Vitamin D and Atopy
2017; Elsevier BV; Volume: 39; Issue: 5 Linguagem: Inglês
10.1016/j.clinthera.2017.03.002
ISSN1879-114X
Autores Tópico(s)Menstrual Health and Disorders
ResumoVitamin D is primarily found in vertebrates and it is mostly responsible for calcium homeostasis and maintenance of healthy bones.1Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10632) Google Scholar, 2Saggese G. Vierucci F. Boot A.M. et al.Vitamin D in childhood and adolescence: an expert position statement.Eur J Pediatr. 2015; 174: 565-576Crossref PubMed Scopus (106) Google Scholar Natural vitamin D is obtained from intake of fish oils and other animal sources. Interestingly, microalgae contain both pre−vitamin D and active vitamin D3.3Japelt R.B. Jakobsen J. Vitamin D in plants: a review of occurrence, analysis, and biosynthesis.Front Plant Sci. 2013; 4: 136Crossref PubMed Scopus (163) Google Scholar In humans, vitamin D synthesis is initiated in the skin by a photochemical conversion of pre−vitamin D3 by ultraviolet B rays, followed by isomerization to vitamin D3 (cholecalciferol).1Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10632) Google Scholar Vitamin D then undergoes the first hydroxylation in the liver to 25-hydroxyvitamin D3 [25(OH)D3], the circulating metabolite, which is what is meant when the term vitamin D is used in this Editorial. The active form of vitamin D is 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] (calcitriol) and is synthesized primarily in the kidneys.1Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10632) Google Scholar Vitamin D exerts its actions by binding to a vitamin D receptor (VDR), which has been found in many cells, including T and B lymphocytes, macrophages, and mast cells (MCs). VDR activation by vitamin D results in transcription of numerous genes. Vitamin D status is assessed by serum 25(OH)D3 levels; unfortunately, there is no accepted standardization of serum vitamin D measurements, which makes comparisons of clinical studies difficult.4Castro M. King T.S. Kunselman S.J. et al.Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized clinical trial.JAMA. 2014; 311: 2083-2091Crossref PubMed Scopus (196) Google Scholar Immunologic studies and epidemiologic investigations have suggested a link between vitamin D deficiency and allergic skin diseases, especially skin inflammation.5Toniato E. Spinas E. Saggini A. et al.Immunomodulatory effects of vitamin D on skin inflammation.J Biol Regul Homeost Agents. 2015; 29: 563-567PubMed Google Scholar Vitamin D deficiency was significantly associated with increased susceptibility to chronic idiopathic urticaria6Movahedi M. Tavakol M. Hirbod-Mobarakeh A. et al.Vitamin D deficiency in chronic idiopathic urticaria.Iran J Allergy Asthma Immunol. 2015; 14: 222-227PubMed Google Scholar and atopic dermatitis (AD).7Pacheco-Gonzalez R.M. Garcia-Marcos P.W. Garcia-Marcos L. Vitamin D And atopic dermatitis.Mini Rev Med Chem. 2015; 15: 927-934Crossref PubMed Scopus (7) Google Scholar The ability of vitamin D to induce terminal differentiation and inhibit proliferation of keratinocytes has resulted in its use for treatment of psoriasis.8Reichrath J. Zouboulis C.C. Vogt T. Holick M.F. Targeting the vitamin D endocrine system (VDES) for the management of inflammatory and malignant skin diseases: an historical view and outlook.Rev Endocr Metab Disord. 2016; 17: 405-417Crossref PubMed Scopus (37) Google Scholar, 9Mattozzi C. Paolino G. Richetta A.G. Calvieri S. Psoriasis, Vitamin D and the importance of the cutaneous barrier׳s integrity: an update.J Dermatol. 2016; 43: 507-514Crossref PubMed Scopus (44) Google Scholar Moreover, vitamin D−deficient mice have an increased contact hypersensitivity response compared with those with normal vitamin D levels.10Quirk S.K. Rainwater E. Shure A.K. Agrawal D.K. Vitamin D in atopic dermatitis, chronic urticaria and allergic contact dermatitis.Expert Rev Clin Immunol. 2016; : 1-9Google Scholar, 11Malley R.C. Muller H.K. Norval M. Woods G.M. Vitamin D3 deficiency enhances contact hypersensitivity in male but not in female mice.Cell Immunol. 2009; 255: 33-40Crossref PubMed Scopus (13) Google Scholar Immune cells express VDRs, activation of which decreases inflammation,12Cannell J.J. Grant W.B. Holick M.F. Vitamin D and inflammation.Dermatoendocrinology. 2014; 6: E983401Crossref PubMed Scopus (132) Google Scholar, 13Lin Z. Li W. The roles of vitamin D and its analogs in inflammatory diseases.Curr Top Med Chem. 2016; 16: 1242-1261Crossref PubMed Scopus (54) Google Scholar, 14Zanetti M. Harris S.S. Dawson-Hughes B. Ability of vitamin D to reduce inflammation in adults without acute illness.Nutr Rev. 2014; 72: 95-98Crossref PubMed Scopus (31) Google Scholar and vitamin D deficiency has been implicated in autoimmunity.15Dankers W. Colin E.M. Van Hamburg J.P. Lubberts E. Vitamin D in autoimmunity: molecular mechanisms and therapeutic potential.Front Immunol. 2016; 7: 697PubMed Google Scholar MCs are important in the pathogenesis of allergies and mastocytosis16Theoharides T.C. Valent P. Akin C. Mast Cells, mastocytosis, and related disorders.N Engl J Med. 2015; 373: 163-172Crossref PubMed Scopus (293) Google Scholar and related diseases,17Theoharides T.C. Atopic conditions in search of pathogenesis and therapy.Clin Ther. 2013; 35: 544-547Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar as well as in inflammation.18Theoharides T.C. Alysandratos K.D. Angelidou A. et al.Mast Cells and inflammation.Biochim Biophys Acta. 2012; 1822: 21-33Crossref PubMed Scopus (542) Google Scholar, 19Galli S.J. Tsai M. Piliponsky A.A. The development of allergic inflammation.Nature. 2008; 454: 445-454Crossref PubMed Scopus (1293) Google Scholar MC-derived tumor necrosis factor can promote T helper 17 cell−dependent neutrophil recruitment.20Nakae S. Suto H. Berry G.J. Galli S.J. Mast cell-derived TNF can promote Th17 cell-dependent neutrophil recruitment in ovalbumin-challenged OTII mice.Blood. 2007; 109: 3640-3648Crossref PubMed Scopus (126) Google Scholar Vitamin D has been shown to suppress immunoglobulin E antibody class switch.21James J. Weaver V. Cantorna Mt Control of circulating IgE by the vitamin D receptor in vivo involves B cell intrinsic and extrinsic mechanisms.J Immunol. 2017; 198: 1164-1171Crossref PubMed Google Scholar Vitamin D also appears to have inhibitory actions on MCs.22Anogeianaki A. Castellani M.L. Tripodi D. et al.Vitamins and mast cells.Int J Immunopathol Pharmacol. 2010; 23: 991-996Crossref PubMed Scopus (10) Google Scholar, 23Yu C. Fedoric B. Anderson P.H. et al.Vitamin D(3) signalling to mast cells: a new regulatory axis.Int J Biochem Cell Biol. 2011; 43: 41-46Crossref PubMed Scopus (23) Google Scholar In fact, human MCs convert vitamin D through CYP27B1 to metabolites that inhibit immunoglobulin E−induced MC inflammatory mediator release.24Yip K.H. Kolesnikoff N. Yu C. et al.Mechanisms of vitamin D(3) metabolite repression of IgE-dependent mast cell activation.J Allergy Clin Immunol. 2014; 133 (1364): 1356-1364Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar A recent paper reported that the human leukemic MC line, human mast cell-1, and the rat leukemic MC RBL-2H3 have higher basal reactivity in the absence of vitamin D, while exposure to the vitamin increased expression of VDR, which complexed with signaling molecules downstream from the surface immunoglobulin E receptor FcεRI and prevented MC degranulation; VDR also bound to the promoter for tumor necrosis factor and inhibited its expression.25Liu Z.Q. Li X.X. Qiu S.Q. et al.Vitamin D contributes to mast cell stabilization.Allergy. 2016; ([Epub ahead of print])Google Scholar Vitamin D also enhances production of the soluble interleukin-33 receptor, ST2, and inhibits interleukin-33 action.26Pfeffer P.E. Chen Y.H. Woszczek G. et al.Vitamin D enhances production of soluble ST2, inhibiting the action of IL-33.J Allergy Clin Immunol. 2015; 135: 824-827Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar This is critical because interleukin-33 is considered a "danger signal"27Theoharides T.C. Danger signals and inflammation.Clin Ther. 2016; 38: 996-999Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar and has been implicated in allergic inflammation.28Saluja R. Ketelaar M.E. Hawro T. et al.The role of the IL-33/IL-1RL1 axis in mast cell and basophil activation in allergic disorders.Mol Immunol. 2015; 63: 80-85Crossref PubMed Scopus (88) Google Scholar, 29Theoharides T.C. Petra A.I. Taracanova A. et al.Targeting IL-33 in autoimmunity and inflammation.J Pharmacol Exp Ther. 2015; 354: 24-31Crossref PubMed Scopus (78) Google Scholar, 30Martin N.T. Martin M.U. Interleukin 33 is a guardian of barriers and a local alarmin.Nat Immunol. 2016; 17: 122-131Crossref PubMed Scopus (290) Google Scholar We have found that IL-33 acts synergistically with the neuropeptide substance P to stimulate skin MCs and induce skin inflammation.31Theoharides T.C. Zhang B. Kempuraj D. et al.IL-33 augments substance P-induced VEGF secretion from human mast cells and is increased in psoriatic skin.Proc Natl Acad Sci U S A. 2010; 107: 4448-4453Crossref PubMed Scopus (274) Google Scholar A systematic review found a significant relationship between low vitamin D levels and severity of polypoid rhinosinusitis.32Stokes P.J. Rimmer J. The relationship between serum vitamin D and chronic rhinosinusitis: a systematic review.Am J Rhinol Allergy. 2016; 30: 23-28Crossref PubMed Scopus (25) Google Scholar Low cord serum vitamin D levels also were associated with increased childhood AD, but not asthma.33Baiz N. Rgent-Molina P. Wark J.D. et al.Cord serum 25-hydroxyvitamin D and risk of early childhood transient wheezing and atopic dermatitis.J Allergy Clin Immunol. 2014; 133: 147-153Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar, 34Bacharier L.B. Vitamin D status at birth: an important and potentially modifiable determinant of atopic disease in childhood?.J Allergy Clin Immunol. 2014; 133: 154-155Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar In addition, low vitamin D levels were associated with atopy35Morales E. Sanchez-Solis M. Garcia-Marcos L. Vitamin D metabolism genes in asthma and atopy.Mini Rev Med Chem. 2015; 15: 913-926Crossref PubMed Scopus (10) Google Scholar, 36Papadopoulou A. Bountouvi E. Papaevaggelou V. Priftis K.N. Maternal vitamin D status and development of asthma and allergy in early childhood.Mini Rev Med Chem. 2015; 15: 900-912Crossref PubMed Scopus (10) Google Scholar and food allergy.37Molloy J. Ponsonby A.I. Allen K.J. et al.Is low vitamin D status a risk factor for food allergy? Current evidence and future directions.Mini Rev Med Chem. 2015; 15: 944-952Crossref PubMed Scopus (10) Google Scholar, 38Tsabouri S. Challa A. Giapros V. Chaliasos N. Vitamin D, breastfeeding and food allergy.Mini Rev Med Chem. 2015; 15: 984-987Crossref PubMed Scopus (3) Google Scholar We and others have reported that allergies, AD, and psoriasis contribute to an increased risk of autism spectrum disorder (ASD)39Theoharides T.C. Is a subtype of autism an "allergy of the brain"?.Clin Ther. 2013; 35: 584-591Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 40Theoharides T.C. Tsilioni I. Patel A.B. Doyle R. Atopic diseases and inflammation of the brain in the pathogenesis of autism spectrum disorders.Transl Psychiatry. 2016; 6: E844Crossref PubMed Scopus (124) Google Scholar through activation of MCs.41Theoharides T.C. Stewart J.M. Panagiotidou S. Melamed I. Mast cells, brain inflammation and autism.Eur J Pharmacol. 2016; 778: 96-102Crossref PubMed Scopus (81) Google Scholar It is, therefore, of great interest that a number of papers reported that low serum vitamin D levels may be associated with neuropsychiatric diseases42Eyles D.W. Burne T.H. Mcgrath J.K. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease.Front Neuroendocrinol. 2013; 34: 47-64Crossref PubMed Scopus (456) Google Scholar and neurocognitive dysfunction,43Buell J.S. Wson-Hughes B. Vitamin D And neurocognitive dysfunction: preventing "D"ecline?.Mol Aspects Med. 2008; 29: 415-422Crossref PubMed Scopus (277) Google Scholar, 44Schlogl M. Holick M.F. Vitamin D and neurocognitive function.Clin Interv Aging. 2014; 9: 559-568PubMed Google Scholar as well as with increased risk for ASD.45Mostafa G.A. Al-Ayadhi L.Y. Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity.J Neuroinflammation. 2012; 9: 201Crossref PubMed Scopus (100) Google Scholar, 46Tostes M.H. Polonini H.C. Gattaz W.F. et al.Low Serum levels of 25-hydroxyvitamin D (25-OHD) in children with autism.Trends Psychiatry Psychother. 2012; 34: 161-163Crossref PubMed Scopus (27) Google Scholar, 47Gong Z.L. Luo C.M. Wang L. et al.Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders.Neuroreport. 2014; 25: 23-27Crossref PubMed Scopus (23) Google Scholar, 48Bener A. Khattab A.O. Al-Dabbagh M.M. Is high prevalence of vitamin D deficiency evidence for autism disorder?: in a highly endogamous population.J Pediatr Neurosci. 2014; 9: 227-233Crossref PubMed Scopus (58) Google Scholar, 49Cannell J.J. Grant W.B. What is the role of vitamin D in autism?.Dermatoendocrinology. 2013; 5: 199-204Crossref PubMed Scopus (83) Google Scholar, 50Fernell E. Bejerot S. Westerlund J. et al.Autism spectrum disorder and low vitamin d at birth: a sibling control study.Mol Autism. 2015; 6: 3Crossref PubMed Scopus (104) Google Scholar In fact, vitamin D supplementation (300 IU/kg/d not to exceed 5,000 IU/d for 3 months) significantly improved clinical outcomes in 80% of children (n = 106) with ASD.51Saad K. Bdel-Rahman A.A. Elserogy Y.M. et al.Vitamin D status in autism spectrum disorders and the efficacy of vitamin D supplementation in autistic children.Nutr Neurosci. 2016; 19: 346-351Crossref PubMed Scopus (127) Google Scholar High oral doses of vitamin D and its analogs are required for systemic anti-inflammatory effects, with possible risk for adverse calcemic effects.52Piotrowska A. Wierzbicka J. Zmijewski M.A. Vitamin D in the skin physiology and pathology.Acta Biochim Pol. 2016; 63: 89-95Crossref PubMed Scopus (63) Google Scholar However, doses of 10,000 to 60,000 IU of 1,25(OH)2D3 were apparently well tolerated by adult males.53Mccullough P. Amend J. Results of daily oral dosing with up to 60,000 international units (IU) of vitamin D3 for 2 to 6 years in 3 adult males.J Steroid Biochem Mol Biol. 2016; ([Epub Ahead Of Print])Google Scholar A systematic review found that a topical combination of calcipotriol and betamethasone diproprionate used for psoriasis vulgaris was tolerable.54Yan R. Jiang S. Wu Y. et al.Topical calcipotriol/betamethasone dipropionate for psoriasis vulgaris: a systematic review.Indian J Dermatol Venereol Leprol. 2016; 82: 135-144Crossref PubMed Scopus (5) Google Scholar A topical formulation developed by the author combines microalgae-derived vitamin D with the natural flavonoid tetramethoxyluteolin; a pilot study of a skin lotion containing only tetramethoxyluteoilin recently reported benefits in AD and psoriasis.55Theoharides TC. Benefit of a tetramethoxyluteolin-containing skin lotion. Int J Immunopath Pharmacol in Press.Google Scholar Tetramethoxyluteolin (tetramethoxyflavone) is a naturally occurring flavonoid, structurally related to luteolin (tetrahydroxyflavone), which has anti-inflammatory activity56Middleton E.J. Kandaswami C. Theoharides T.C. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease and cancer.Pharmacol Rev. 2000; 52: 673-751PubMed Google Scholar but also inhibits keratinocytes57Weng Z. Patel A.B. Vasiadi M. et al.Luteolin inhibits human keratinocyte activation and decreases NF-kappab induction that is increased in psoriatic skin.PLoS One. 2014; 9Crossref Scopus (60) Google Scholar and MCs.58Weng Z. Patel A.B. Panagiotidou S. Theoharides T.C. The novel flavone tetramethoxyluteolin is a potent inhibitor of human mast cells.J Allergy Clin Immunol. 2015; 135: 1044-1052Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar In fact, a luteolin-containing dietary supplement significantly improved symptoms of ASD in 2 pilot clinical trials.59Theoharides T.C. Asadi S. Panagiotidou S. A case series of a luteolin formulation (Neuroprotek®) in children with autism spectrum disorders.Intl J Immunopathol Pharmacol. 2012; 25: 317-323Crossref PubMed Scopus (75) Google Scholar, 60Taliou A. Zintzaras E. Lykouras L. Francis K. An open-label pilot study of a formulation containing the anti-inflammatory flavonoid luteolin and its effects on behavior in children with autism spectrum disorders.Clin Ther. 2013; 35: 592-602Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar We recently reported that tetramethoxyluteolin is a better inhibitor than luteolin of MCs58Weng Z. Patel A.B. Panagiotidou S. Theoharides T.C. The novel flavone tetramethoxyluteolin is a potent inhibitor of human mast cells.J Allergy Clin Immunol. 2015; 135: 1044-1052Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar and microglia,61Patel AB, Tsilioni I, Leeman SE, Theoharides TC. Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism. Proc Natl Acad Sci U S A in press.Google Scholar which are increasingly invoked in the pathogenesis of ASD.40Theoharides T.C. Tsilioni I. Patel A.B. Doyle R. Atopic diseases and inflammation of the brain in the pathogenesis of autism spectrum disorders.Transl Psychiatry. 2016; 6: E844Crossref PubMed Scopus (124) Google Scholar, 62Gupta S. Ellis S.E. Ashar F.N. et al.Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism.Nat Commun. 2014; 5: 5748Crossref PubMed Scopus (319) Google Scholar, 63Takano T. Role of microglia in autism: recent advances.Dev Neurosci. 2015; 37: 195-202Crossref PubMed Scopus (79) Google Scholar, 64Koyama R. Ikegaya Y. Microglia in the pathogenesis of autism spectrum disorders.Neurosci Res. 2015; 100: 1-5Crossref PubMed Scopus (80) Google Scholar In conclusion, vitamin D deficiency has been associated with increased risk of atopic diseases and ASD, possibly through reduced ability to inhibit MCs and other inflammatory cells. Vitamin D supplementation alone, or together with other natural immunomodulatory agents, might prove useful in atopic and inflammatory diseases. In this issue, 5 expert groups address additional aspects of vitamin D in immunity, asthma, tuberculosis, and cancer.65Chirumbolo S. Bjorklund G. Sboarina A. Vella A. The role of vitamin D in the immune system as a pro-survival molecule.Clin Ther. 2017; 39: 894-916Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 66Pandolfi F. Franza L. Mandolini C. Conti P. Immune Modulation by vitamin D: special emphasis on its role in prevention and treatment of cancer.Clin Ther. 2017; 39: 884-893Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 67Hall S.C. Agrawal D.K. Vitamin D and bronchial asthma: an overview of the last five years.Clin Ther. 2017; 39: 917-929Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 68Murugesan H. Selvara P. Influence of Cdx-2 and Taq I gene variants on vitamin D3 modulated intracellular chemokine positive T-cell subsets in pulmonary tuberculosis.Clin Ther. 2017; 39: 946-957Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, 69Lang P.O. Aspinall R. Vitamin D status and the host resistance to infections: what it is currently (not) understood.Clin Ther. 2017; 39: 930-945Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar The author thanks Dr. Irene Tsilioni for help with the literature search and Mrs. Julia Stewart, RN for useful discussions. The author is the recipient of the trademark (GentleDerm®; US patents nos. 86442451; 6689748, 6984667, 7906153, 8268365, 9050275 and 9176146, as well as patent applications WIPO/MADRID 1319301, EP2710893 and WO 2014046700 covering brain and skin inflammation.
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