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Complementary and alternative medicine: Herbs, phytochemicals and vitamins and their immunologic effects

2009; Elsevier BV; Volume: 123; Issue: 2 Linguagem: Inglês

10.1016/j.jaci.2008.12.023

1097-6825

Timothy Mainardi, Simi Kapoor, Leonard Bielory,

Medicinal Plants and Bioactive Compounds

Complementary and alternative medicines (CAMs) are used in more than 80% of the world's population and are becoming an increasing component of the US health care system, with more than 70% of the population using CAM at least once and annual spending reaching as much as $34 billion. Since the inception of the National Center for Complementary and Alternative Medicine, there has been an enormous increase in the number of basic science and therapy-based clinical trials exploring CAM. The subspecialty of allergy and immunology represents a particularly fertile area with a large number of CAM therapies that have been shown to affect the immune system. Recent work has uncovered potential biochemical mechanisms involved in the immunomodulatory pathway of many supplemental vitamins (A, D, and E) that appear to affect the differentiation of CD4+ cell TH1 and TH2 subsets. Other research has shown that herbs such as resveratrol, quercetin, and magnolol may affect transcription factors such as nuclear factor-κB and the signal transducer and activator of transcription/Janus kinase pathways with resultant changes in cytokines and inflammatory mediators. Clinically, there have been hundreds of trials looking at the effect of CAM on asthma, allergic rhinitis, and atopic dermatitis. This article reviews the history of CAM and its use among patients, paying special attention to new research focusing on herbals, phytochemicals, and vitamins and their potential interaction with the immune system. Complementary and alternative medicines (CAMs) are used in more than 80% of the world's population and are becoming an increasing component of the US health care system, with more than 70% of the population using CAM at least once and annual spending reaching as much as $34 billion. Since the inception of the National Center for Complementary and Alternative Medicine, there has been an enormous increase in the number of basic science and therapy-based clinical trials exploring CAM. The subspecialty of allergy and immunology represents a particularly fertile area with a large number of CAM therapies that have been shown to affect the immune system. Recent work has uncovered potential biochemical mechanisms involved in the immunomodulatory pathway of many supplemental vitamins (A, D, and E) that appear to affect the differentiation of CD4+ cell TH1 and TH2 subsets. Other research has shown that herbs such as resveratrol, quercetin, and magnolol may affect transcription factors such as nuclear factor-κB and the signal transducer and activator of transcription/Janus kinase pathways with resultant changes in cytokines and inflammatory mediators. Clinically, there have been hundreds of trials looking at the effect of CAM on asthma, allergic rhinitis, and atopic dermatitis. This article reviews the history of CAM and its use among patients, paying special attention to new research focusing on herbals, phytochemicals, and vitamins and their potential interaction with the immune system. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACIWeb site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: February 2009. Credit may be obtained for these courses until January 31, 2011.Copyright Statement: Copyright © 2009-2011. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.List of Design Committee Members:Authors: Timothy Mainardi, MD, MS, Simi Kapoor, MD, and Leonard Bielory, MDActivity Objectives1. To recognize the frequent practice of complementary and alternative medicines.2. To understand the potential risks and benefits associated with complementary and alternative medicines.3. To provide a critical review of the literature supporting and opposing the use of alternative medication to treat atopic disorders.Recognition of Commercial Support: This CME activity has not received external commercial support.Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: Leonard Bielory has received research support from Lev Pharma, Otsuka, Schering-Plough, Novartis, Astellas, and Dyax; has served a consultant, speaker, or advisory board member for Forest, Schering-Plough, GlaxoSmithKline, Merck, Novartis, UCB Pharma, Alcon, Meda, Inspire, Santen, Nycomed, Bausch & Lomb, Ocusense, Vistakon, Genentech, Sanofi-Aventis, and Jerini; owns stocks in Ocusense and APPI; and has provided legal consultation or expert witness testimony on the topics of ocular allergy and asthma and allergy. Timothy Mainardi and Simi Kapoor have no significant relationships to disclose.Complementary and alternative medicines (CAMs) represent a diverse group of interventions that exist outside the realm of traditional medical therapeutics in that their efficacy and safety have yet to be determined. In the 1998 editorial accompanying an article on alternative therapies to prostate cancer, Marcia Angell, then editor of the New England Journal of Medicine, stated that what sets alternative medicine apart from conventional medicine “is that it has not been scientifically tested and its advocates largely deny the need for such testing”1Angell M. Kassirer J.P. Alternative medicine—the risks of untested and unregulated remedies.N Engl J Med. 1998; 339: 839-841Crossref PubMed Scopus (460) Google Scholar and that “alternative medicine also distinguishes itself by an ideology that largely ignores biologic mechanisms, [and] often disparages modern science.”1Angell M. Kassirer J.P. Alternative medicine—the risks of untested and unregulated remedies.N Engl J Med. 1998; 339: 839-841Crossref PubMed Scopus (460) Google Scholar (pp 839-40) This is all too often a viewpoint shared by many health care practitioners in the United States, and is also engrained in many medical school curriculums. However, to provide a balance, the US Congress in 1991 enacted funding for the National Institute of Health's Office of Alternative Medicine, which in 1998 evolved to become the National Center for Complementary and Alternative Medicine (NCCAM). One year later, Dr Stephen Straus was named as its first director. He focused on discovering the biochemical mechanisms and clinical application of a variety of alternative therapies (Fig 1). Being a member of the National Institute of Allergy and Infectious Diseases, Dr Straus had a particular interest in the immunologic mechanisms surrounding complementary and alternative medicine. This article is a review of the recent advances in CAM on the immune system and its clinical relevance.Fig 1National Institutes of Health NCCAM timeline. A graphical timeline of the events surrounding the formation of NCCAM. CDC, Centers for Disease Control and Prevention; HHS, Health and Human Services; NIH, National Institutes of Health; OAM, Office of Alternative Medicine; WHO, World Health Organization.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACIWeb site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted. Date of Original Release: February 2009. Credit may be obtained for these courses until January 31, 2011. Copyright Statement: Copyright © 2009-2011. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. List of Design Committee Members:Authors: Timothy Mainardi, MD, MS, Simi Kapoor, MD, and Leonard Bielory, MD Activity Objectives 1. To recognize the frequent practice of complementary and alternative medicines. 2. To understand the potential risks and benefits associated with complementary and alternative medicines. 3. To provide a critical review of the literature supporting and opposing the use of alternative medication to treat atopic disorders. Recognition of Commercial Support: This CME activity has not received external commercial support. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: Leonard Bielory has received research support from Lev Pharma, Otsuka, Schering-Plough, Novartis, Astellas, and Dyax; has served a consultant, speaker, or advisory board member for Forest, Schering-Plough, GlaxoSmithKline, Merck, Novartis, UCB Pharma, Alcon, Meda, Inspire, Santen, Nycomed, Bausch & Lomb, Ocusense, Vistakon, Genentech, Sanofi-Aventis, and Jerini; owns stocks in Ocusense and APPI; and has provided legal consultation or expert witness testimony on the topics of ocular allergy and asthma and allergy. Timothy Mainardi and Simi Kapoor have no significant relationships to disclose. The number of researchers publishing general CAM articles has exploded with more than 1700 articles cited in PubMed using “complementary medicine” as a keyword for the year 2007, compared with only 355 in 1990. There has been a similar upswing in the number of articles and the general interest in the effect of CAM on allergy and immunology. The number of articles published every year just using the key words immunology and complementary medicine has tripled since 1990 (Fig 2). Complementary and alternative medicine encompasses several major categories: alternative medical systems, biologically based therapies, manipulative therapies, mind-body therapies, and energy therapies (Fig 3). The use of CAM in the United States has been increasing at a substantial rate over the past 2 decades from a total of 34% (427 million) to 42% (628 million), which was in excess of the 385 million visits to a primary care physician visits in both 1990 and 1997 combined.2Resnick E.S. Bielory B.P. Bielory L. Complementary therapy in allergic rhinitis.Curr Allergy Asthma Rep. 2008; 8: 118-125Crossref PubMed Scopus (10) Google Scholar, 3Barnes PM, Powell-Griner E, McFann K, Nahin RL. Complementary and alternative medicine use among adults: United States, 2002.Google Scholar, 4Eisenberg D.M. Davis R.B. Ettner S.L. Appel S. Wilkey S. Van Rompay M. et al.Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey.JAMA. 1998; 280: 1569-1575Crossref PubMed Google Scholar Because the costs of CAM are mostly paid out-of-pocket, the annual spending for CAM is approximately $27 to $34 billion, compared with $29 billion in out-of-pocket expenditures for all other US physician services.4Eisenberg D.M. Davis R.B. Ettner S.L. Appel S. Wilkey S. Van Rompay M. et al.Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey.JAMA. 1998; 280: 1569-1575Crossref PubMed Google Scholar, 5Eisenberg D.M. Kessler R.C. Foster C. Norlock F.E. Calkins D.R. Delbanco T.L. Unconventional medicine in the United States: prevalence, costs, and patterns of use.N Engl J Med. 1993; 328: 246-252Crossref PubMed Scopus (2708) Google Scholar, 6WHO Traditional medicine. World Health Organization, Geneva, Switzerland2003Google Scholar In a recent report, the use of CAM at least once in a lifetime, including prayer, was as high as 75%. Similarly, the use of CAM in the past 12 months was 62%, with 26% of respondents stating that they used 1 or more CAM modalities at the suggestion of a physician.3Barnes PM, Powell-Griner E, McFann K, Nahin RL. Complementary and alternative medicine use among adults: United States, 2002.Google Scholar When this is compared to a recent survey of allergists (see letter to the editor by Engler et al in this issue), there are many similarities to the trends noted, except for the large difference among those who have ever used herbal medicines (8% vs 25%; Fig 4).Fig 4National versus allergist survey. A comparison of the allergy and immunology (AI) subspecialty survey conducted in 2007 compared with the Centers for Disease Control and Prevention survey3Barnes PM, Powell-Griner E, McFann K, Nahin RL. Complementary and alternative medicine use among adults: United States, 2002.Google Scholar of the US population use of CAM demonstrates an overall similarity in use except for the US population using more prayer, herbal, and chiropractic interventions, whereas the allergy and immunology subspecialty was more inclined to use special diets.View Large Image Figure ViewerDownload Hi-res image Download (PPT) When evaluating the potential risk of a medication, one must consider intrinsic risks, which consist of predictable and expected adverse reactions (type A) and idiosyncratic reactions (type B). Type A reactions account for 80% of adverse reactions, whereas type B reactions account for 6% to 10%.7Myers S.P. Cheras P.A. Myers S.P. Cheras P.A. The other side of the coin: safety of complementary and alternative medicine.Med J Aust. 2004; 181: 222-225PubMed Google Scholar In addition, there are extrinsic risks that are attributed to erroneous handling and manufacturing of the product, resulting in misidentified materials, contamination, substitutions, lack of standardization of the product, adulteration, incorrect preparation of the dose, and incorrect labeling and advertising. Although CAM is viewed as natural, it too runs these same risks.8Heimall J. Bielory L. Defining complementary and alternative medicine in allergies and asthma: benefits and risks.Clin Rev Allergy Immunol. 2004; 27: 93-103Crossref PubMed Google Scholar Unfortunately, unlike pharmacotherapy, there is no comprehensive list of potential or predictable reactions with CAM. Along with the listed intrinsic and extrinsic risks, some additional risks of using CAM involve the interruption of conventional therapies because of to the lack of perceived necessity or direct interference of therapeutic actions and the failure to recognize the precautions of the treatment because of the misassumption that the products are “natural” and hence “safe.”9Studdert D.M. Eisenberg D.M. Miller F.H. Curto D.A. Kaptchuk T.J. Brennan T.A. Medical malpractice implications of alternative medicine.JAMA. 1998; 280: 1610-1615Crossref PubMed Google Scholar This misconception is alarming if one considers that 18% of people in the United States (equivalent to 2-4 million people in February 2004) are simultaneously using CAM and conventional medical therapies and are thus at potential risk for a herb-drug interaction. However, some relief is offered if one considers that in 2001, a systematic review of herb-drug interactions included 41 case reports and 17 formal clinical trials relating to 5 herbs that seemed to have the most potential for such an adverse interaction. Of the 17 clinical trials, 10 trials involved St John's wort (Hypericum perforatum), and the remainder involved garlic (Allium sativum), ginseng (Panax ginseng), ginkgo (Ginkgo biloba), and kava (Piper methysticum). Considering the millions of people using CAM, this would suggest that the real risks from the hundreds of medicinal plants is underreported, hypothetical, or still unknown.7Myers S.P. Cheras P.A. Myers S.P. Cheras P.A. The other side of the coin: safety of complementary and alternative medicine.Med J Aust. 2004; 181: 222-225PubMed Google Scholar Some examples of adverse reactions with herbs are reviewed in this article's Table E1 in the Online Repository at www.jacionline.org. Examples of agents commonly used by patients for allergic and immune disorders include ma huang, a Chinese herb containing ephedra previously used to promote weight loss, which has been associated with cardiovascular events10Chen C. Biller J. Willing S.J. Lopez A.M. Ischemic stroke after using over the counter products containing ephedra.J Neurol Sci. 2004; 217: 55-60Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 11Samenuk D. Link M.S. Homoud M.K. Contreras R. Theoharides T.C. Wang P.J. et al.Adverse cardiovascular events temporally associated with ma huang, an herbal source of ephedrine.Mayo Clin Proc. 2002; 77: 12-16Abstract Full Text Full Text PDF PubMed Google Scholar that in 2004 resulted in the US Food and Drug Administration (FDA) banning the sale of dietary supplements with ephedrine alkaloids. Vitamin A, which has some immunopotentiating properties (relative risk), was studied in the Beta-Carotene and Retinol Efficacy Trial,12Omenn G.S. Goodman G.E. Thornquist M.D. Balmes J. Cullen M.R. Glass A. et al.Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease.N Engl J Med. 1996; 334: 1150-1155Crossref PubMed Scopus (2195) Google Scholar which evaluated the effects of β-carotene and vitamin A on the development of lung cancer in smokers and workers exposed to asbestos. The results showed the intervention group had a higher mortality from lung cancer (relative risk, 1.46) and cardiovascular disease (relative risk, 1.26). A meta-analysis of placebo-controlled trials involving vitamin E, vitamin A, and β-carotene demonstrated increased mortality in the intervention groups.13Bjelakovic G. Nikolova D. Gluud L.L. Simonetti R.G. Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis.JAMA. 2007; 297: 842-857Crossref PubMed Scopus (931) Google Scholar In addition, a recent study of Ayurvedic preparations showed that more than 20% had been found to be contaminated with potentially toxic levels of heavy metals including lead, mercury, and arsenic.14Saper R.B. Kales S.N. Paquin J. Burns M.J. Eisenberg D.M. Davis R.B. et al.Heavy metal content of Ayurvedic herbal medicine products.JAMA. 2004; 292: 2868-2873Crossref PubMed Scopus (258) Google Scholar, 15Saper R.B. Phillips R.S. Sehgal A. Khouri N. Davis R.B. Paquin J. et al.Lead, mercury, and arsenic in US- and Indian-manufactured Ayurvedic medicines sold via the Internet.JAMA. 2008; 300: 915-923Crossref PubMed Scopus (119) Google Scholar Concerns for the subspecialty of allergy and immunology are the development of allergic responses such as anaphylaxis, asthma, urticaria, contact dermatitis,8Heimall J. Bielory L. Defining complementary and alternative medicine in allergies and asthma: benefits and risks.Clin Rev Allergy Immunol. 2004; 27: 93-103Crossref PubMed Google Scholar and the reports of drug interactions with herbal remedies16Fugh-Berman A. Ernst E. Herb-drug interactions: review and assessment of report reliability.Br J Clin Pharmacol. 2001; 52: 587-595Crossref PubMed Scopus (206) Google Scholar such as St John's wort because of its ability to interact with cytochrome oxidases, including CYP3A, resulting in alterations in concentrations of fexofenadine, cyclosporine, and antiretroviral agents such as indinavir.17Ruschitzka F. Meier P.J. Turina M. Luscher T.F. Noll G. Acute heart transplant rejection due to Saint John's wort.Lancet. 2000; 355: 548-549Abstract Full Text Full Text PDF PubMed Google Scholar, 18Piscitelli S.C. Burstein A.H. Chaitt D. Alfaro R.M. Falloon J. Indinavir concentrations and St John's wort.Lancet. 2000; 355: 547-548Abstract Full Text Full Text PDF PubMed Google Scholar Despite the 100-fold rise in reported adverse reactions to traditional Chinese medicine (TCM) in the last 20 years, the number of adverse events is still negligible compared with the number of adverse events reported from conventional medical therapies, although are certainly not to be considered without risk. In the world of scientific research, randomized controlled trials are accepted as the gold standard when defining the methodologic quality of a clinical trial, especially a double-blind trial. When a clinical trial is designed, attempts are made to minimize bias (placebo effects, observational bias, sampling bias), exclude effects of cointerventions, and prevent the progression of the natural disease course to obtain reliable, reproducible, and generalizable results worthy of recognition. However, some barriers exist that make such scientific designs difficult to achieve and in some cases impossible for researchers investigating complementary and alternative medical therapies. Examples include finding and randomizing representative CAM sample populations into equal comparison groups. This is challenging as a result of the differing world views regarding CAM, because the motivation to follow the treatment regimen is influenced by the patient's preference. Some have alluded to allocating patients to their preference group and randomizing those who have no preference; however, this suggestion has the potential for biased reporting of a positive response. In another example resulting from ethical implications, some institutions are hesitant to approve clinical trials using CAM when conventional therapies exist that are both effective and evidence-based. As a result, many clinical trials are designed using the CAM intervention as an adjuvant to the conventional therapy, as opposed to being the primary treatment under investigation. Blinding in some CAM therapies is also difficult, especially in mind-body therapies such as tai chi, acupuncture, biofeedback, and other manipulative therapies, because the investigator is critical to the treatment intervention. Similarly, finding a suitable control or placebo for comparison is a hurdle that researchers have tried to overcome using sham interventions, as in the case of acupuncture; however, this attempt has received scrutiny by many, because some claim that sham acupuncture offers some benefits through the process of needling. Because the mechanism of action for most CAM therapies is yet unknown, standardized diagnostic criteria and endpoint measurements to determine the treatment efficacy are lacking, making it difficult to compare multiple study results accurately. Also, some CAM regimens, such as TCM, are individualized and cannot always be standardized for the large groups preferred in conventional randomized controlled trials, which decreases the external validity of the results and increases the likelihood of type II error in these studies. In addition, this form of therapy yields results with less internal validity than orthodox medical trials because the formulations are often polyherbal and the effectiveness cannot be attributed to any 1 ingredient but rather is a product of the synergistic effect of the formulation as a whole. By the same token, the efficacious results of some Chinese herbal remedies have been linked to contamination by steroids, as in 1 case of atopic dermatitis treated with a topical herbal formula.19Wood B. Wishart J. Potent topical steroid in a Chinese herbal cream.N Z Med J. 1997; 110: 420-421PubMed Google Scholar However, despite the potential for the surreptitious inclusion of glucocorticoids in polyherbal formulations, which can explain the positive outcome, some herbal remedies have withstood rigorous tests disproving the presence of glucocorticoid contamination while demonstrating efficacy.20Hon K.L. Lee V.W. Leung T.F. Lee K.K. Chan A.K. Fok T.F. et al.Corticosteroids are not present in a traditional Chinese medicine formulation for atopic dermatitis in children.Ann Acad Med Sing. 2006; 35: 759-763PubMed Google Scholar, 21Hon K.L. Leung T.F. Ng P.C. Lam M.C. Kam W.Y. Wong K.Y. et al.Efficacy and tolerability of a Chinese herbal medicine concoction for treatment of atopic dermatitis: a randomized, double-blind, placebo-controlled study.Br J Dermatol. 2007; 157: 357-363Crossref PubMed Scopus (59) Google Scholar Considering all the obstacles in making a well designed clinical trial, it seems that the best approach is to allow the question under investigation to dictate the methodology of the study design and to take an interdisciplinary approach when determining the therapeutic effectiveness, considering both the qualitative and quantitative data before defining the clinical significance of the results.22Critchley J.A. Zhang Y. Suthisisang C.C. Chan T.Y. Tomlinson B. Alternative therapies and medical science: designing clinical trials of alternative/complementary medicines—is evidence-based traditional Chinese medicine attainable?.J Clin Pharmacol. 2000; 40: 462-467Crossref PubMed Google Scholar NCCAM has developed a scientifically appropriate support mechanism that has resulted in funding for more than 228 general CAM clinical trials. Many of the initial trials have shown enough promise to warrant further investigations, with several investigating CAM and immunity. 1α-25-Dihydroxyvitamin D3 (vitamin D) is a fat-soluble vitamin necessary in the human diet whose affects include not only calcium homeostasis and bone metabolism but also immune function. Vitamin D has its actions promoted through binding to the vitamin D receptor (VDR) and translocating to the nucleus. A variety of immune cells express VDR and are under investigation into the effect of vitamin D on autoimmune or infectious diseases.23Nagpal S. Na S. Rathnachalam R. Noncalcemic actions of vitamin D receptor ligands.Endocr Rev. 2005; 26: 662-687Crossref PubMed Scopus (404) Google Scholar Early studies demonstrated24Rigby W.F. Stacy T. Fanger M.W. Inhibition of T lymphocyte mitogenesis by 1,25-dihydroxyvitamin D3 (calcitriol).J Clin Invest. 1984; 74: 1451-1455Crossref PubMed Google Scholar that the addition of vitamin D interrupted mitogenesis of T cells because vitamin D appears to suppress preferentially the differentiation of CD4+ cells to the TH1 subtype, with subsequent shifting of the CD4+ cells to the TH2 subtype,25Thien R. Baier K. Pietschmann P. Peterlik M. Willheim M. Interactions of 1 alpha,25-dihydroxyvitamin D3 with IL-12 and IL-4 on cytokine expression of human T lymphocytes.J Allergy Clin Immunol. 2005; 116: 683-689Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 26van Etten E. Mathieu C. Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts.J Steroid Biochem Mol Biol. 2005; 97: 93-101Crossref PubMed Scopus (314) Google Scholar and lower levels of vitamin D showing negative effects in both multiple sclerosis and inflammatory bowel disease.27Munger K.L. Levin L.I. Hollis B.W. Howard N.S. Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis.JAMA. 2006; 296: 2832-2838Crossref PubMed Scopus (698) Google Scholar, 28Munger K.L. Zhang S.M. O'Reilly E. Hernan M.A. Olek M.J. Willett W.C. et al.Vitamin D intake and incidence of multiple sclerosis.Neurology. 2004; 62: 60-65Crossref PubMed Google Scholar Vitamin E is a lipid soluble molecule that is known to have at least 8 different isoforms (α, β, γ, and δ-tocopherols and α, β, γ, and δ-tocotrienols), all with a chromanol nucleus surrounded by different lipophilic side chains. Vitamin E intercalates itself into lipid membranes of cells, and it can help in halting peroxidation of lipid molecules. The activity of vitamin E in gene expression and transcription in mast cells has been described recently as affecting the activation of protein kinase C, protein phosphatase 2A, and protein kinase B in mast cells,29Zingg J.M. Vitamin E and mast cells.Vitam Horm. 2007; 76: 393-418PubMed Google Scholar with inhibition of protein kinase C halting the proliferation of mast cells in vitro,30Kempna P. Reiter E. Arock M. Azzi A. Zingg J.M. Inhibition of HMC-1 mast cell proliferation by vitamin E: involvement of the protein kinase B pathway.J Biol Chem. 2004; 279: 50700-50709Crossref PubMed Scopus (45) Google Scholar and other studies showing inhibition of eosinophilic infiltration of mucosal surfaces.31Wagner J.G. Jiang Q. Harkema J.R. Ames B.N. Illek B. Roubey R.A. et al.Gamma-tocopherol prevents airway eosinophilia and mucous cell hyperplasia in experimentally induced allergic rhinitis and asthma.Clin Exp Allergy. 2008; 38: 501-511Crossref PubMed Scopus (26) Google Scholar Using the theory that high levels of vitamin A shift the immune system from a predominantly TH1 to a TH2 paradigm,32Schuster G.U. Kenyon N.J. Stephensen C.B. Vitamin A deficiency decreases and high dietary vitamin A increases disease s