IN ORTHOMOLECULAR RESEARCH...

VOLUME 3 • ISSUE 5

ADVANCESIN ORTHOMOLECULAR RESEARCH

Allergies

research-driven botanical integrative orthomolecular groundbreaking

Quercetin - Rosemary - Perilla -Butterbur - Mangiferin - Vitamin D

Advances in Orthomolecular Researchis published and distributed through integrative physicians, health carepractitioners, and progressive health food retailers.

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VOLUME 3 • ISSUE 5

1 Allergies: The Immune System Gone Haywire11 Quercetin: Sweet Allergy Relief15 Rosemary: Where Tradition Meets Science17 Perilla: An Allergy Fighting Herb21 Butterbur: Beyond Migraines21 Anti-Allergen Therapy from the Mango Tree25 The Role of Vitamin D in Immunity10 & 20 Questions and Answers


Volume 3 Issue 5 ADVANCES in orthomolecular research 1

Allergies:The Immune System GoneHaywireRunny noses, itchy eyes, upset stomachs, inflamedskin… most of us have experienced these symptoms orhave a family member or a friend that suffers fromthem. Allergies are a modern era pandemic. It isestimated that 30-50% of the population in the UnitedStates suffers from allergies. Allergies in the US comewith a hefty yearly price tag of over 2 billion dollars inlost productivity, medical expenses and medication.1-5

Allergies are a long term health problem; typicallybeginning between 8 and 12 years of age and lastingfor decades if not for a lifetime.6,7 And to add insult toinjury, research shows that the incidence of allergies ison the rise in most developed countries. Thankfully, asour understanding of allergic disorders improves, newtreatment and preventive approaches emerge, becauseat times, scratching an itch truly makes it worse.

Allergies and the Immune SystemAllergies are a disorder of the immune system that iscaused by the improper activation of the immuneresponse. Allergies are almost always linked to thepresence of an excessive amount of allergic antibodiesknown as IgE. Allergies occur because a substancepresent in the environment that is normally harmlessenters our body and is mistakenly identified as athreat. Most pathogens that we are exposed to, frombacteria to viruses, are proteins and are eliminatedthrough the activation of the immune system. In thecase of harmless proteins, like proteins from food, theimmune response must be suppressed through aprocess known as oral tolerance. Inducing oraltolerance has been used as a strategy to preventallergies for years. For instance, Native Americansused to eat poison ivy leaves to prevent contact

dermatitis associated with skin exposure to the plant.8

Understanding the process of oral tolerance isessential for the prevention and treatment of allergies.

Although true or immediate allergies are mediated byIgE, other antibodies and immune cells have also beenlinked to allergic diseases. Contact dermatitis forinstance occurs through the effect of T-cells and IgM orIgG are often responsible for drug allergies or what isknown as cytotoxic allergies.9

Food intolerances are also probably allergies sincesignificant immune factors are involved in the process.Infants with milk, soy and egg intolerance were foundto have IgG levels significantly higher than the controlgroup.10 Trials in animals also show a clearinvolvement of IgG immunoglobulins when peanutsensitivities are present.11 Other studies point to a clearimmunological link in irritable bowel syndrome, withresults showing that elimination diets that focus on thefoods which elicit an IgG response in IBS patients leadto significant improvements of the disease in amajority of patients.12,13 IgG immune reactions aredelayed occurring several hours after exposure to theoffender and are often not immediately identified asallergies.14

When Intolerance Sets InThe immune system is designed to protect our bodyfrom pathogens and must respond and eliminatethreats. On the other hand, the immune system mustalso be able to tolerate the cells of our body, theproteins from food as well as the bacteria naturallypresent on our body. Most of the interaction withforeign proteins occurs in the intestine which explainswhy the gastrointestinal tract is the largest immuneorgan in the body. Given the complexities of theimmune response and the abundance of proteins andbacteria in our diet, it is not surprising that allergiesare common. There are two important immunereactions occurring in our intestines, the activation ofthe immune system when pathogens are present in thegastrointestinal tract and the suppression of theimmune response when food proteins are digested.

If tolerance fails, which means that the immune systemis inappropriately activated, B cells produce antibodiesspecific to the antigen and antibody’s known as IgEare produced to neutralize the perceived threat. Thisleads to the release of histamines, leukotrienes,tryptase, chemokines, cytokines and prostaglandinsfrom mast cells. These in turn lead to inflammationthrough the recruitment of basophils, eosinophils andleukocytes. These cells increase the blood flow to the

2 ADVANCES in orthomolecular research Volume 3 Issue 5

area which accentuates symptoms such as swellingand itching. There are two main phases to allergies,the first phase is the immediate phase characterized bythe release of histamine and vasodilators. The secondphase is mediated by the mobilization of immune cellsand occurs 4 to 6 hours after the initial reaction.15

Immune tolerance is a process that begins duringpregnancy, as early as 20 weeks of age throughtransfer of immune factors from the mother.16 Severalresearchers have focused on the age at whichexposure to a protein first occurs and its consequenceon allergies. Experiments in mice have shown thatwhen the exposure occurs at a younger age, especiallywhen exposure occurs prior to the normal weaningtime, allergies are more likely to occur. For many ofthese mice tolerance develops with age.17

More than an InconvenienceAlthough the symptoms of allergies are often seen asa mere nuisance, they have been shown to causeheadaches, fatigue, difficulty learning, loss of sleep,and reduced productivity.18,19 There are also severalassociated problems such as headaches, loss of smell

and taste, cough, wheezing, snoring, ear infectionsand nasal polyps.20 The most severe kind of allergicreaction, known as anaphylaxis, is very serious, canprogress very quickly and can be lethal due to theinvolvement of several body systems. Other allergiessuch as seasonal allergies, which affect up to 35% ofthe North American population, are not lifethreatening but lead to seriously unpleasant sideeffects. By far the most common symptoms associatedwith air borne allergies are a runny nose and itchyeyes. The eyes are typically quite inflamed in seasonalallergy sufferers as allergens can impact the eyesurface directly.21 Severe allergies are oftenoverwhelming because avoidance strategies areneeded. The most common kind of this type of allergyis peanut or tree nut allergy, which affects roughly 1%of children under the age of 5.22,23 In Canada, peanutallergy affects 1.34% of children.24 Food allergies ingeneral affect 6-8% of children and 4% of the UnitedStates population older than 10 years of age. Everyyear in the US alone, 30 000 anaphylactic reactionsare caused by allergies, of those, 2000 lead tohospitalization and 200 are lethal.

Appropriate history of exacerbatingfactors

Perennial or seasonal symptoms, withtiming correlated to specific pollen or mold

spore exposureSymptom triggering with identifiable

agents such as animalsFamilial history of asthma, allergic rhinitis,

or atopic eczema

Medication and medical historyOral aggravators such as acetylsalicylic

acid, nonsteroidal anti-inflammatorydrugs, anti-hypertensive agents

Topical aggravators such as alpha agonistsHypothyroidism

Pregnancy

Physical findingsRhinorrhea, clear or mucoid discharge

Erythema of nasal mucosaNasal congestion“Allergic facies”

Collaborative findingsImmediate hypersensitivity skin testing

Serum specific IgE

Comorbid conditionsSinusitis

Nasal polyposisAsthma

Eustachian tube dysfunctionSerous otitis media

Diagnosis of Allergies25,26

Figure 1. Skin prick testing remains the most specificand most cost effective way to diagnose allergies.

An Inborn PredispositionAllergies are still poorly understood. We know that theytend to run in families, which indicates a genetic bias.Most allergy sufferers have inherited their allergiesthrough an immune predisposition to a Th2 immunityprofile (mediated by antibodies) which is often seen inautoimmune disorders. Allergies are therefore linkedto an abnormal immune system, tend to occur inclusters and are often associated with otherhypersensitivity reactions. 27

Some allergies take a long time to develop, whileothers appear very quickly.Generally, allergies are more likely to be a problemfor foods that are introduced early in life and that areeaten more commonly. Delaying the introduction ofpotential allergens may be a good idea and studieshave demonstrated that exclusive breast feeding forthe first 4 months of life reduces the risk of developingatopic dermatitis, a hereditary inflammatory skincondition.33

Some allergies are life-long while others lessenwith time.For all allergies, there seems to be a tendency towardseventual tolerance. 20% of children with peanutallergies will eventually outgrow them.34 For eggallergy, which affects 1-2% of children, 4% developtolerance by 4 years of age, 12% by the age of 6, 37%by the age of 10 and 68% by the age of 16 years.35

Other trials demonstrate similar results with 35% of thechildren on an elimination diet developing tolerancewithout any other form of treatment.36 However, severeallergies are less likely to subside and patients with IgElevels to egg exceeding 50 ku/L and patients withmultiple food allergies are less likely to see theirallergies subside.37


Allergies, genes and theimmune system

Women suffering from allergic symptoms earlyin their pregnancy are 6 times more likely to

have children who also have allergies.28

Animal studies have demonstrated that in themost susceptible strain 87-100% of the animalsdeveloped allergies to milk or peanut while the

least susceptible animals did not developallergies.29

A very clear indication of the central role theimmune system plays in allergic disease is thatbone marrow recipients develop the allergies of

their donor.30

Children with egg allergies and eczema have a20% chance of having peanut allergy.31

There is a concordance between allergies andasthma.32

Potential Determinantsof Allergic Disease38

GeneticsFamily history

Low birth weightExposure to pets

Exposure to allergensInfections

Exposure to parasitesObesity

Dietary fatty acidsDietary antioxidants

Exposure to tobacco smokeExposure to pollutants

Avoidance as a StratagemThe best way to control allergies once they havedeveloped is to prevent exposure to the allergen.

Unfortunately, as seasonal allergy sufferers know toowell, avoidance is not always a possibility. While mostof us rejoice once spring has arrived, for seasonalallergy sufferers, the powdery grains released fromtrees and grasses can wreak havoc on their immunesystem. Pollens from trees and grasses that are carriedby the wind to pollinate other plants can cause anallergic reaction if the person is sensitive to pollen.Springtime allergies are typically caused by pollenfrom trees, summertime allergies are a result of pollenfrom grass and fall allergies are caused by weedpollen. Unlike avoidance to dust or pet dander,allergies to pollen or mold spores are more difficult toavoid. This problem is made worse by the “primingeffect”, which results in progressively worseningsymptoms as the inflammation from the initial allergicreaction is made worst by subsequent exposure.39

Typical prescription medications for the treatment ofallergies include antihistamines, which prevent therelease or action of histamine. Histamine can causesneezing, itchiness, irritation and excess mucousproduction. One major inconvenience to prescribedantihistamines is that they have a sedative effect andcan lead to drowsiness, increasing the risk foraccidents and injuries. Antihistamines are also typicallyineffectual for nasal congestion and other treatmentoptions often need to be considered in allergysufferers.

A commonly used treatment for allergy sufferers iscutaneous allergen immunotherapy, a techniquewhere allergens are periodically injected under theskin in gradually increasing quantities. If successful thetechnique eventually leads to desensitization.Unfortunately, this technique is not used for foodallergies as the risk of adverse reactions is too great.40

Several studies have reported an increase in theprevalence of allergies in recent decades. In the UK forinstance, the prevalence of peanut allergy has risenfrom 1.3% of 3 year olds to 3.2% of 3 year olds in1995.41,42 These increases are common throughout thedeveloped world with several European countries nowreporting one in ten children suffering from asthmaand one in three affected by allergies. Such increasesare unlikely to be caused by genetic factors alone.43

Possible explanations have included the “hygienetheory” and an increase in air pollution. The hygienetheory has been put forth to explain the rise inincidence of several immune disorders in developed

countries. The theory’s basic premise is that limitedexposure to microbes in early childhood increases thesusceptibility to allergic disease and other immunedisorders such as asthma. Such exposure would beimportant to educate the immune system and a sterileenvironment would predispose to immune dysfunctionand autoimmune diseases.44,45 This may also explainwhy certain strains of probiotics seem to have aprotective role in immune diseases.46 This also explainswhy children who grow up with dogs in their home areless likely to suffer from allergies.47 Surprisingly,children born through C-section were also more likelyto develop food sensitivities. It has been speculatedthat contact with the bacteria in the birth canal mayreduce the risk of allergy. It is also possible that thepresence of antibiotics in the mother to preventinfections post surgery may predispose to thedevelopment of allergies.48 Studies looking at theimportance of early exposure to specific bacteria haveshown that children who develop allergies aresignificantly less likely to have been exposed to S.aureus, a bacteria that has a strong stimulatory effecton T-cells, another indication that exposure tomicrobes in early childhood is important for the properdevelopment of the immune system.49 This would alsoexplain why children drinking milk fortified withprobiotics missed fewer days from day care due tosickness and were less likely to receive antibiotictherapy.50,51

Figure 2. Peanut Allergy - A problem on the rise.


Observational studies continue to strengthen the linkbetween air pollution and allergic conditions. Pollutionhas long been known to induce asthma and toacerbate inhaled allergens in asthmatics.52 The linkbetween pollution and allergies has been explained byan increase in oxidative stress and free radicals inpeople that are more likely to suffer from allergies.People with allergies would be more sensitive topollution due to a lessened ability to detoxifypollutants.53 Other possible explanations for theincrease in allergic disorders have included themanner in which foods are prepared. For instance, inthe case of peanut allergies, it has been postulatedthat the formation of advanced glycation end productsin roasted peanuts may increase the susceptibility ofdeveloping peanut allergies. The presence ofadvanced glycation end-products in heat treatedpeanuts could therefore increase their allergenicityand previously non-allergenic raw peanut proteinshave been shown to trigger an immune reaction onceheated.54 However, more research is needed toconfirm those results as they have not beenreproduced by other researchers.55

Since foods that are introduced at a young age aremore likely to be candidates for allergies, theAmerican Academy of Pediatrics has recommendedthat children should not consume peanuts for the firstthree years of their life to help prevent thedevelopment of allergies.56 Others have suggested thatthis measure is counterproductive and that theconsumption of peanuts at an early age may actuallyprevent allergies and countries where peanut snacksare available for infants have lower rates of allergiesto peanuts.58,59

It has also been postulated that skin exposure topeanut oil may contribute to allergies but thosefindings remain tenuous and are only based onpopulation studies.61 More work is needed todetermine the role exposure plays in the developmentof allergies.

Other work in the prevention of allergies has looked atproducing transgenic plants that are free of theproteins that lead to the allergy.62

Newer research has revealed ways of reducing thelikeliness of developing allergies. Probiotics forinstance have demonstrated promise in this new field.Vitamin D has also been portrayed to be a significantfactor in allergies and epidemiological studiesdemonstrate that there is a very strong North-Southgradient for the sales of EpiPen prescription in theUnited States. This may point to a link between vitamin

D and allergies, an interesting finding given newresearch showing that vitamin D is important for selftolerance. Other possibilities include the shift in dietarylipid consumption with a significant decline in theconsumption of Omega 3 fatty acids. It has beenproposed that omega 3 fatty acid consumption wouldhave a protective effect against allergic disease due tothe anti-inflammatory effect of those oils. Higheromega 3 fatty acid levels in the breast milk decreasedthe risk of allergic disease in infants.63 Increasedmaternal consumption of omega 3 fatty acids duringpregnancy may have even greater health benefits forthe infant, with studies suggesting a long term immuneeffect associated with early exposure to omega 3 fattyacids.64 Several mechanisms have been identified asfar as how these fatty acids can influence the functionof the immune system (see figure 6 from65). Omega 3fatty acids may also have a direct effect on the immunesystem and on the structure and function of cellularmembranes. The effect of omega 3 long chainpolyunsaturated fatty acids on cellular membranesreduces T-cell signaling and activation.66 Theprevention of T-cell proliferation and the inhibition ofthe production of immune messengers such as IL-2and IFN-by omega 3 fatty acids are key to theirbeneficial effects for allergy sufferers.

Figure 3. EpiPen, the treatment for anaphylaxis

You wouldn’t play the piano with a mallet, or swat a flywith a bat… unfortunately, that is what your body isdoing if you experience allergies. Instead ofaddressing a problem by eradicating a pathogen, itcreates havoc by unleashing an array of immune cellsand their mediators, creating inflammation, swellingand itchiness. Most of us will experience allergies,which is not surprising given the difficult task ofseparating threatening substances from harmlessones. As more research surfaces on allergies, ourunderstanding of the disease process will improve. Forthe time being, suffice it to say that when we stray fromthe natural way and the natural environment weevolved in, problems arise. For example, althoughgrowing up in a cleaner and more germ-freeenvironment seems like a good way to prevent


infection and disease, in reality it also predisposes toautoimmune diseases. We evolved with germs andbacteria and it seems that this interaction is needed forthe proper development and maturation of theimmune system. Exposure to the sun is another keyfactor in the prevention or allergies. Our ancestorswould have spent most of their time in the sun andwould have had much higher vitamin D levels thanmost of us do. Since vitamin D is extremely importantfor immune tolerance, it is not surprising to see such astrong North-South gradient for immune diseases.Despite all of modern medicine’s advancements,Mother Nature still knows best.

References1 K. Singh and L. Bielory, Epidemiology of ocular allergy symptomsin United States adults (1988–1994), Ann Allergy (1) (2007).2 K. Singh and L. Bielory, Epidemiology of ocular allergy symptomsin regional parts of the United States in the adult population(1988–1994), Ann Allergy (1) (2007).3 K. Singh and L. Bielory, Ocular allergy: a national epidemiologicstudy, J Allergy Clin Immunol 119 (1 Suppl 1) (2007), p. S154.4 Savage JH, Matsui EC, Skripak JM, Wood RA. The natural historyof egg allergy.J Allergy Clin Immunol. 2007 Dec;120(6):1413-7.5 Weber RW. Allergic rhinitis.Prim Care. 2008 Mar;35(1):1-10, v.6 Ferri’s7 Weber RW. Allergic rhinitis.Prim Care. 2008 Mar;35(1):1-10, v.8 Dakin R.Remarks on a cutaneous affection produced by certainpoisonous vegetables. Am J Med Sci, 1829;4:98-100. J DtschDermatol Ges. 2007 Nov;5(11):1015-28.9 Averbeck M, Gebhardt C, Emmrich F, Treudler R, Simon JC.Immunologic principles of allergic disease.10 McDonald PJ, Goldblum RM, Van Sickle GJ, Powell GK. Foodprotein-induced enterocolitis: altered antibody response to ingestedantigen. Pediatr Res. 1984 Aug;18(8):751-5.11 Cardoso CR, Teixeira G, Provinciatto PR, Godoi DF, Ferreira BR,Milanezi CM, Ferraz DB, Rossi MA, Cunha FQ, Silva JS. Modulationof mucosal immunity in a murine model of food-induced intestinalinflammation. Clin Exp Allergy. 2008 Feb;38(2):338-49.12 Yang CM, Li YQ. [The therapeutic effects of eliminating allergicfoods according to food-specific IgG antibodies in irritable bowelsyndrome][Article in Chinese]. Zhonghua Nei Ke Za Zhi. 2007Aug;46(8):641-3.13 Atkinson W, Sheldon TA, Shaath N, Whorwell PJ. Foodelimination based on IgG antibodies in irritable bowel syndrome: arandomised controlled trial. Gut. 2004 Oct;53(10):1459-64.14 Crowe SE, Perdue MH. Gastrointestinal food hypersensitivity:basic mechanisms of pathophysiology. Gastroenterol1992;103:1075–95.15 Weber RW. Allergic rhinitis.Prim Care. 2008 Mar;35(1):1-10, v.16 Calder PC, Krauss-Etschmann S, de Jong EC, Dupont C, Frick JS,Frokiaer H, Heinrich J, Garn H, Koletzko S, Lack G, Mattelio G,Renz H, Sangild PT, Schrezenmeir J, Stulnig TM, Thymann T, WoldAE, Koletzko B. Early nutrition and immunity - progress andperspectives. Br J Nutr. 2006 Oct;96(4):774-90.

17 Strobel S, Ferguson A. Immune responses to fed protein antigensin mice. 3. Systemic tolerance or priming is related to age at whichantigen is first encountered. Pediatr Res 1984; 18:588-94.18 E.F. Juniper, A.K. Thompson and P.J. Ferrie et al., Validation ofthe standardized version of the Rhinoconjunctivitis Quality of LifeQuestionnaire, J Allergy Clin Immunol 104 (2 Pt 1) (1999), pp.364–369.19 E.F. Juniper, W.C. Howland and N.B. Roberts et al., Measuringquality of life in children with rhinoconjunctivitis, J Allergy ClinImmunol 101 (2 Pt 1) (1998), pp. 163–17020 Weber RW. Allergic rhinitis.Prim Care. 2008 Mar;35(1):1-10, v.21 Bielory L. Ocular allergy overview. Immunol Allergy Clin NorthAm. 2008 Feb;28(1):1-23, v.22 HA Sampson, Update on food allergy, J Allergy Clin Immunol113 (2004), pp. 805–819.23 SH Sicherer and HA Sampson, 9. Food allergy, J Allergy ClinImmunol 117 (Suppl 2) (2006), pp. S470–S475.24 RS Kagan, L Joseph and C Dufresne et al., Prevalence of peanutallergy in primary-school children in Montreal, Canada, J AllergyClin Immunol 112 (2003), pp. 1223–1228.25 Ferri’s26 Weber RW. Allergic rhinitis.Prim Care. 2008 Mar;35(1):1-10, v.27 Oboki K, Ohno T, Saito H, Nakae S. Th17 and allergy. AllergolInt. 2008 Jun;57(2):121-34.28 Shinohara M, Wakiguchi H, Saito H, Matsumoto K. Symptoms ofallergic rhinitis in women during early pregnancy are associatedwith higher prevalence of allergic rhinitis in their offspring. AllergolInt. 2007 Dec;56(4):411-7.29 Li X, Huang CK, Schofield BH, Burks AW, Bannon GA, Kim KH,Huang SK, Sampson HA. Strain-dependent induction of allergicsensitizationcaused by peanut allergen DNA immunization in mice. J Immunol.1999 Mar 1;162(5):3045-52.30 Agosti JM, Sprenger JD, Lum LG et al. Transfer of allergen-specific IgE-mediated hypersensitivity with allogeneic bone marrowtransplantation. N. Engl. J. Med. 1988; 319: 1623-1628.31 Burks AW, Laubach S, Jones SM. J Allergy Clin Immunol. 2008Jun;121(6):1344-50.32 Weber RW. Allergic rhinitis.Prim Care. 2008 Mar;35(1):1-10, v.33 Laubereau B, Brockow I, Zirngibl A, Koletzko S, Gruebl A, vonBerg A, Filipiak-Pittroff B, Berdel D, Bauer CP, Reinhardt D, HeinrichJ, Wichmann HE; GINI Study Group. Effect of breast-feeding on thedevelopment of atopic dermatitis during the first 3 years of life--results from the GINI-birth cohort study. J Pediatr. 2004May;144(5):602-7.34 DM Fleischer, MK Conover-Walker, L Christie, AW Burks and RAWood, The natural progression of peanut allergy: resolution andthepossibility of recurrence, J Allergy Clin Immunol 112 (2003), pp.183–189.35 Savage JH, Matsui EC, Skripak JM, Wood RA. The naturalhistory of egg allergy. J Allergy Clin Immunol. 2007Dec;120(6):1413-7.36 Staden U, Rolinck-Werninghaus C, Brewe F, Wahn U,Niggemann B, Beyer K. Specific oral tolerance induction in foodallergy in children: efficacy and clinical patterns of reaction.Allergy. 2007 Nov;62(11):1261-9.37 Savage JH, Matsui EC, Skripak JM, Wood RA. The naturalhistory of egg allergy. J Allergy Clin Immunol. 2007Dec;120(6):1413-7.



38 Calder PC, Krauss-Etschmann S, de Jong EC, Dupont C, Frick JS,Frokiaer H, Heinrich J, Garn H, Koletzko S, Lack G, Mattelio G,Renz H, Sangild PT, Schrezenmeir J, Stulnig TM, Thymann T, WoldAE, Koletzko B. Early nutrition and immunity - progress andperspectives. Br J Nutr. 2006 Oct;96(4):774-90.39 Weber RW. Allergic rhinitis.Prim Care. 2008 Mar;35(1):1-10, v.40 Nelson HS, Lahr J, Rule R, Bock A, Leug D. Treatment ofanaphylactic sensitivity to peanuts by immunotherapy withinjections of aqueous peanut extract. J Allergy Clin Immunol.1997;99:744-5141 J Grundy, S Matthews, B Bateman, T Dean and SH Arshad,Rising prevalence of allergy to peanut in children: data from 2sequential cohorts, J Allergy Clin Immunol 110 (2002), pp.784–789.42 Kabesch M, Schaal W, Nicolai T, von Mutius E. Lowerprevalence of asthma and atopy in Turkish children living inGermany. Eur Respir J. 1999 Mar;13(3):577-82.43 Calder PC, Krauss-Etschmann S, de Jong EC, Dupont C, Frick JS,Frokiaer H, Heinrich J, Garn H, Koletzko S, Lack G, Mattelio G,Renz H, Sangild PT, Schrezenmeir J, Stulnig TM, Thymann T, WoldAE, Koletzko B. Early nutrition and immunity - progress andperspectives. Br J Nutr. 2006 Oct;96(4):774-90.44 von Mutius E. Allergies, infections and the hygiene hypothesis--the epidemiological evidence. Immunobiology. 2007;212(6):433-9.45 Renz H, Blümer N, Virna S, Sel S, Garn H. The immunologicalbasis of the hygiene hypothesis. Chem Immunol Allergy.2006;91:30-48.46 Isolauri E, Salminen S. Probiotics: Use in Allergic Disorders: ANutrition, Allergy, Mucosal Immunology, and Intestinal Microbiota(NAMI) Research Group Report. J Clin Gastroenterol. 2008 Jun 5.47 Zirngibl A, Franke K, Gehring U, von Berg A, Berdel D, BauerCP, Reinhardt D, Wichmann HE, Heinrich J; GINI study group.Exposure to pets and atopic dermatitis during the first two years of life.A cohort study. Pediatr Allergy Immunol. 2002 Dec;13(6):394-401.48 Laubereau B, Filipiak-Pittroff B, von Berg A, Grübl A, ReinhardtD, Wichmann HE, Koletzko S; GINI Study Group. Caesareansection and gastrointestinal symptoms, atopic dermatitis, andsensitisation during the first year of life. Arch Dis Child. 2004Nov;89(11):993-7.49 Adlerberth I, Lindberg E, Aberg N, Hesselmar B, Saalman R,Strannegård IL, Wold AE. Reduced enterobacterial and increasedstaphylococcal colonization of the infantile bowel: an effect ofhygienic lifestyle? Pediatr Res. 2006 Jan;59(1):96-101.50 Hatakka K, Savilahti E, Pönkä A, Meurman JH, Poussa T, NäseL, Saxelin M, Korpela R. Effect of long term consumption ofprobiotic milk on infections in children attending day care centres:double blind, randomised trial. BMJ. 2001 Jun 2;322(7298):1327.51 Weizman Z, Asli G, Alsheikh A. Effect of a probiotic infantformula on infections in child care centers: comparison of twoprobiotic agents. Pediatrics. 2005 Jan;115(1):5-9.52 Peden DB. Effect of air pollution in asthma and respiratoryallergy. Otolaryngol Head Neck Surg. 1996 Feb;114(2):242-7.53 Riedl MA. The effect of air pollution on asthma and allergy. CurrAllergy Asthma Rep. 2008 Apr;8(2):139-46.54 SY Chung and ET Champagne, Allergenicity of Maillard reactionproducts from peanut proteins, J Agric Food Chem 47 (1999), pp.5227–5231.55 L Mondoulet, E Paty and MF Drumare et al., Influence of thermalprocessing on the allergenicity of peanut proteins, J Agric FoodChem 53 (2005), pp. 4547–4553.

56 HA Sampson, Update on food allergy, J Allergy Clin Immunol113 (2004), pp. 805–819.57 G Lack, D Fox, K Northstone and J Golding, Factors associatedwith the development of peanut allergy in childhood, N Engl J Med348 (2003), pp. 977–985.58 A Khakoo and G Lack, Preventing food allergy, Curr AllergyAsthma Rep 4 (2004), pp. 36–42.59 Yeh KW. Allergens and allergic diseases in children. ActaPaediatr Taiwan. 2006 Jul-Aug;47(4):169-74.60 Levy Y, Broides A, Segal N, Danon YL. Peanut and tree nutallergy in children: role of peanut snacks in Israel? Allergy. 2003Nov;58(11):1206-7.61 J Strid, J Hourihane, I Kimber, R Callard and S Strobel,Epicutaneous exposure to peanut protein prevents oral toleranceand enhances allergic sensitization, Clin Exp Allergy 35 (2005), pp.757–766.62 BE Moseley, How to make foods safer—genetically modifiedfoods, Allergy 56 (suppl 67) (2001), pp. 61–63.63 Yu G, Kjellman NI, Björkstén B. Phospholipid fatty acids in cordblood: family history and development of allergy. Acta Paediatr.1996 Jun;85(6):679-83.64 Lauritzen L, Kjaer TM, Fruekilde MB, Michaelsen KF, Frøkiaer H.Fish oil supplementation of lactating mothers affects cytokineproduction in 2 1/2-year-old children. Lipids. 2005 Jul;40(7):669-76.65 Calder PC, Krauss-Etschmann S, de Jong EC, Dupont C, Frick JS,Frokiaer H, Heinrich J, Garn H, Koletzko S, Lack G, Mattelio G,Renz H, Sangild PT, Schrezenmeir J, Stulnig TM, Thymann T, WoldAE, Koletzko B. Early nutrition and immunity - progress andperspectives. Br J Nutr. 2006 Oct;96(4):774-90.66 Zeyda M, Stulnig TM. Lipid rafts& co.: An Integrated Model ofMembrane Organization in T cell Activation. Progr Lipid Res. 200645, 187-202


The Allergic Reaction:

SensitizationDendritic cells Peanut - specific

T-cells

Allergic Reaction


Antigens from allergens like peanuts are engulfed and then presented by immune cells calleddendritic cells that in turn activate T-cells, causing a Th2 immune response. This causes therelease of cell signaling molecules called cytokines (IL-4, IL-5 and IL-13), triggering theproduction of antibodies specifically matched to the antigen. Antibodies then activate Mastcells, causing the release of histamines and pro-inflammatory molecules, this in turn producesthe symptoms of allergies.

Th2

IL-4IL-5

IL-13

FcERI

B cells Peanut-specificlgE

Mast cells


Q&AVitamin DWhat is the optimal vitamin D3 dosage?

All of the research on vitamin D clearly points to theneed for a complete overhaul of the currentrecommendations for vitamin D supplementation. TheCanadian government recommends a minimum of0.2 mcg (8 IU) of vitamin D up to 13 years of age and0.8 mcg (32 IU) per day thereafter. The currentmaximum allowed by Health Canada remains at 25mcg (1000 IU) per day for all age groups.1

The situation is very similar in the United States, withthe National Institute of Health establishing AdequateIntakes of 200 IU from birth until 50 years of age, 400IU per day from 51-70 years and 600 IU afterwards.2

The Tolerable Upper Intake levels for vitamin D havebeen set at 1000 IU for the first year of life and 2000IU for all other age groups.3

These recommendations were established in 1997and therein lies the problem. There have been almost20,000 medical publications on vitamin D since thattime. To put this number in perspective, Lipitor®, theprescription medication with the highest dollar volumeof sales in the US, has a total of less than 3700publications under its name. Needless to say that ourknowledge and understanding of the amounts ofvitamin D required for health has significantlyimproved since the establishment of the AdequateIntake guidelines.

The last ten years of research into the health benefitsassociated with vitamin D have shown that vitamin Dpossesses greater than expected health benefits. Thevitamin has been shown to reduce the risk ofdeveloping cancer, help lower blood pressure, helpmaintain physical strength and reduces bone fractures.

An abundance of clinical information is now showingthat the current intake recommendations are far toorestrictive and are detrimental to the health of thepopulations they are meant to protect. There is goodevidence showing that dosages up to 10,000 IU ofvitamin D are safe for long term use and that singledosages of up to 5 times this amount are notharmful.4,5

Studies also point to natural physiological levels ofvitamin D that are far greater than what can beobtained from the current recommended intake levels.The maximum amount of vitamin D produced in theskin is similar to that obtained from an oral dose of10,000 IU, ten times the maximum allowed by HealthCanada.6

To prevent immune dysfunction, when shouldvitamin D3 therapy be initiated?

Breast feeding does not provide infants with theamount of vitamin D they require. Breast milk,although the preferred food for newborn infants, isquite low in vitamin D (roughly 25 IU of vitamin D perliter). Infants can produce additional vitamin D whenexposed to sunlight but some reports of rickets havebeen documented in exclusively breastfed infants. TheAmerican Academy of Pediatrics recommends aminimum of 400 IU of vitamin D per day for allbreastfed infants.7 The same recommendations of400 IU per day have been made by Health Canada8

and the Canadian Pediatric Society advocates up to800 IU per day for children in Northern Nativecommunities which are more prone to vitamin Ddeficiency.9

Research has shown that supplementation with vitaminD during infancy and pregnancy is associated with adecreased risk of type 1 diabetes, allergies andmultiple sclerosis.10-13 Vitamin D supplementationshould start at birth and dosages should vary from400 IU to 2000 IU per day depending on whether ornot there is a vitamin D deficiency to begin with.14

References: see page 20


Quercetin: ubiquitous in the world of botanicalsand the most abundant of polyphenolicflavonoids, this vibrantly colored substance ismaking quite the name for itself in healthcircles. With the benefits of being an anti-inflammatory, anti-proliferative, anti-oxidant,anti-bacterial, anti-atherogenic, anti-hypertensive, and of course anti-allergenic1-5

it’s lucky for us that 70% of flavonoidconsumption in the diet is actually quercetin.6

Apples and onions are the most well knownsources of quercetin but there are also healthydoses of this flavonoid favorite in kale, broccoli,green and black teas, berries, and even redwine.7-9

Figure 1: The Chemical Structure of Quercetin

Of the 5000 different flavonoids discovered, withmore being added to this count everyday, quercetin isstealing the show as studies are demonstrating againand again how it is one of the most potent andeffective of the polyphenolic flavonoids.1 Flavonoids in

general are composed of a three-ringed structure thatallows for the antioxidant and anti-inflammatoryactions they are famous for. Quercetin in particularcontains a catechol group (B ring) and a strategicallyplaced hydroxy group (at position 3) that contribute toits more potent antioxidative actions, allowing it toscavenge free radicals more efficiently.10

The antioxidant action of quercetin, that is its ability toscavenge reactive oxygen species (ROS), ishypothesized to be the source of its beneficial effects,and particularly its anti-inflammatory properties.1 Thisis mediated through the actions of a regulatorymolecule called Nuclear factor kappa beta (NF-kB)which, when stimulated, promotes production ofinflammatory molecules including tumour necrosisfactor (TNF)-alpha and others.11 ROS increase NF-kBstimulation, which through TNF-alpha leads toinflammatory cytokines, which leads to the productionof ROS and the cycle continues.12 Quercetin acts toboth inhibit NF-kB13 and neutralize the ROSproduced14, thus breaking the cycle of oxidative stressand down regulating the progression of diseaseprocesses.

This effect leads to the many benefits associated withthis flavonoid powerhouse. Quercetin is used in themanagement of pain and inflammation as it works toblock the action of lipoxygenases and cycloxygenases,enzymes that produce proinflammatory, and thus painproducing, mediators.15,16 Quercetin inhibits aldosereductase, an enzyme that promotes the formation offructose and sorbitol from circulating glucose,suggesting a use in diabetes related conditions such ascataracts, glaucoma, nephropathy and neuropathy.17

Quercetin is also showing great promise incardiovascular health, including a recent double-blindplacebo controlled trial, which demonstrated thatquercetin supplementation at 730mg/day for 28 days

Quercetin:Sweet Allergy

Relief

A C

B3’

4’2’

5’

6’

34

8

7

65


was effective in reducing blood pressure in stage Ihypertensive patients.18 Due to its free-radicalscavenging structure quercetin also has a role incancer prevention and treatment, particularly colonand lung cancers.19 Interestingly, quercetin has alsoshown benefit in the treatment of chronic prostatitisspecifically in treating the associated pelvic pain,which can be attributed to the anti-inflammatory andanalgesic properties of quercetin.20

Figure 2: The antioxidant and anti-inflammatoryactions of quercetin

The list of benefits goes on, but the topic of interest thisseason is, of course, quercetin’s ability to ease thewoes of allergy sufferers. Both seasonal and chronicallergies are associated with debilitating symptomssuch as itchy, watery eyes, nasal congestion, hives,atopic dermatitis, asthma and in severe cases ofallergen exposure, anaphylaxis. Fortunately for thoseafflicted, one of quercetin’s most well known effects isthat of allergy relief. Since the early 1980’s quercetinhas been studied for its effects on allergy relatedimmune cells in the body.21 These immune cells, mostnotably basophils, mast cells, eosinophils, and T-helper cells, are part of the intricate network in thebody that works to prevent invasion by infectiousoffenders, however they can become part of anoveractive response leading to allergic reactions,autoimmunity and inflammation.22

Mast Cell StabilizerMast cells and basophils are at the root of allergicsymptoms. Found in numerous tissue locationsthroughout the body, they house inflammatorymediators such as histamine as well as pro-inflammatory cytokines like TNF-alpha, tryptase and

several Interleukin (IL) molecules: IL-6, IL-8, and IL-13.20,23 It’s these contents that, once released whenmast cells ‘degranulate’, lead to the symptoms seen inallergies. The antibody IgE is an important player inmast cell degranulation, and is found in higheramounts in allergy sufferers.20 Quercetin’s claim toallergy fame is indeed its ability to stabilize these mastcells, leading to less degranulation episodes andsubsequently, lower occurrence of allergy symptoms.Studies show that quercetin inhibits IgE mediatedhistamine release from mast cells to have an overalleffect of down-regulating mast cell activation.21 Mastcell activation doesn’t only result in degranulation, butalso results in the production of more inflammatorycytokines through the action of NF-kB, therebyperpetuating the allergic cycle.24,25 Quercetin not onlyworks to stabilize the mast cells and inhibit NF-kB, butalso down-regulates the production of inflammatorymediators such as tryptase, IL-6, histidinedecarboxylase, and TNF-alpha.26,27

Figure 3. Quercetin is a flavonoid found in manycommon foods including apples and onions

Th-1/Th-2 BalanceIn light of this it may be tempting to see the mast cellas an immune enemy, however they are importantinflammatory cells of the immune system that respondto danger signals; it is the moderation of their actionthat is of concern. This is where the T-helper (Th) cellsplay an important role in what is called the Th-1/Th-2balance. Th-2 immune cells are associated withcytokines that encourage the development of mastcells, basophils and eosinophils, all of which areimplicated in allergies.28 Allergy sufferers are thoughtto have a dominance of Th-2 to Th-1 immune cells.Thankfully quercetin acts on this level as well tomoderate the actions of the immune system, lesseningthe effects of allergic symptoms. Quercetin has beenshown in vitro to reduce the expression of Th-2 derived


cytokine IL-4 and increase the expression andproduction of the Th-1 derived cytokine Interferon(IFN)-γ.29 In an animal model of allergic asthma,quercetin was also shown to modulate the Th1/Th2balance through this decrease in IL-4 and increase inIFN-γ: The result was a decrease in allergic airwayconstriction and airway hyper responsiveness, as seenin allergic asthma.30

Another group of allergy associated immune cells,eosinophils, are found in the blood of allergy andallergic asthma sufferers.31 Eosinophils are a source ofcytokines and chemokines and are known to produceleukotrienes, inflammatory products that causebronchoconstriction, and mucus hypersecretionassociated with allergic asthma.32-35 Quercetin hasbeen shown in animal models of asthma to decreaseeosinophils in lung tissue thereby reducing asthmaticsymptoms. This effect was demonstrated both with oralsupplementation and with an inhaled application ofquercetin.29,36,37 Once again, researchers are looking atquercetin’s ability to inhibit NF-kB in order to explainthis decrease in eosinophil levels, since it is known thatNF-kB is associated with eosinophil recruitment toallergy sites.38

Many of these studies are test tube or animal modelstudies, and although these have shown promisingresults, the need for more human studies is apparent.However, research is surfacing in human trials. A veryrecent double-blind randomized placebo controlledtrial looked at the effect of an enzymatically modifiedquercetin glycoside on symptoms of cedar pollinosiscommon in Japan.39 20 subjects positive for Japanesecedar pollen IgE were assigned either 100mg twicedaily of the quercetin glycoside or placebo for 8 weeksin the pollen season.37 The effect was a significantreduction in ocular symptoms, that is a decrease in thesymptoms of itchy watery eyes associated withseasonal pollen allergies.37

With the research results so far it’s no wonderquercetin is gaining a name in anti-allergy treatment,not to mention the plethora of benefits being shown toresult from its consumption. Of course eating a diethigh in flavonoids will benefit overall health, but oftenthe body needs an extra kick of flavonoid action tosupport the immune system against an oncomingallergy season. And with quercetin in the allergyarsenal, this pollen season just got better.

Bioavailability of QuercetinQuercetin is most commonly found in nature asa glycoside, meaning that there is a sugargroup in place of one of the OH (hydroxy)groups. Quercetin glycosides include rutin,quercitrin, isoquercitrin and hyperoside. Due toit’s structure, the aglycone form of quercetin isthe most effective antioxidant and anti-inflammatory.

Quercetin was previously thought to have avery low bioavailability, and it’s obsorption inthe intestines was questioned. In addition tothis, because quercetin is bound by albumin (ablood protein) in the body, some thought this

made it less available for use in the body.40 Thisled to the belief that supplementation with adigestive enzyme such as bromelain wouldresult in better availability of quercetin bothintestinally and in the serum.

However, research is lacking to support thisclaim. The aglycone has actually been shown tohave an absorption rate of 24%, and theglycosidic forms (those with a sugar moleculeattached) have an absorption rate of 52%.41 It isalso now understood that quercetin is convertedby enzymes in the intestinal tract to glycosidicforms to be absorbed,42,43 suggesting an evenhigher absorption rate. In addition to this,quercetin has a relatively long half-life, and onrepeated supplementation of the pureaglycone, quercetin blood levels increasesignificantly.44 This suggests that concurrentsupplementation with digestive enzymes isunnecessary to absorb and utilize the quercetinaglycone.


References1 Boots, A.W., Haenen, G., Bast, A. Health effect of quercetin: fromantioxidant to nutraceutical. (2008) 585: 325-337.2 Cushnie, T.P., Lamb, A.J., Antimicrobial activity of flavonoids. Int. J.Antimicrob. Agents (2005) 26: 343–3563 Perez-Vizcaino, F., Bishop-Bailley, D., Lodi, F., Duarte, J., Cogolludo, A.,Moreno, L., Bosca, L., Mitchell, J.A., Warner, T.D.,The flavonoid quercetininduces apoptosis and inhibits JNK activation in intimal vascular smoothmuscle cells. Biochem. Biophys. Res. Commun. (2006) 346: 919–9254 Perez-Vizcaino, F., Duarte, J., Jimenez, R., Santos-Buelga, C., & Osuna, A.Antihypertensive effects of the flavonoid quercetin. Pharmac Rep. (2009)61:67-755 Gulati, N., Laudet, B., Zohrabian, V.M., Murali, R., Jhanwar-Uniyal,M.,The antiproliferative effect of quercetin in cancer cells is mediated viainhibition of the PI3K-Akt/PKB pathway. Anticancer Res. (2006) 26:1177–11816 De Vries, J.H., Janssen, P.L., Hollman, P.C., van Staveren, W.A., Katan,M.B., Consumption of quercetin and kaempferol in free-living subjectseating a variety of diets. Cancer Lett. (1997) 114: 141-1447 Hertog, MGL, Hollman PCH, Katan MB. Content of potentiallyanticarcinogenic flavonoids of 28 vegetables and 9 fruits commonlyconsumed in The Netherlands. J Agric Food Chem (1992) 40:2379.8 Hertog, MGL, Hollman PCH, van de Putte B. Content of potentiallyanticarcinogenic flavonoids of tea infusions, wines and fruit juices. J AgricFood Chem (1993) 41:1242.9 Aherne, S.A & O’Brien N.M. Dietary flavonols: chemistry, food contentand metabolism. Nutr. (2002) 18: 75-81.10 Heijnen, C.G., Haenen, G.R.M.M., Oostveen, R.M., Stalpers, E.M., Bast,A., 2002. Protection of flavonoids against lipid peroxidation: the structureactivity relationship revisited. Free Radic. Res. 36: 575–581.11 Sarkar, F.H., Li, Y., Wang, Z., & Kong, D. NF-kB signaling pathway andits therapeutic implications in human disease. Int Rev immunol. (2008).27:293-31912 Rahman, I., Gilmour, P.S., Jimenez, L.A., MacNee, W., Oxidative stressand TNF alpha induce histone acetylation and NF-kappaB/AP-1 activationin alveolar epithelial cells: potential mechanism in gene transcription in lunginflammation. Mol. Cell. Biochem. (2002) 234–235, 239–248.13 Comalada M, Camuesco D, Sierra S, Ballester I, Xaus J, Galvez J,Zarzuelo A. In vivo quercitrin anti-inflammatory effect involves release ofquercetin, which inhibits inflammation through down-regulation of the NF-kappaB pathway. Eur J Immunol. (2005) 35:584–92.14 Hanasaki, Y., Ogawa, S., Fukui, S., The correlation between activeoxygens scavenging and antioxidative effects of flavonoids. Free Radic.Biol. Med. (1994) 16:845–850.15 Baumann J, et al Flavonoids and related compounds as inhibition ofarachidonic acid peroxidation P.rostaglandins (1980) 20:627‐639.16 Welton AF, Hurley J, Will P Flavonoids and arachidonic acid metabolism.Prog Clin Biol Res (1988) 280:301-312.17 Dvornik E, Simard-Duquesne N, Krami M, et al. Polyol accumulation ingalactosemic and diabetic rats: control by an aldose reductase inhibitor.Science (1973) 182:1146-1148.18 Edwards RL, Lyon T, Litwin SE, Rabovsky A, Symons JD, Jalili T. Quercetinreduces blood pressure in hypertensive subjects. J Nutr. (2007)137(11):2405-11.19 Murakami, A., Ashida, H., Terao, J. Multitargeted cancer prevention byquercetin. Canc Lett. (2008) 269:315-325.20 Shoskes, D.A., Zeitlin, S.I., Shahed, A. & Rajfer, J. Quercetin in men withcategory III chronic prostatitis: a preliminary, prospective, placebocontrolled trial. Urol. (1999) 54:960-963.21 Middleton, E. Et al. Quercetin: an inhibitor of antigen-induced humanbasophil histamine release. J. Immunol. (1981) 127(2): 546-55022 Prussin, C. & Metcalfe, D. IgE, mast cells, basophils, and eosinophils. JAllergy Clin Immunol. (2003) 111(2): S486-S49423 Park, H. Et al. Flavonoids inhibit histamine release and expression ofpro-inflammatory cytokines in mast cells. Arch Pharm Res (2008) 31(10):1303-1311.

24 Min, Y. Et al. Quercetin inhibits expression of inflammatory cytokinesthrough attenuation of NK-kB and p38 MAPK in HMC-1 human mast cellline. Inflamm. Res. (2007) 56: 210-215.25 Park, H. H., Lee, S., Oh, J. M., Lee, M. S., Yoon, K. H., Park, B. H., Kim,J. W., Song, H., and Kim, S. H., Antiinflammatory activity of fisetin in humanmast cells (HMC-1). Pharmacol. Res. (2007) 55:31-37.26 Ruiz, P.A Et al. Quercetin inhibits TNF-induced NF-kB transcription factorrecruitement to proinflammatory gene promotors in murine intestinalepithelial cells. J.Nutr. (2007) 137: 1208-1215.27 Kempuraj, D. Et al. Inhibitory effect of quercetin on tryptase andinterleukin-6 release, and histidine decarboxylase mRNA transcription byhuman mast cell-1. Clin Exp Med; (2006) 6:150-156.28 Miller, A. The etiologies, pathophysiology, andalternative/complementary treatment of asthma. Alt Med Rev. (2001) 6(1):20-47.29 Nair, M. Et al. The flavonoid, quercetin, differentially regulates Th-1(IFN-γ) and Th-2 (IL4) cytokine gene expression by normal peripheral bloodmononuclear cells. Biochimica et Biophysica Acta (2002) 1593:29-36.30 Park, H., Et al. Quercetin regulates Th1/Th2 balance in a murine modelof asthma. Int. Immunopharm. (2008) 9:261-267.31 Rogerio, A.P Et al. Anti-inflammatory activity of quercetin andisoquercitrin in experimental murine allergic asthma. Inflamm Res. (2007)56: 402-408.32 Heller PF, Lee CW, Foster DW, Corey DM, Austen KF, Lewis RA.Generation and metabolism of 5-lipoxygenase pathway leukotrienes byhuman eosinophils: predominant production of leukotriene C4. Proc NatlAcad Sci USA (1983) 80: 7626–30.33 Bandeira-Melo C, Weller PF. Eosinophils and cysteinyl leukotrienes.Prostagl Leukot Essent Fatty Acids (2003) 69: 135–43.34 Drazen JM. Leukotrienes as mediators of airway obstruction. Am J RespirCrit Care Med (1998) 158: S193–200.35 Holgate ST, Sampson AP. Antileukotriene therapy. Future directions. AmJ Respir Crit Care Med (2000) 161: 147–53.36 Moon, H. Et al. Quercetin inhalation inhibits the asthmatic responses byexposure to aerosolized-ovalbumin in conscious guinea pigs. Arch PharmRes. (2008) 31(6): 771-778.37 Jung, C. H., Lee, J. Y., Cho, C. H., and Kim, C. J., Antiasthmatic actionof quercetin and rutin in conscious guineapigs challenged with aerosolizedovalbumin. Ach. Pharm. Res. (2007) 30, 1599-1607.38 Jia GQ, Gonzalo JA, Hidalgo A, Wagner D, Cybulsky M, Gutierrez‐JiaGQ et al. Selective eosinophil transendothelial migration triggered byeotaxin via modulation of Mac-1/ICAM-1 and VLA- 4/VCAM-1 interactions.Int Immunol (1999) 11: 1–10.39 Kawai, M. Et al. Effect of enzymatically modified isoquercetrin, aflavonoid, on symptoms of Japanese cedar pollinosis: A randomizeddouble-blind placebo controlled trial. Int Arch Allergy Immunol (2009)149:359-368.40 Boulton DW, Walle UK, and Walle T: Extensive binding of thebioflavonoid quercetin to human plasma proteins. J Pharm Pharmacol(1998) 50: 243–249.41 Hollman, P.C., de Vries, J.H., van Leeuwen, S.D., Mengelers, M.J.,Katan, M.B., Absorption of dietary quercetin glycosides and quercetin inhealthy ileostomy volunteers. Am. J. Clin. Nutr. (1995) 62, 1276–1282.42 Sesink, A.L., Arts, I.C., Faassen‐Peters, M., Hollman, P.C., Intestinaluptake of quercetin-3-glucoside in rats involves hydrolysis by lactasephlorizin hydrolase. J. Nutr. (2003) 133: 773–776.43 Nemeth, K., Plumb, G.W., Berrin, J.G., Juge, N., Jacob, R., Naim, H.Y.,Williamson, G., Swallow, D.M., Kroon, P.A., Deglycosylation by smallintestinal epithelial cell beta-glucosidases is a critical step in the absorptionand metabolism of dietary flavonoid glycosides in humans. Eur. J. Nutr.(2003) 42: 29–42.44 Egert, S. Et al. Daily quercetin supplementation dose dependentlyincreases plasma quercetin concentrations in healthy humans. J Nutr.(2008) 138:1615-1621.

Rosemary:Where traditionmeets science

Rosemary is a bushy shrub with whitish blue flowersthat grows wildly along the coasts of theMediterranean.1 It has been cultivated since ancientdays in Europe, Central America, and other regions2.Now it is a common household plant that is used forflavoring and in cosmetics, and whose fragrantneedle-like leaves are used in cooking.3 Rosemary hasbeen used in folk medicine as an antispasmodic, forrelief of respiratory disorders, and for stimulating hairgrowth. It has also been used as a pain killer, adiuretic, and for human fertility. Its extracts relax thesmooth muscles of the trachea and intestine and haveantioxidant, liver protective and tumour fightingactivities.2 One of the ancient cult plants, it is closelyassociated with love and marriage, birth and death,and is still used in bridal bouquets in England andGermany as a symbol of remembrance. Rosemarywas also traditionally put in the cradles of infants toguard against harm.2 Modern science is now showingthat rosemary extracts can indeed guard againstcertain kinds of harm, including the damage causedby allergies and inflammation.

Dealing with AllergiesStudies of rosemary have found that its major chemicalcomponents are polyphenolics with antioxidantactivities. These substances include rosmarinic acid,caffeic acid, carnosolic acid, rosmanol and carnosol.4

Besides acting as antioxidants to prevent cell damage,several of rosemary’s components also serve to blockinflammation. Allergies are inextricably linked withinflammatory processes since inflammation is themechanism behind most of the unpleasant andpotentially dangerous allergic symptoms. Inflammatoryevents involve very complex pathways, and can beblocked at a number of steps in a variety of ways. Theinitiation and continuation of inflammation is causedby inflammatory signaling mediators such asprostaglandins, leukotrienes, chemokines and

cytokines. Histamine is another signaling moleculewhose effects contribute to a number of allergicsymptoms. Anti-inflammatory compounds often workby blocking such mediators. Immune cells such asmacrophages, eosinophils and basophils play animportant part in the pathogenesis of allergic diseaseby releasing inflammatory mediators. Mast cells areparticularly detrimental because they store histamineand other agents of allergy inside granules, all readyto be released as soon as the signal is given.Blocking the activation of these cells can reduceallergic responses. Inflammation can also bemodulated by preventing the recruitment ofinflammatory cells to the tissues being targeted for anallergic response, and blocking their infiltration intothese tissues.5

Rosemary’s Anti-inflammatory TeamOne of rosemary’s key components, rosmarinic acid,is a substance that is well absorbed from thegastrointestinal tract and that has therapeutic potentialin the treatment and prevention of bronchial asthma,spasmogenic disorders, peptic ulcers, inflammatorydiseases, liver toxicity, atherosclerosis, ischemic heartdisease, and even cancer.2 In the inflammatoryprocess, rosmarinic acid increases the production ofanti-inflammatory signaling molecules while reducingthe production of pro-inflammatory leukotrienes. Italso inhibits a key step of the complement system.6

This system is a biological cascade that provides analternate pathway of inflammation, eventually leadingto increased blood vessel permeability, recruitment ofinflammatory cells, enhancement of platelet activationand aggregation, and an enhancement ofproinflammatory signal molecule production.2

Another of rosemary’s main components, caffeic acid,also has benefits in inflammatory conditions. Whentested against various anti-inflammatory plantpolyphenols, caffeic acid showed the most potentinhibition of tumour necrosis factor alpha, a majorpro-inflammatory cytokine.7

Carnosic acid also has anti-inflammatory actions. Inchronic inflammation, cytokines induce the productionof nitric oxide (NO), which shifts the balance of theimmune system to favor inflammation. Elevated levelsof NO are found in patients with allergic diseases suchas asthma.8 A study of rosemary extract found that itwas able to suppress the production of NO. Thisactivity was attributed to carnosic acid and carnosol.3

Furthermore, the antioxidant properties of rosemary’sextracts can help reduce the cellular damage causedby free radicals that are released during theinflammatory process.2


Outside the Test TubeWhile the anti-allergic and anti-inflammatoryproperties of rosemary’s components have been welltested in cell studies, they also hold up in vivo. Onestudy found that rosemary’s volatile oil inhibited thecontraction of tracheal smooth muscle induced byacetylcholine and histamine in rabbits and guineapigs.9 Rosemary also blocked the complement systemin various animal models6, and inhibited cutaneousanaphylaxis (a severe allergic reaction) in rats, blockedthe activation of macrophages in mice, and reducedpaw swelling in rats.2

Another study tested the effects of a rosemary extractin mice that were exposed to diesel exhaust particles.These pollutants exaggerate the severity of allergicconditions and are involved in increased morbidity

and mortality from lung diseases10. In this study, lunginflammation in mice was characterized by theinfiltration of immune cells into lung tissue, by thecellular profile of bronchoalveolar lavage fluid, and byhistological examination. Mice that were exposed todiesel exhaust particles and given rosemary extracthad significantly less lung inflammation andsuppressed expression of proinflammatory signalingmolecules compared to mice that were only exposed tothe exhaust. Rosemary also inhibited the increase innumbers of inflammatory cells.11

Rosmarinus is Latin for “dew of the sea”. While notquite accurate, the name evokes entirely appropriateimages of refreshment. By blocking inflammation at anumber of levels, rosemary helps to cool the heat ofinflammation and sooth the irritation of allergies.

References1. Tyler VE, Brady LR and Robbers JE. Pharmacognosy. 1976;171.2. Al-Sereitia MR, Abu-Amerb KM and Sena P. Pharmacology of rosemary(Rosemarinus officinalis Linn.) and its therapeutic potentials. Indian Journalof Experimental Biology. 1999;37:124-131.3. Peng C-H, Su J-D, Chyau C-C, Sung T-Y, Ho S-S, Peng C-C and Peng RY.Supercritical fluid extracts of rosemary leaves exhibit potent anti-inflammation and anti-tumor effects. Biosci. Biotechnol. Biochem.2007;71(9):2223-2232.4. Hoefler C, Fleurentin J, Mortier F, Pelt JM and Guillemain J. Comparativecholeretic and hepatoprotective properties of young sprouts and total plantextracts of Rosmarinus officinalis in rats. J Ethnopharmacol.1987;19(2):133-143.5. Kindt TJ, Goldby RA and Osborne BA. Kuby Immunology 6th Ed. WHFreeman and Company. NY 2007.6. Englberger W, Hadding U, Etchenberg E, Graf E, Leyck S, Winkelmann Jand Parnham MJ. Rosmarinic acid: A new inhibitor of complement C3-convertase with anti-inflammatory activity. Int J Immunopharmacol.1988;10(6):639-784

7. Molna V, Gray J. Plant-derived anti-inflammatory compounds affect MIFtautomerase activity. International Immunopharmacology. 2005;5:849-856.8. Barnes PJ and Liew FY. Nitric oxide and asthmatic inflammation.Immunology Today. 1995;16(3):128-130.9. Aqel MB. Relaxant effect of the volatile oil of Rosmarinus officinalis ontracheal smooth muscle. J Ethnopharmacol. 1991;33:57-62.10. Sagai M, Furuyama A and Ichinose T. Biological effects of dieselexhause particles (DEO). III. Pathogenesis of asthma like symptoms in mice.Free Radic Biol Med. 1996;21:199-209.11. Inoue E-I, Takano H, Shiga A, Fujita Y, Makino H, Yanagisawa R, KatoY and Yoshikawa T. Effects of volatile constituents of rosemary extract onlung inflammation induced by diesel exhaust particles. Basic & ClinicalPharmacology & Toxicology. 2006;99:52-57.


Therapeutic Potentials of the Rosemary Plant2

Therapeutic PotentialBronchial asthma

Antispasmodic

Bronchial asthma, Peptic ulcer, Inflammatorydiseases

Hepatotoxicity, Atherosclerosis and Ischaemicheart disease, Inflammatory diseases,Asthenozoospermia

Inflammatory diseases

Cancer (protection)

Pharmacological Actions1. Relaxation of bronchial smooth muscle

2. Relaxation of intestinal smooth muscle

3. Reduction of leukotrienes and increasedPGE2 production

4. Inhibition of lipid peroxidation

5. Inhibition of the complement pathway

6. Prevention of carcinogen-DNA adductformation


Perilla frutescens is a plant whose leaves arecommonly used as a garnish with raw fish in Japan. Itis also used in Chinese herbal medicine1, and itsleaves are used medicinally as a sedative, forindigestion, and for food poisoning treatment.2 Thefunctional components of perilla are flavonoidaglycones such as luteolin, apigenin, and rosmarinicacid. These substances have been studied for theiranti-allergic and anti-inflammatory potential.

Perilla’s Mechanisms at all 3 Levels of StudyIn cell studies, perilla effectively inhibits mast cells from“degranulating” and releasing histamine, which is oneof the principle mechanisms behind allergicsymptoms. One study found that perilla not only dose-dependently inhibited the release of histamine frommast cells, but also significantly inhibited theproduction of a main pro-inflammatory cytokine.3

Perilla also selectively blocks the activity of 5-lipoxygenase, a key enzyme in one of the pathways ofinflammation.4

Figure 1. Inhibitory effect of Perilla on histaminerelease

The effects of perilla extracts have also been tested inanimal models of allergy. In rats, Perilla frutescensextract inhibited mast cell-mediated allergic reactions.It dose-dependently decreased plasma levels ofhistamine and inhibited systemic and local allergicreactions.3 In another study, a perilla extract containingluteolin, scutellarin, apigenin and rosmarinic acidsignificantly suppressed cutaneous anaphylaxis, asevere allergic reaction, in mice. This type of reactionis related to the second and third stages of commonallergic responses, when mast cells are activated torelease mediators such as histamine, serotonin andleukotrienes, and when these mediators causeinflammatory reactions such as enhancing vascularpermeability and causing smooth muscle to constrict.2

This then leads to allergic symptoms such as swellingand redness. A second trial confirmed the ability ofperilla extracts to suppress cutaneous anaphylaxis.5

Other studies have indicated that perilla extracts mayinhibit the production of immunoglobulin E (IgE).6 IgEis the antibody that is responsible for recognizing“allergens”, which are proteins from substances suchas food, plant pollens, latex, animal hair, etc. andpriming the immune system for an allergic reaction.Total serum levels of IgE have been roughly correlatedwith the severity of allergic disease.7 Blocking IgEproduction is therefore an effective way to block anallergic reaction at the first step.In humans, perilla has been found to reduce theseverity of asthma. One trial compared the clinicalfeatures of patients with asthma who had been givenperilla seed oil for 4 weeks to those of asthmatics whohad not been given perilla extracts. In the group givenperilla seed oil, pro-inflammatory leukotriene synthesiswas significantly decreased, whereas it increasedsignificantly in the control group. Perilla seed oil alsosignificantly increased breathing measurements suchas peak expiratory flow, forced vital capacity andforced expiratory volume in one second.8 Anotherstudy observed the effects of perilla seed extracts involunteers with allergic symptoms such as sneezing,nasal obstruction, and itchy skin and eyes. 20participants were given perilla seed extracts for 2-4weeks, and their change in symptoms was evaluated.Symptoms were improved in all 20 patients, withsignificant improvements in sneezing (almost 40%),stuffed nose (over 60%) and itchy eyes (50%). Two ofthe patients had blood samples taken to determine theeffect of the extract on IgE concentrations. IgE levelswere significantly lower in both patients, without anychange in other antibody levels.9

PerillaAn Allergy Fighting Herb

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Figure 2. Effect of Perilla seed extract on a patient withallergy

LuteolinLuteolin is considered by many scientists to be themajor active constituent in Perilla frutescens. Studies ofthis component have found that it exerts antimutagenicand anti-inflammatory-allergic effects. It is alsorecognized as an antioxidant scavenger of damagingfree radicals, and as an inhibitor of protein kinase C,which is a key regulator in the initiation ofinflammatory events such as smooth muscleconstriction.9 Luteolin has been shown to be a potentinhibitor of human mast cell activation.10,11 One studycompared the effects of luteolin, baicalein andquercetin on the inhibition of the releaseof histamine, leukotrienes, cytokines and otherinflammatory factors from human mast cells, andfound that luteolin was the most effective at inhibitingthe release of these components.10 Another studyfound that luteolin could completely block thestimulation of mast cells, inhibiting the IgE-mediatedrelease of histamine and pro-inflammatory cytokines.11

Luteolin is effective at preventing the production ofproinflammatory cytokines.3,12 Some of the cytokinesthat are primarily responsible for allergic diseasesinclude interleukin (IL)-4 and IL-5. IL-4 is one of themost important cytokines in the production of IgE andallergic inflammation.12 IL-5 is responsible forrecruiting eosinophils.13 Eosinophils are immune cellsthat assist in priming the immune system for anallergic response. When they infiltrate the inflamedtissue, eosinophils become activated and releasemediators such as histamines, cytokines, leukotrienesand other pro-inflammatory mediators.14 Eosinophilaccumulation is a distinctive feature of allergicinflammation.14 One study compared the anti-inflammatory activities of 37 flavonoids and relatedcompounds, and found that luteolin and compoundswith a similar structure were the strongest inhibitors of

interleukin-4 production by basophils.12 Other studieshave found that luteolin reduces levels of IL-5.15

Luteolin’s effects hold up in animal studies as well.Mice that were orally given luteolin had a significantlyinhibited production of the cytokine tumour necrosisfactor alpha. Luteolin also inhibited ear swelling inmice that was induced by pro-inflammatorymolecules.1

Luteolin has shown benefits in models of asthma.Asthma is an inflammatory disease of the airwayswhich is characterized by difficulty in breathing due toinflammation which causes smooth muscles in thebronchi to constrict. It is also characterized by elevatedlevels of IgE in the blood, and infiltration of eosinophilsinto the airways.15 The development of asthma ismediated by the cytokines IL-4 and IL-5, IgE,eosinophils and other mediators such as leukotrienes.On the other hand, the cytokine interferon gamma(IFN-y) blocks the process. In a mouse model of airwayhyperactivity which mimicssome of the characteristic features of asthma, orallyadministered luteolin significantly decreased airwayhyperreactivity and blood levels of IgE. It also reducedlevels of IL-4 and IL-5 in the bronchoalveolar lavagefluid while increasing levels of IFN-y.15

Rosmarinic ReliefLike rosemary, one of perilla’s active constituents isrosmarinic acid. This compound’s antioxidant andanti-inflammatory properties have been shown to helpwith allergic disease in several studies. One studyobserved a mouse model in which an allergic reactionwas induced using a dust mite allergen. Mice that weregiven rosmarinic acid in a perilla extract had stronglyinhibited recruitment of inflammatory cells. Rosmarinicacid also decreased the numbers of mucus-containingairway cells and significantly prevented the intensity ofinfiltration of eosinophils and other inflammatory cellsinto tissues, and it prevented the allergy-inducedincrease in the production of IL-4 and IL-5.Furthermore, rosmarinic acid reduced the productionof antibodies that react to allergens. All of these resultsindicate that rosmarinic acid is capable of stronglyblocking allergic inflammation14.Rosmarinic acid has also proved its worth in helpingwith human allergies. In one randomized, double-blind, age-matched placebo-controlled parallel groupstudy, 30 patients with seasonal allergicrhinoconjunctivitis (SAR) were given either a low orhigh dose of Perilla frutescens extract enriched with


Effect on Patient with AllergySneeze

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rosmarinic acid or a placebo for 21 days. Theirsymptoms were recorded, and their levels of infiltratinginflammatory cells and histamine in the nasal lavagefluid were measured. Serum levels of IgE were alsomeasured. At the end of the trial period, there was asignificant increase in responder rates for itchy nose,watery eyes, itchy eyes and total symptoms. 55.6% ofpatients given a lower dose of the extract and 70% ofpatients given the higher dose reported globalsymptom relief, compared to only 30% of the placebogroup. The extract also significantly decreased thenumber of eosinophils and other inflammatory cells inthe nasal lavage fluid at both doses. These results weresuggested to be due to the inhibition of immune cellsfrom infiltrating into the nostrils. Since there were noadverse effects or significant abnormalities in bloodtests, the study concluded that rosmarinic acid fromperilla extract is an effective intervention for SAR.16

Figure 3. Patients’ evaluations of global symptomsusing the health-related quality of life questionnaire.Patients’ assessments of global symptoms at studyendpoint relative to prestudy levels are shown for eachgroup.16

Apigenin vs IgEApigenin is another flavonoid constituent of perillawith anti-allergic activity. Studies have found that itblocks the expression of the receptor on basophil cellsthat IgE antibodies bind to, thereby preventing IgEfrom stimulating these cells to release pro-inflammatory mediators.17 Dietary apigenin alsodecreases serum levels of IgE in mice.18 Another studyfound that mice fed apigenin for 3 weeks andsensitized to develop an allergic reaction hadsuppressed levels of IgE, while other antibody levelswere unaffected. Apigenin also blocked the productionof IL-4.19

An Effective Way to Scratch the Allergy ItchOverall, Perilla frutescens is full of anti-allergicpotential. By blocking the production and release ofpro-inflammatory mediators, reducing levels of IgE,and reducing the infiltration of inflammatory cells,luteolin, rosmarinic acid and apigenin help prevent themisery of a full-blown allergic reaction.

References1. Ueda H, Yamazaki C and Yamazaki M. Luteolin as an anti-inflammatoryand anti-allergic constituent of Perilla frutescens. Biol Pharm. Bull.2002;25(9):1197-1202.2. Makino T, Furuta Y, Wakushima H, Fujii H, Saito K and Kano Y. Effect oforal treatment of Perilla frutescens and its constituents on type-I allergy inmice. Biol. Pharm. Bull. 2001;24(10):1206-1209.3. Shin TY, Kim SH, Kim SH, Kim YK, Park HJ, Chae BS, Jung HJ, Kim HM.Inhibitory effect of mast cell-mediated immediate-type allergic reactions inrats by Perilla frutescens. Immunopharmacol Immunotoxicol2000;22(3);489-500.4. Oryza oil&fat chemical co., LTD. Anti-allergic effects of perilla seedextract in patient with allergy. 1997.5. Makino T, Furuta Y, Wakushima H, Fujii H, Saito K and Kano Y. Anti-allergic effect of Perilla frutescens and its active constituents. PhytotherapyResearch. 2004;17:240-243.6. Imaoka K, Inoue S, Takahashi T, Ojima Y. 1993. Effect of Perillafrutescens extract on anti-DNP IgE antibody production in mice. Jpn JAllergol 42: 74–80.7. Mosmann TR and Coffman RL. Heterogeneity of cytokine secretionpatterns and functions of helper T cells. Adv Immunol. 1989;46:111-147.8. Okamoto M, Mitsunobu F, Ashida K, Mifune T, Hosaki Y, Tsugeno H,Harada S, Tanizaki Y, Kataoka M, Niiya K, Harada M. Effects of perilla seedoil supplementation on leukotriene generation by leukocytes in patients withasthma associated with lipometabolism. Int Arch Allergy Immunol. 2000Jun;122(2):137-42.9. Shimoi K. Okada H, Kaneko J, Michiyo F, Goda T, Takase S, Suzuki M,Hara Y and Kinae N. Bioavailability and antioxidant properties of luteolin.10. Kimata M, Shichijo M, Miura T, Serizawa I, Inagaki N and Nagai H.Effects of luteolin, quercetin and baicalein on immunoglobulin E-mediatedmediator release from human cultured mast cells. Clinical and ExperimentalAllergy. 2000;30:501-508.11. Theoharides TC, Kempuraj D and Iliopoulou BP. Mast cells, T cells, andinhibition by luteolin: implications for the pathogenesis and treatment ofmultiple sclerosis. Adv Exp Med Biol. 2007;601:423-30.12. Hirano T, Higa S, Arimitsu J, Naka T, Ogata A, Shima Y, Fujimoto M,Yamadori T, Ohkawara T, Kuwabara Y, Kawai M, Matsuda H, YoshikawaM, Maezaki N, Tanaka T, Kawase I, Tanaka T. Luteolin, a flavonoid, inhibitsAP-1 activation by basophils. Biochemical and Biophysical ResearchCommunications. 2006;340:1-7.13. Kindt TJ, Goldby RA and Osborne BA. Kuby Immunology 6th Ed. WHFreeman and Company. NY 2007.14. Sanbongi C, Takano H, Osakabe N, Sasa N, Natsume M, YanagisawaR, Inoue K-I, Sadakane K, Icinose T and Yoshikawa T. Rosmarinic acid inperilla extract inhibits allergic inflammation induced by mite allergen, in amouse model. Clin Exp Allergy. 2004;34:971-977.15. Das M, Ram A and Ghosh B. Luteolin alleviates bronchoconstriction andairway hyperreactivity in ovalbumin sensitized mice. Inflammation Research.2003;52:101-106.16. Takano H, Osakabe N, Sanbongi C, Yanagisawa R, Inoue K-I, YasudaA, Natsume M, Baba S, Ichiishi E-I and Yoshikawa T. Extract of Perillafrutescens enriched for rosmarinic acid, a polyphenolic phytochemical,inhibits seasonal allergic rhinoconjunctivitis in humans. Exp Biol Med.2004;229:247-254.17. Yano S, Tachibana H and Yamada K. Flavones suppress the expressionof the high-affinity IgE receptor Fc‐RI in human basophilic KU812 cells. JAgric Food Chem. 2005;53:1812-1817.18. Yano S, Umeda D, Maeda N, Fujimura Y, Yamada K and Tachibana H.Dietary apigenin suppresses IgE and inflammatory cytokines production inC57BL/6N mice. J Agric Food Chem. 2006;54:5203-5207.19. Yano S, Umeda D, Yamashita T, Ninomiya T, Sumida M, Fujimura Y,Yamada K and Tachibana H. Dietary flavones suppresses IgE and Th2cytokines in OVA-immunized BALB/c mice. European Journal of Nutrition.2007;46:257-263.

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Q&AAllerControl™ At what age can children start using AllerControl™?Allercontrol™ is a multi-ingredient formula thatcontains Perilla seed extract, Butterbur Extract,Quercetin, Luteolin, Rosmarinic acid and Mangiferin.

Although most of the ingredients have a long history ofuse as spices or food, some of the ingredients found inthe formula have not been clinically tested in youngchildren. There is no reason to expect any side effectsor adverse reaction for AllerControl™ but it is best toavoid using the product without medical supervision inchildren younger than 12 years of age.

Is AllerControl™ effective for asthmatics?Absolutely, several of the ingredients have been shownto improve the symptoms associated with asthma. Inone study, supplementation with Butterbur, one of theingredients found in AllerControl™ was shown toimprove several of the symptoms related to asthmaand also decreased the frequency and duration ofattacks. Furthermore, 40 percent of the patients whowere using medication to help control their symptomswere able to reduce their intake of those medicationsafter using butterbur for two months.15

ProbioticsCan probiotics also decrease the risk of allergies inchildren?The list of health benefits associated with the use ofprobiotics never ceases to grow. Over the pastdecades, research on probiotics has focused on theirbeneficial effects on the immune system. Trials havedemonstrated that probiotics improve the function ofthe gut barrier, help to regulate the immune systemand reduce the inflammatory response.16 The initialtrials looking into the link between probioticsupplementation and the risk of atopic eczema were

very encouraging and showed that infants who hadreceived probiotics were less likely to develop eczemathan children who had received the placebo.17

However, such results have not been confirmed infollow up trials and no benefits were seen for otherconditions related to the immune system such asallergic rhinitis and asthma.18,19

QuercetinI am allergic to citrus, can I use quercetin?Although most quercetin supplements available toCanadians are extracted from citrus, AOR is proud tooffer a quercetin product that is derived from the seedsof Dimorphandra mollis and therefore, citrus free.

Q & A References1. Health Canada, Vitamin D Monograph, August 20072. NIH, Office of Dietary Supplements, Dietary Supplement Fact Sheet:Vitamin D3. Institute of Medicine, Food and Nutrition Board. Dietary ReferenceIntakes: Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride.Washington, DC: National Academy Press, 1997.4. Barger-Lux MJ, Heaney RP, Dowell S, Chen TC, Holick MF. VitaminD and its major metabolites: serum levels after graded oral dosing inhealthy men. Osteoporos Int 1998;8:222–30.5. Heaney RP, DaviesKM,Chen TC, HolickMF,Barger-Lux MJ.Humanserum 25-hydroxycholecalciferol response to extended oral dosingwith cholecalciferol. Am J Clin Nutr 2003;77:204 –10.6. Holick MF. Vitamin D. The underappreciated D-lightful hormone thatis important for skeletal and cellular health. Curr Op Endocrinol Diabetes2002;9:87–98.7. Centers for Disease Control and Prevention. Breastfeeding. Vitamin DSupplementation, American Academy of Pediatrics, Nov 20088. Health Canada. Vitamin D supplementation for breastfed infants – 2004Health Canada recommendation.9. Canadian Paediatric Society, First Nations and Inuit Health Committee[Principal author: J Godel]. Vitamin D supplementation in northern Nativecommunities. Paediatr Child Health 2002;7:459-63.10. Hypponen E, Laara E, Reunanen A et al. Intake of vitamin D and risk oftype 1 diabetes: a birth cohort study. Lancet 2001; 358:1500-3.11. Brekke HK, Ludvigsson J. Vitamin D supplementation and diabetes-related autoimmunity in the ABIS study. Pediatr Diabetes. 2007Feb;8(1):11-4.12. Annesi-Maesano I. Perinatal events, vitamin D, and the development ofallergy. Pediatr Res 2002; 52:3-513. Hypponen E, Laara E, Reunanen A et al. Intake of vitamin D and risk oftype 1 diabetes: a birth cohort study. Lancet 2001; 358:1500-3.14. Gordon CM, Williams AL, Feldman HA, May J, Sinclair L, Vasquez A,Cox JE. Treatment of hypovitaminosis D in infants and toddlers. J ClinEndocrinol Metab. 2008 Jul;93(7):2716-21.15. Danesch UC. Petasites hybridus (Butterbur root) extract in the treatmentof asthma--an open trial. Altern Med Rev. 2004 Mar;9(1):54-62.16. Kalliomäki MA, Isolauri E. Probiotics and down-regulation of the allergicresponse. Immunol Allergy Clin North Am. 2004 Nov;24(4):739-52, viii.17. Kalliomäki M, Salminen S, Poussa T, Arvilommi H, Isolauri E. Probioticsand prevention of atopic disease: 4-year follow-up of a randomisedplacebo-controlled trial. Lancet. 2003 May 31;361(9372):1869-71.18. Kopp MV, Salfeld P. Probiotics and prevention of allergic disease. CurrOpin Clin Nutr Metab Care. 2009 May;12(3):298-303.19. Niers LE, Rijkers G, Knol EF, Meijer Y, Hoekstra MO. Probiotics forprevention of atopic disease? Lancet. 2003 Aug 9;362(9382):496; authorreply 496.


Butterbur:Beyond MigrainesIntroductionButterbur (genus Petasites) is a Eurasian plant thatgrows mainly along the damp, marsh areas andriverbanks of Europe and Northern Asia. Uponripening, it bears a strong resemblance to rhubarb,and it has been utilized as part of the folk medicine ofvarious Eurasian cultures for at least two millennia.One of its earliest recorded uses was by the Greekphysician Dioscorides, who prescribed using itsgrinded leaves to treat skin ulcers in the first centuryAD. In northern Europe during the Middle Ages, it wasused to treat the feverish symptoms of the infamousBlack Death, the ominous name given to the plaguethat wiped out a third of the continent. In the 17thcentury, butterbur’s use was also noted for treatingcoughs and asthma. Since then, it has consolidated areputation as an anti-spasmodic and an analgesic,with the latter gaining particular acceptance andrecognition in the treatment of migraines. The former,however, holds promise for the treatment of allergies.In fact, butterbur has been clinically tested amongpatients with seasonal allergic rhinitis, bronchitis andasthma. This research has led to a renewed interest inbutterbur, particularly in the Far East and Japan (wherepollinosis affects 10% of the population), as apreventative treatment for common allergies.

How Does Butterbur Work?Researchers in Japan have identified within JapaneseButterbur (Petasites Japonicus) specific sesquiterpenes– biologically active fractions – with demonstratedanti-allergenic activity.1 The full biological activity ofJapanese butterbur is actually quite diverse, with anti-oxidative2, anti-inflammatory3, and vasodilative4

capabilities (among others) being well documented.

While all of these activities contribute indirectly to thealleviation of allergy symptoms, there are some veryspecific parameters for measuring the inhibition of theallergic response itself, as well as identifying whichsesquiterpenes within butterbur affect thoseparameters.A primary parameter of the allergic response isdegranulation. This happens when the body of anallergy-prone individual produces excess IgE, orImmunoglobin E (a type of antibody meant to protectagainst infections), which in turn attaches itself to mastcells, causing degranulation. Degranulation is therelease of granules from the mast cells in an immuneresponse process called exocytosis. Granules arecytotoxic, antimicrobial molecules whose release isaccompanied by a corresponding synthesis andrelease of histamine, cytokines, and leukotrienes, all ofwhich launch an inflammatory cascade leading to thestandard symptoms of an allergic reaction (mucousbuildup, runny nose, irritated eyes, etc). Anaphylaxisrepresents the most severe form of such a reaction.

Defusing DegranulationJapanese scientists have identified those biologicallyactive sesquiterpenes within butterbur that are mosteffective in their inhibition of degranulation. The mostpotent is a particularly novel sesquiterpine glycosidesulfate called fukinolic acid.5 Fukinolic acid’s anti-degranulation effects have been evaluated in both in-vitro and in-vivo (animal) studies by measuring itsimpact on beta-hexosaminidase, an antigen-dependent enzyme central to degranulation. Thesestudies reveal that while many fractions of JapaneseButterbur (Petasites Japonicus) suppress this enzyme,fukinolic acid does so at a rate that is more than twiceas effective as butterbur extract as a whole.6 It isimportant to appreciate that degranulation from themast cells is an early and primary initiator of theallergic reaction (after elevated IgE production) andprecedes the release of histamines – which are thepoint of intervention for most prescribed anti-allergymedications. This helps to define the role of butterburextract as a natural remedy, which (in general) differfrom their pharmaceutical counterparts by elicitingtheir effects in a manner that is more fundamentallypreventative than interventionist.The biological course of events that followdegranulation is a familiar one: inflammation causedby an increase in leukotriene and TNF-alphaproduction, leading to the previously mentioned andall too-familiar symptoms of an allergic reaction.



Japanese butterbur extract has also been shown toinhibit both leukotriene release and TNF-alphaproduction over and above its concurrent inhibition ofdegranulation.7

Real World ResultsThe clinical studies that have examined butterbur’seffectiveness in alleviating the symptoms of allergicrhinitis, asthma and bronchitis have been known forabout a decade now. A 1998 Polish study examinedthe effect of butterbur on the lung ventilation andbronchial reactivity in chronic obstructive bronchitis orasthma patients. Some patients reported ‘significantdecreases’ in bronchial reactivity within just two hoursof receiving an oral dose of 600 mg of butterburextract. Some patients were also given corticosteroidsto reduce severity, yet those patients given butterburextract without concurrent corticosteroid treatmentexperienced the most pronounced improvements. Thisled the scientists to conclude that “Petasites might behelpful in improving lung ventilation in patients withasthma or chronic obstructive bronchitis.”8 Suffice tosay, the symptomatic overlap between these conditionsand common allergies is significant.In a more recent 2004 trial in Germany, 80 subjectsdiagnosed with asthma (including 16 children) weregiven butterbur extract in a prospective, non-randomized, open trial. The study permitted theconcomitant use of asthma medications. At the end ofthe study, the number, duration, and severity of asthmaattacks decreased, while pulmonary functionsimproved. Furthermore, more than 40% of the subjects

who were using asthma medications at the beginningof the study had reduced the intake of thesemedications by the study’s end.9 In yet another study,this one conducted in 2002 with 131 seasonal allergicrhinitis patients as subjects, butterbur extract wasfound to be as effective as the commonly prescribedantihistamine cetirizine in the treatment of symptomsassociated with seasonal allergic rhinitis. In addition,about two-thirds of those receiving cetirizine reportedsymptoms of drowsiness and fatigue (in spite of thefact that cetirizine is not considered a sedativeantihistamine), while no such sedative effects werereported in the butterbur group.10

In ConclusionExtracts of the genus Petasites have been associatedwith reports of the potential for hepatic damage andcarcinogenic activity due to the plant’s pyrrolizidinealkaloids. However, commercial extracts are availablethat have these alkaloids removed, especially inEurope where the pharmaceutical giant Weber &Weber ® have a patented procedure to remove suchalkaloids from their own finished butterbur extractknown as Petadolex®. The commercially availableJapanese subspecies of butterbur (Petasites japonicus)do not contain these alkaloids at all.

References1 Tobinaga S, et al. Anti-histaminic and anti-allergic principles of Petasitesjaponicus Maxim. Chem Pharm Bull (Tokyo) 1983 Feb;31(2):745-8.2 Watanabe S, et al. Proceeding of general meeting of Japan Society forBioscience, Biotechnology, and Agrochemistry in 2004. Pp. 87 (2004).3 Lee DK, et al. Butterbur, an herbal remedy, confers complementary anti-inflammatory activity in asthmatic patients receiving inhaled corticosteroids.Clin Exp Allergy. 2004 Jan;34(1):110-4.4 Noguchi M, et al. Vasoactive effects of cimicifugic acids C and D, andfukinolic acid in cimicifuga rhizome. Biol Pharm Bull. 1998Nov;21(11):1163-8.5 Yoshikawa M, et al. Medicinal Foodstuffs. XXXII. Novel SesquiterpeneGlycoside Sulfate, Fukinoside A, with Antiallergic Activity from JapaneseButterbur (Petasites Japonicus).6 Shimoda H, et al. Anti type I allergic property of Japanese butterburextract and its mast cell degranulation inhibitory ingredients. J AgricFoodChem. 2006 Apr 19;54(8):2915-20.7 Ibid.8 Ziolo G, Samochowiec L. “Study on clinical properties and mechanism ofaction of Petasites in bronchial asthma and chronic obstructive bronchitis.”Pharmaceutica Acta Helvetica 1998;72:359-380.9 Danesch UC. “Petasites hybridus (Butterbur root) extract in the treatmentof asthma--an open trial.” Altern Med Rev. 2004 Mar;9(1):54-62.10 Schapowal A. “On behalf of Petasites Study Group: Randomisedcontrolled trial of butterbur and ceterizine for treating seasonal allergicrhinitis.” BMJ 2002;324:144–146.What Is Mangifera indica L. Extract ?


Anti-AllergenTherapy from theMango TreeWhat Is: Mangifera indica L. Extract ?The mango tree has been a rich source of medicinalfolk remedies in many traditional societies. One partof the mango tree, namely the stem bark (known asMangifera indica L.) has been used by such societiesfor the treatment of a variety of ailments ranging fromanaemia to scabies to diarrhea.Mangifera indica extract contains an impressive arrayof phytonutrients, of which mangiferin (aglucosylxanthone) is the largest as well as the greatestsingle source of biological activity. Other constitiuentsof Mangifera indica extract include gallates, catechins,epicatechins, benzoic acid, triterpenes, phytosterols,fatty acids and trace amounts of vitamins andminerals. This diverse profile is reflected in thebiological activity of Mangifera indica, which in bothin-vitro and in-vivo studies has demonstratedantioxidant, analgesic, anti-inflammatory andimmunomodulating properties. From such a broadspectrum of benefits, Mangifera indica extract seemsto have found a practical application as an anti-allergen.

The Allergic Reaction and Mangifera Indica’s RoleWithin ItThe aforementioned spectrum of pharmacokineticactivity, aside from the indication of the potency andpotential of its source, also relates – to varying degrees– to how the body deals with an allergy. Antioxidants,for example, can inhibit the generation of reactiveoxygen species (ROS-free radicals that can exacerbatean allergic reaction).1 Analgesics can provide relieffrom the pain and discomfort caused by allergicreactions2, while the importance of anti-inflammatories cannot be overstated. This is because

an allergic reaction is essentially an inflammatoryresponse, with cytokines such as TNFα, IL-1, IL-4, IL-12, IL-13, IL-15, and IL-16 playing highly significantroles.3 Antioxidants, analgesics and anti-inflammatories all serve to strengthen the immunesystem as a whole.Again, in the face of a spectrum of biological activityso broad that the risk of descending into ambiguity isvery real, how does Mangifera indica extractspecifically elicit an anti-allergy effect?

A Proactive Approach: IgEIgE, or immunoglobulin E, is a type of antibody meantto protect against infections. However, allergy suffererstend to produce IgE in excessive amounts, which is inresponse to their IgE recognizing a common allergen(i.e. pollens) as a threat. The IgE levels of non-allergysufferers are much lower because their IgE onlyrecognizes parasites in such a manner. IgE thenattaches itself to mast cells, and when it does this inexcessive amounts, the mast cells respond bygranulating and releasing excessive amounts ofhistamines and cytokines. Very succinctly, the formerleads to increased mucous production and the latter toinflammation, resulting in the most commonsymptoms of an allergic reaction, namely congestion,eye irritation, skin rashes and lung spasms, amongothers.Supplements, unlike drugs, are more often than notproactive rather than reactive. They do not attackafflictions so much as they strengthen the defensesagainst them. Such a simplistic interpretation is moreof a principle than a rule, with a more concisedefinition being that supplements elicit their effects ona more preliminary metabolic level than theirpharmaceutical counterparts. In the case of allergicreactions, the standard pharmaceutical route ofintervention is anti-histamines, which as their nameimplies, inhibits the action of histamine - usually bytargeting the H1 histamine receptor.

Mangifera Indica: IgE InhibitorSince excessive IgE activity is a root cause of allergicreactions, inhibiting its production is a proactive way oflimiting the frequency and effect of such reactions. Thisprecedes the actions of standard allergy medications(anti-histamines) by one key biological step, since theadhesion of excessive IgE to the mast cells is whatleads to the release of histamine in the first place, notto mention cytokines with subsequent inflammation andassociated symptoms (irritated eyes, congestion, etc.).


In-vivo studies have demonstrated that MangiferaIndica extract (standardized for 10% mangiferin) canindeed inhibit IgE production by more than 22%.4

Mangiferin as an isolate has also been studied, and itwas determined to lower IgE production by nearly52%.5 These studies – conducted on laboratorymice–determined (predictably) that histamine releasewas also inhibited by both Mangifera indica andmangiferin supplementation, theoretically due to theprecursory effect of lower IgE production. Ironically,however, Mangifera indica extract was slightly moreeffective than mangiferin in lowering both histaminelevels and histamine-induced skin reactions.Mangifera indica lowered the latter by 66%, comparedwith 63% for mangiferin.6 Similar results were alsoseen when the two compounds were tested for theirability to inhibit the most severe allergic reactions ofanaphylaxis.7

It must be noted that an extract offering advantagesover its isolated main medicinal ingredient is nothingnew. This has been seen with whole extracts and theirrespective isolates from grape seed, green tea,curcumin, and numerous others. While conclusiveevidence is scarce, it would seem that whole extractscan offer a broader spectrum of support while isolatescan provide a more concentrated potency withinspecifically set targets. In the case of Mangifera indicaand mangiferin, it would appear that the most effectivecompromise is a Mangifera indica. extractstandardized to a degree higher than 10% mangiferin.

Other Benefits of Mangifera IndicaLike many natural ingredients, the beneficialapplications of Mangifera indica extract are relativelywidespread and cannot always be neatly categorized.

One recent study indicates that the extract may alsopossess the ability to alleviate iron-induced oxidativedamage by increasing iron excretion from the liver.8 Itdoes this in part due to an electrochemical capacity tobind to iron (as a chelator), and while this protectsagainst iron-overload, Mangifera indica also actssynergistically with iron for an enhanced anti-oxidanteffect, particularly against 2,2-diphenyl-1-picrylhydrazyl (DPPH) and superoxide free radicals.9

Mangifera indica also protects against lipidperoxidation and increases glutathione levels, leadingresearchers to suggest that it may provide‘therapeutically useful effects in iron overloaddiseases.’10

References1 Szlagatys-Sidorkiewicz A, et al. Reactive oxygen species and antioxidativebarrier in asthma. Pneumonol Alergol Pol. 2007;75(2):158-62.2 George RB, et al. Brief Report: A randomized controlled trial of SyneraTMversus lidocaine for epidural needle insertion in labouring parturients:[Compte-rendu court : Une etude randomisee controlee du SyneraTM vslidocaine dans l'insertion de l'aiguille peridurale chez les parturientes entravail]. Can J Anaesth. 2008 Mar;55(3):168-171.3 Rivera DG, et al. Anti-allergic properties of Mangifera indica L. extract(Vimang) and contribution of its glucosylxanthone mangiferin. JPP 2006,58:385- 392.4 Ibid., P.388.5 Ibid.6 Ibid. P. 3897 Ibid. P. 3888 Pardo-Andreu GL, et al. Protective effects of Mangifera indica L extract(Vimang), and its major component mangiferin, on iron-induced oxidativedamage to rat serum and liver. Pharmacol Res. 2008 Jan;57(1):79-86.9 Pardo-Andreu GL, et al. Interaction of Vimang (Mangifera indica L.extract) with Fe(III) improves its antioxidant and cytoprotecting activity.Pharmacol Res. 2006 Nov;54(5):389-95.10 Pardo-Andreu GL, et al. Protective effects of Mangifera indica L extract(Vimang), and its major component mangiferin, on iron-induced oxidativedamage to rat serum and liver. Pharmacol Res. 2008 Jan;57(1):79-86.

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The Role ofVitamin D inImmunityVitamin D is well-known for the important role it playsin calcium utilization and the proper development ofbones. For example, most people are aware thatvitamin D deficiency in young children can lead torickets, a condition where the bones become weakand soft.1 More recently, however, vitamin D hasgained attention for a plethora of other importantbenefits, and low levels of vitamin D have now beenlinked to increased hypertension, increasedautoimmune diseases, an increased risk for variousforms of cancer including breast, prostate and skin,chronic pain, premenstrual syndrome (PMS), poorimmune system, diabetes, seasonally affectivedisorders and even an increased risk of mortality by allcauses.2-7

Immune System ModulationMany of the benefits of vitamin D relate to the veryimportant role the vitamin plays in the normalfunctioning of the immune system. The immune systemis made up of a number of different types of cells thatwork together to protect the body from threats.Dendritic cells are important for activating the rest ofthe immune system, and are specialized in antigenpresentation. This means that they will engulf invaders,and then display markers of the invader, or antigens,which in turn activate other cells of the immune system,such as helper T-cells. Activated helper T-cells thenstimulate other cells including killer T-cells, whichattack and kill cells infected by the invader, and B-cells, which produce antibodies that identify and attachto the invader, marking it for elimination.This is an extremely complicated process, and requiresa delicate balance for proper functioning. The immunesystem is critical for protecting our bodies from foreignpathogens and invaders. However, it must also be ableto distinguish between a dangerous invader andharmless food proteins, friendly bacteria and cells ofthe body. In other words, the immune system must

develop “tolerance” for these types of proteins andcells. When tolerance fails, an inappropriate immuneresponse occurs – resulting in allergies, where theimmune system reacts to normally harmless moleculesas if they were dangerous invaders, or evenautoimmunity, where the body attacks its own cells.This delicate balance is mostly established by thehelper T-cells, which are responsible for themoderation and regulation of the immune response.There are two types of helper T-cells– Th1 and Th2.Autoimmunity seems to be related to anoverabundance of Th1, whereas allergies have beenlinked to an overactive Th2 response.8 The activemetabolite of vitamin D3, 1,25(OH)2D3, has beenshown to affect both the Th1 and Th2 responses, andplays a very important role in immune systemregulation.

The Regulatory Role of Vitamin DFirstly, vitamin D inhibits the formation of dendriticcells, which in turn reduces the activation of T-cells,and the T-cell mediated immune response.8,9 VitaminD also acts on T-cells themselves, regulating thedifferentiation and activation of Th1 and Th2. Studieshave shown that vitamin D3 down-regulates Th1,whose expression is related to autoimmunity. VitaminD’s actions on Th2 are less certain, with some studiesshowing increased Th2 function and others showingsuppressed function.8,9 Vitamin D has also been shownto increase the production of regulatory T-cells, whichplay a very important role in self-tolerance, andtherefore in the prevention of autoimmunity.8

In addition to the regulation of T-cells, vitamin D alsohas an effect on the actions of B-cells. It seems to acton them in two primary ways; first, it stimulatesincreased production of interleukin (IL)-10, whichinhibits antigen presentation by dendritic cells andprevents T-cell activation, and second, it inhibits theproduction of IgE antibodies, the primary antibodyassociated with the allergic response.10

Overall, vitamin D is critical for the regulation andproper functioning of the immune system, and may actto prevent inappropriate immune system responsesand help to restore proper immune system balance.

Innate ImmunityBeyond its role in immune system modulation, vitaminD is also critically involved in the body’s innateimmune response. Specifically, vitamin D has beenshown to activate important antibacterial proteinscalled defensin and cathelicidin.8 Researchers haverelated these actions to numerous beneficial effects,including a reduction in the risk of skin infection inindividuals with atopic dermatitis11, a reduced risk ofplacental infections during pregnancy12, and even areduction in the occurrence of the common cold.13


Figure 1. Asthma is a chronic inflammatory disease of the airways that isoften associated with allergies. Asthma affects 8.4% of Canadians and 12%of Canadian children (Statistics Canada, 2001).

The Link to Allergies and AsthmaRecent research on vitamin D has established a clearlink between vitamin D and autoimmune disorders,and with self-tolerance. For example, low vitamin Dlevels have been related to the occurrence ofautoimmune diseases including multiple sclerosis (MS)and inflammatory bowel disease (IBD).8,14,15

Furthermore, studies in mice have suggested thattreatment with vitamin D could be beneficial for a widerange of autoimmune diseases including MS, IBD andrheumatoid arthritis.8

With vitamin D playing such a major role in thefunction of the human immune system, it seemsevident that there must also be some link to allergies,and indeed this seems to be the case. However, therole of vitamin D in the allergic response has not yetbeen fully clarified. For example, one study in mice hassuggested potentially dual influences of vitamin D onallergies, with administration of active vitamin Dresulting in increased T-cell activation and cytokineproduction in the mice, while at the same timereducing airway eosinophilia – a key pathologicalfeature of asthma.14

Studies in humans have also demonstrated animportant link between vitamin D levels and thedevelopment of asthma. Two recently publishedstudies have reported that children under the age of 5,whose mothers had higher vitamin D intakes duringpregnancy, had a reduced incidence of wheezingsymptoms.17,18 In fact, it has been demonstrated thathigher vitamin D intakes during pregnancy mayreduce the risk of childhood asthma by as much as40%, and suggest a dose of 2000 IU daily duringpregnancy to achieve adequate levels.19 In yet anotherstudy involving 616 asthmatic children, low serumvitamin D levels were associated with increased levelsof well-known markers of asthma and allergy severity,including IgE and eosinophil levels.20

The association between asthma and vitamin D is alsosupported by genetic studies, which have revealedvariations in the vitamin D receptor in asthmaticindividuals.21,22 Furthermore, research has indicatedthat vitamin D is vital for proper lung development,and may also influence lung function later in life.23,19

Two studies, one involving 2112 adolescents and theother 14901 adults, found that higher vitamin D intakeis associated with improved lung function.24,25

Another interesting link between vitamin D andallergies was established by a group of Americanresearchers examining the prevalence of EpiPenprescriptions across the United States.26 EpiPens areautoinjectors that administer epinephrine as anemergency treatment for severe and potentially deadlyallergic reactions called anaphylaxis. The studyrevealed a strong north-south gradient in EpiPenprescriptions, with northern states having asignificantly higher number of prescriptions thansouthern states. The Researchers inferred that thisgradient is related to sunshine exposure, and thusvitamin D levels.26

Figure 2. Regional Difference in EpiPen prescriptions per 1000 persons.26

How it worksThe mechanism by which vitamin D influencesallergies and asthma is quite complex. Vitamin D hasbeen shown to influence IgE levels, which is highlysignificant as IgE is the main antibody involved in theinitiation of the allergic response. There have,however, been some conflicting results regardingvitamin D’s influence on IgE. A recent study conductedin Europe offers some potential insight into thisconflict. Scientists in Europe and the UK examinedboth the IgE and serum vitamin D levels of 7288individuals and found that those with both extremelylow (< 25 nmol/L) and extremely high (> 135 nmol/L)vitamin D levels in the blood expressed elevated IgElevels, and thus a higher potential for allergies.28 Theseresults indicate the importance of balanced vitamin D


levels, and are consistent with other studies suggestinga lower threshold of 75-100 nmo/L for serum vitaminD levels.28

More and more evidence suggests, however, that themost important role of vitamin D may be during earlydevelopment, especially before birth.19 As mentionedabove, vitamin D’s effects on Th2 are inconsistent, withsome studies showing upregulation of Th2 cytokinesassociated with allergies, and others showing theirsuppression.8,9 Researchers have suggested that theseseemingly contradictory effects may relate to thetiming of vitamin D exposure (i.e. pre or post-natal)and also to the role of regulatory T-cells (Tregs).19

Vitamin D has been shown to increase Tregs, and alsoto increase the secretion of IL-10. Both of these actionshave been shown to benefit individuals with steroid-resistant asthma – a well-established Th2 disorder.27

Achieving BalanceVitamin D3 has wide-ranging effects on the immunesystem. Due to its actions on both Th1 and Th2mediated immune responses, vitamin D deficiency hasbeen purported as a potential unifying factor in therise of the prevalence of both Th1 disorders(autoimmunity) and Th2 disorders (allergies) over asimilar time span.19 Vitamin D may be of particularlycritical importance at early stages of development toensure proper immune function later in life. It hasbeen hypothesized that vitamin D is essential fornormal Treg development, and in turn the suppressionof improper Th1 and Th2 responses and a morebalanced immune response.19 Although more researchand clinical trials are required, it is clear that the“Sunshine” vitamin is an essential component of goodhealth and in the development and maintenance of ahealthy, balanced immune system.

References:1 Ward LM, Gaboury I, Ladhani M, Zlotkin S. Vitamin D-deficiency ricketsamong children in Canada. CMAJ. 2007 Jun 28.2 Melamed ML, Michos ED, Post W, Astor B. 25-Hydroxyvitamin D Levelsand the Risk of Mortality in the General Population. Arch Intern Med.2008;168(15):1629-1637.3 Thomas J. Wang, Michael J. Pencina, Sarah L. Booth, Paul F. Jacques, ErikIngelsson, Katherine Lanier, Emelia J. Benjamin, Ralph B. DAgostino, MylesWolf and Ramachandran S. Vasan. Vitamin D Deficiency and Risk ofCardiovascular Disease. Circulation published online Jan 7, 2008.4 Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP.Vitamin D and calcium supplementation reduces cancer risk: results of arandomized trial. Am J Clin Nutr. 2007 Jun;85(6):1586-91.

5 Bailey R, Cooper JD, Zeitels L, Smyth DJ, Yang JH, Walker NM, HyppönenE, Dunger DB, Ramos-Lopez E, Badenhoop K, Nejentsev S, Todd JA.Association of the vitamin D metabolism gene CYP27B1 with type 1diabetes. Diabetes. 2007 Jul 2.6 Svoren BM, Volkenning LK, Wood JR, Laffel LMB. Significant Vitamin DDeficiency in Youth with Type 1 Diabetes Mellitus. Journal of Pediatrics.2009; 154(1): 132-134.7 Atherton K, Berry DJ, Parsons T, Macfarlane GJ, Power C, Hyppönen E.Vitamin D and chronic widespread pain in a white middle-aged Britishpopulation: evidence from a cross-sectional population survey. Ann RheumDis. 2008; Early online publication8 Hyppönen E, Berry DJ, Wjst M and Power C. Serum 25-hydroxyvitamin Dand IgE – a significant but non-linear relationship. 2009. Allergy. 64: 613-620.9 Cantorna MT and Mahon BD. Mounting evidence for vitamin D as anenvironmental factor affecting autoimmune disease prevalence. Exp BiolMed. 2004. 229: 1136-1142.10 Heine G, Niesner U, Chang H, Steinmeyer A, Zügel U, Zuberbier T,Radbruch A, Worm M. 1,25-dihydroxyvitamin D promotes IL-10 productionin human B-cells. Eur J Immunol. 2008. 38: 2210-2218.11. Hata TR et al. Administration of oral vitamin D induces cathelicidinproduction in atopic individuals. J Allergy Clin Immunol; 122(4): 829-831.12 Liu N, Kaplan AT, Low J, Nguyen L, Liu GY, Equils O and Hewison M.Vitamin D induces innate antibacterial responses in human trophoblasts viaan intracrine pathway. Biology of Reproduction. Published online November12, 2008.13 Ginde AA, Mansbach JM, Camargo CA. Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the thirdnational health and nutrition examination survey. Arch Intern Med. 2009;169(4): 384-390.14 Ramagopalan SV et al. Expression of the Multiple Sclerosis-AsscoiatedMHC Class II Allele of HLA-DRB1*1501 is Regulated by Vitamin D. PLoSGenetics. 2009; 5(2): e1000369.15 Raghuwanshi A, Joshi SS, Christakos S. Vitamin D and Multiple Sclerosis.Journal of Cellular Biochemistry; 2008, Early online publication.16 Matheu V, Back O, Mondoc E, Issazadeh-Navikas S. Dual effects ofvitamin D-induced alteration of TH1/TH2 cytokine expression: enhancingIgE production and decreasing airway eosinophilia in murine allergic airwaydisease. J Allergy Clin Immunol 2003; 112:585–592.17 Devereux G, Litonjua AA, Turner SW, Craig LC, McNeill G, Martindale Set al. Maternal vitamin D intake during pregnancy and early childhoodwheezing. Am J Clin Nutr 2007;85: 853–859.18 Camargo CA Jr, Rifas-Shiman SL, Litonjua AA, Rich-Edwards JW, WeissST, Gold DR et al. Maternal intake of vitamin D during pregnancy and riskof recurrent wheeze in children at 3 y of age. Am J Clin Nutr2007;85:788–795.19 Litonjua AA and Weiss ST. Is vitamin D deficiency to blame for theasthma epidemic. J Allergy Clin Immunol. 2007. 120: 1031‐1035.20 Brehm JD, Celedòn AC, Soto‐Quiros ME, Avila L, Hunninghake JM,Forno E, Laskey D, Sylvia JS, Hollis BW, Weiss ST, Litonjua AA. SerumVitamin D Levels and Markers of Severity of Childhood Asthma in CostaRica. AJRCCM. 2009. doi:10.1164/rccm.200808-1361OC21 Poon AH, Laprise C, Lemire M, Montpetit A, Sinnett D, Schurr E, HudsonTJ. Association of vitamin D receptor genetic variants with susceptibility toasthma and atopy. Am J Respir Crit Care Med 2004;170:967-973.22 Raby BA, Lazarus R, Silverman EK, Lake S, Lange C, Wjst M, Weiss ST.Association of vitamin D receptor gene polymorphisms with childhood andadult asthma. Am J Respir Crit Care Med 2004;170:1057-1065.23 Nguyen M, Trubert CL, Rizk-Rabin M, Rehan VK, Besancon F, Cayre YE,et al. 1,25-Dihydroxyvitamin D3 and fetal lung maturation: immunogolddetection of VDR expression in pneumocytes type II cells and effect onfructose 1,6 bisphosphatase. J Steroid Biochem Mol Biol 2004;89-90:93-724 Burns JS, Dockery DW, Speizer FE. Low levels of dietary vitamin D intakeand pulmonary function in adolescents. Proc Am Thoracic Soc2006;3:A526.25 Black PN, Scragg R. Relationship between serum 25-hydroxyvitamin Dand pulmonary function in the third national health and nutritionexamination survey. Chest 2005;128:3792-8.26 Camargo CA, Clark S, Kaplan MS, Lieberman P, Wood RA. Regionaldifferences in EpiPen prescriptions in the United States: The potential role ofvitamin D. J Allergy Clin Immunol. 2007. 120: 131-136.27 Xystrakis E, Kusumakar S, Boswell S, Peek E, Urry Z, Richards DF, et al.Reversing the defective induction of IL-10-secreting regulatory T cells inglucocorticoid-resistant asthma patients. J Clin Invest 2006;116:146-55.

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