Vohra, K.; Khan, A.J.; Telang, V.; Rosenfeld, W.; Evans, H.E. Improvement of neutrophil migration by systemic vitamin C in neonates. J. Perinatol., 1990, 10(2), 134-136.
[PMID: 2358895]
Manning, J.; Mitchell, B.; Appadurai, D.A.; Shakya, A.; Pierce, L.J.; Wang, H.; Nganga, V.; Swanson, P.C.; May, J.M.; Tantin, D.; Spangrude, G.J. Vitamin C promotes maturation of T-cells. Antioxid. Redox Signal., 2013, 19(17), 2054-2067.
[] [PMID: 23249337]
van Gorkom, G.N.Y.; Klein Wolterink, R.G.J.; Van Elssen, C.H.M.J.; Wieten, L.; Germeraad, W.T.V.; Bos, G.M.J. Influence of vitamin C on lymphocytes: An overview. Antioxidants, 2018, 7(3), 41.
[] [PMID: 29534432]
Cobley, J.N.; McHardy, H.; Morton, J.P.; Nikolaidis, M.G.; Close, G.L. Influence of vitamin C and vitamin E on redox signaling: Implications for exercise adaptations. Free Radic. Biol. Med., 2015, 84, 65-76.
[] [PMID: 25841784]
Valko, M.; Leibfritz, D.; Moncol, J.; Cronin, M.T.; Mazur, M.; Telser, J. Free radicals and antioxidants in normal physiological functions and human disease. Int. J. Biochem. Cell Biol., 2007, 39(1), 44-84.
[] [PMID: 16978905]
Forman, H.J.; Maiorino, M.; Ursini, F. Signaling functions of reactive oxygen species. Biochemistry, 2010, 49(5), 835-842.
[] [PMID: 20050630]
Holmström, K.M.; Finkel, T. Cellular mechanisms and physiological consequences of redox-dependent signalling. Nat. Rev. Mol. Cell Biol., 2014, 15(6), 411-421.
[] [PMID: 24854789]
King, M.R.; Ismail, A.S.; Davis, L.S.; Karp, D.R. Oxidative stress promotes polarization of human T cell differentiation toward a T helper 2 phenotype. J. Immunol., 2006, 176(5), 2765-2772.
[] [PMID: 16493032]
Frossi, B.; De Carli, M.; Piemonte, M.; Pucillo, C. Oxidative microenvironment exerts an opposite regulatory effect on cytokine production by Th1 and Th2 cells. Mol. Immunol., 2008, 45(1), 58-64.
[] [PMID: 17588662]
Jeong, Y.J.; Hong, S.W.; Kim, J.H.; Jin, D.H.; Kang, J.S.; Lee, W.J.; Hwang, Y.I. Vitamin C-treated murine bone marrow-derived dendritic cells preferentially drive naïve T cells into Th1 cells by increased IL-12 secretions. Cell. Immunol., 2011, 266(2), 192-199.
[] [PMID: 21074755]
Tan, P.H.; Sagoo, P.; Chan, C.; Yates, J.B.; Campbell, J.; Beutelspacher, S.C.; Foxwell, B.M.; Lombardi, G.; George, A.J. Inhibition of NF-kappa B and oxidative pathways in human dendritic cells by antioxidative vitamins generates regulatory T cells. J. Immunol., 2005, 174(12), 7633-7644.
[] [PMID: 15944264]
Noh, K.; Lim, H.; Moon, S.K.; Kang, J.S.; Lee, W.J.; Lee, D.; Hwang, Y.I. Mega-dose Vitamin C modulates T cell functions in Balb/c mice only when administered during T cell activation. Immunol. Lett., 2005, 98(1), 63-72.
[] [PMID: 15790510]
Härtel, C.; Strunk, T.; Bucsky, P.; Schultz, C. Effects of vitamin C on intracytoplasmic cytokine production in human whole blood monocytes and lymphocytes. Cytokine, 2004, 27(4-5), 101-106.
[] [PMID: 15271375]
Molina, N.; Morandi, A.C.; Bolin, A.P.; Otton, R. Comparative effect of fucoxanthin and vitamin C on oxidative and functional parameters of human lymphocytes. Int. Immunopharmacol., 2014, 22(1), 41-50.
[] [PMID: 24975831]
Kuiper, C.; Dachs, G.U.; Currie, M.J.; Vissers, M.C.M. Intracellular ascorbate enhances hypoxia-inducible factor (HIF)-hydroxylase activity and preferentially suppresses the HIF-1 transcriptional response. Free Radic. Biol. Med., 2014, 69, 308-317.
[] [PMID: 24495550]
Camarena, V.; Wang, G. The epigenetic role of vitamin C in health and disease. Cell. Mol. Life Sci., 2016, 73(8), 1645-1658.
[] [PMID: 26846695]
Ang, A.; Pullar, J.M.; Currie, M.J.; Vissers, M.C.M. Vitamin C and immune cell function in inflammation and cancer. Biochem. Soc. Trans., 2018, 46(5), 1147-1159.
[] [PMID: 30301842]
Gan, R.; Eintracht, S.; Hoffer, L.J. Vitamin C deficiency in a university teaching hospital. J. Am. Coll. Nutr., 2008, 27(3), 428-433.
[] [PMID: 18838532]
Golriz, F.; Donnelly, L.F.; Devaraj, S.; Krishnamurthy, R. Modern American scurvy - experience with vitamin C deficiency at a large children’s hospital. Pediatr. Radiol., 2017, 47(2), 214-220.
[] [PMID: 27778040]
Ververs, M.; Muriithi, J.W.; Burton, A.; Burton, J.W.; Lawi, A.O. Scurvy outbreak among South Sudanese adolescents and young men – Kakuma Refugee Camp, Kenya, 2017–2018. MMWR Morb. Mortal. Wkly. Rep., 2019, 68(3), 72-75.
[] [PMID: 30677009]
Schleicher, R.L.; Carroll, M.D.; Ford, E.S.; Lacher, D.A. Serum vitamin C and the prevalence of vitamin C deficiency in the United States: 2003-2004 National Health and Nutrition Examination Survey (NHANES). Am. J. Clin. Nutr., 2009, 90(5), 1252-1263.
[] [PMID: 19675106]
Cahill, L.; Corey, P.N.; El-Sohemy, A. Vitamin C deficiency in a population of young Canadian adults. Am. J. Epidemiol., 2009, 170(4), 464-471.
[] [PMID: 19596710]
Depeint, F.; Bruce, W.R.; Shangari, N.; Mehta, R.; O’Brien, P.J. Mitochondrial function and toxicity: role of the B vitamin family on mitochondrial energy metabolism. Chem. Biol. Interact., 2006, 163(1-2), 94-112.
[] [PMID: 16765926]
Depeint, F.; Bruce, W.R.; Shangari, N.; Mehta, R.; O’Brien, P.J. Mitochondrial function and toxicity: role of B vitamins on the one-carbon transfer pathways. Chem. Biol. Interact., 2006, 163(1-2), 113-132.
[] [PMID: 16814759]
Wintergerst, E.S.; Maggini, S.; Hornig, D.H. Contribution of selected vitamins and trace elements to immune function. Ann. Nutr. Metab., 2007, 51(4), 301-323.
[] [PMID: 17726308]
Tamura, J.; Kubota, K.; Murakami, H.; Sawamura, M.; Matsushima, T.; Tamura, T.; Saitoh, T.; Kurabayshi, H.; Naruse, T. Immunomodulation by vitamin B12: augmentation of CD8+ T lymphocytes and natural killer (NK) cell activity in vitamin B12-deficient patients by methyl-B12 treatment. Clin. Exp. Immunol., 1999, 116(1), 28-32.
[] [PMID: 10209501]
Partearroyo, T.; Úbeda, N.; Montero, A.; Achón, M.; Varela-Moreiras, G. Vitamin B(12) and folic acid imbalance modifies NK cytotoxicity, lymphocytes B and lymphoprolipheration in aged rats. Nutrients, 2013, 5(12), 4836-4848.
[] [PMID: 24288024]
Paul, L.; Selhub, J. Interaction between excess folate and low vitamin B12 status. Mol. Aspects Med., 2017, 53, 43-47.
[] [PMID: 27876554]
Troen, A.M.; Mitchell, B.; Sorensen, B.; Wener, M.H.; Johnston, A.; Wood, B.; Selhub, J.; McTiernan, A.; Yasui, Y.; Oral, E.; Potter, J.D.; Ulrich, C.M. Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J. Nutr., 2006, 136(1), 189-194.
[] [PMID: 16365081]
Courtemanche, C.; Elson-Schwab, I.; Mashiyama, S.T.; Kerry, N.; Ames, B.N. Folate deficiency inhibits the proliferation of primary human CD8+ T lymphocytes in vitro. J. Immunol., 2004, 173(5), 3186-3192.
[] [PMID: 15322179]
Wu, C.H.; Huang, T.C.; Lin, B.F. Folate deficiency affects dendritic cell function and subsequent T helper cell differentiation. J. Nutr. Biochem., 2017, 41, 65-72.
[] [PMID: 28040582]
Yamaguchi, T.; Hirota, K.; Nagahama, K.; Ohkawa, K.; Takahashi, T.; Nomura, T.; Sakaguchi, S. Control of immune responses by antigen-specific regulatory T cells expressing the folate receptor. Immunity, 2007, 27(1), 145-159.
[] [PMID: 17613255]
Makino, E.; Fukuyama, T.; Watanabe, Y.; Tajiki-Nishino, R.; Tajima, H.; Ohnuma-Koyama, A.; Takahashi, N.; Ohtsuka, R.; Okazaki, Y. Subacute oral administration of folic acid elicits anti-inflammatory response in a mouse model of allergic dermatitis. J. Nutr. Biochem., 2019, 67, 14-19.
[] [PMID: 30831459]
Chandra, R.K.; Heresi, G.; Au, B. Serum thymic factor activity in deficiencies of calories, zinc, vitamin A and pyridoxine. Clin. Exp. Immunol., 1980, 42(2), 332-335.
[PMID: 7193541]
Doke, S.; Inagaki, N.; Hayakawa, T.; Tsuge, H. Effect of vitamin B6 deficiency on an antibody production in mice. Biosci. Biotechnol. Biochem., 1997, 61(8), 1331-1336.
[] [PMID: 9301116]
Doke, S.; Inagaki, N.; Hayakawa, T.; Tsuge, H. Effects of vitamin B6 deficiency on cytokine levels and lymphocytes in mice. Biosci. Biotechnol. Biochem., 1998, 62(5), 1008-1010.
[] [PMID: 9648235]
Qian, B.; Shen, S.; Zhang, J.; Jing, P. Effects of vitamin B6 deficiency on the composition and functional potential of T cell populations. J. Immunol. Res., 2017.20172197975
[] [PMID: 28367454]
Ueland, P.M.; McCann, A.; Midttun, Ø.; Ulvik, A. Inflammation, vitamin B6 and related pathways. Mol. Aspects Med., 2017, 53, 10-27.
[] [PMID: 27593095]
Percudani, R.; Peracchi, A. The B6 database: a tool for the description and classification of vitamin B6-dependent enzymatic activities and of the corresponding protein families. BMC Bioinformatics, 2009, 10, 273.
[] [PMID: 19723314]
Bourquin, F.; Capitani, G.; Grütter, M.G. PLP-dependent enzymes as entry and exit gates of sphingolipid metabolism. Protein Sci., 2011, 20(9), 1492-1508.
[] [PMID: 21710479]
Aoki, M.; Aoki, H.; Ramanathan, R.; Hait, N.C.; Takabe, K. Sphingosine-1-Phosphate signaling in immune cells and in-flammation: Roles and therapeutic potential. Mediators Inflamm., 2016.20168606878
[PMID: 26966342]
Małaczewska, J.; Siwicki, A.K.; Wójcik, R.M.; Turski, W.A.; Kaczorek, E. The effect of kynurenic acid on the synthesis of selected cytokines by murine splenocytes - in vitro and ex vivo studies. Cent. Eur. J. Immunol., 2016, 41(1), 39-46.
[] [PMID: 27095921]
Planells, E.; Sánchez, C.; Montellano, M.A.; Mataix, J.; Llopis, J. Vitamins B6 and B12 and folate status in an adult Mediterranean population. Eur. J. Clin. Nutr., 2003, 57(6), 777-785.
[] [PMID: 12792662]
Majchrzak, D.; Singer, I.; Männer, M.; Rust, P.; Genser, D.; Wagner, K.H.; Elmadfa, I. B-vitamin status and concentrations of homocysteine in Austrian omnivores, vegetarians and vegans. Ann. Nutr. Metab., 2006, 50(6), 485-491.
[] [PMID: 16988496]
Morris, M.S.; Picciano, M.F.; Jacques, P.F.; Selhub, J. Plasma pyridoxal 5′-phosphate in the US population: the National Health and Nutrition Examination Survey, 2003-2004. Am. J. Clin. Nutr., 2008, 87(5), 1446-1454.
[] [PMID: 18469270]
McLean, E.; de Benoist, B.; Allen, L.H. Review of the magnitude of folate and vitamin B12 deficiencies worldwide. Food Nutr. Bull., 2008, 29(2)(Suppl.), S38-S51.
[] [PMID: 18709880]
Pawlak, R. Is vitamin B12 deficiency a risk factor for cardiovascular disease in vegetarians? Am. J. Prev. Med., 2015, 48(6), e11-e26.
[] [PMID: 25998928]
Kjeldby, I.K.; Fosnes, G.S.; Ligaarden, S.C.; Farup, P.G. Vitamin B6 deficiency and diseases in elderly people--a study in nursing homes. BMC Geriatr., 2013, 13, 13.
[] [PMID: 23394203]
Wong, C.W. Vitamin B12 deficiency in the elderly: is it worth screening? Hong Kong Med. J., 2015, 21(2), 155-164.
[] [PMID: 25756278]
Dhonukshe-Rutten, R.A.M.; de Vries, J.H.M.; de Bree, A.; van der Put, N.; van Staveren, W.A.; de Groot, L.C. Dietary intake and status of folate and vitamin B12 and their association with homocysteine and cardiovascular disease in European populations. Eur. J. Clin. Nutr., 2009, 63(1), 18-30.
[] [PMID: 17851461]
EFSA (European Food Safety Authority); Dietary reference values for nutrients: Summary report; EFSA supporting publication . , 2017. p. e15121. 92
Parekh, P.P.; Khan, A.R.; Torres, M.A.; Kitto, M.E. Concen-trations of selenium, barium, and radium in Brazil nuts. J. Food Compos. Anal., 2008, 21, 332-335.
French Agency for Food; Environmental and Occupational Health & Safety., ANSES-CIQUAL French food composition table version. 2017. (Accessed November 12, 2018)
Fan, M.S.; Zhao, F.J.; Poulton, P.R.; McGrath, S.P. Historical changes in the concentrations of selenium in soil and wheat grain from the Broadbalk experiment over the last 160 years. Sci. Total Environ., 2008, 389(2-3), 532-538.
[] [PMID: 17888491]
Centre d’étude et de valorisation des algues (CEVA): Fiche nutritionelle. Porphyra. . (Accessed March 14, 2019).

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