1. health and fitness
2. disease
3. allergies

ADVANCES
VOLUME 3 • ISSUE 5
IN ORTHOMOLECULAR RESEARCH
Allergies
Quercetin - Rosemary - Perilla Butterbur - Mangiferin - Vitamin D
research-driven
botanical
integrative
orthomolecular
groundbreaking
ADVANCES
VOLUME 3 • ISSUE 5
IN ORTHOMOLECULAR RESEARCH
1
11
15
17
21
21
25
10 & 20
Allergies: The Immune System Gone Haywire
Quercetin: Sweet Allergy Relief
Rosemary: Where Tradition Meets Science
Perilla: An Allergy Fighting Herb
Butterbur: Beyond Migraines
Anti-Allergen Therapy from the Mango Tree
The Role of Vitamin D in Immunity
Questions and Answers
21
15
1
25
11
17
ADVANCES
IN ORTHOMOLECULAR RESEARCH
Published in Canada by
Advanced Orthomolecular
Research Inc.
Publisher/Editor-in-Chief
Dr. Traj P.S. Nibber
Research & Writing
Ludo Brunel, ND
Keith Karamitsos, BA
Megan Johnson, MSc
Meaghan McCollum
Karli Lytle, BSc
Graphic Design/Art Production
Neil Bromley
Graphics@aor.ca
23
Advances in Orthomolecular Research
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Allergies:
The Immune
System Gone
Haywire
Runny noses, itchy eyes, upset stomachs, inflamed
skin… most of us have experienced these symptoms or
have a family member or a friend that suffers from
them. Allergies are a modern era pandemic. It is
estimated that 30-50% of the population in the United
States suffers from allergies. Allergies in the US come
with a hefty yearly price tag of over 2 billion dollars in
lost productivity, medical expenses and medication.1-5
Allergies are a long term health problem; typically
beginning between 8 and 12 years of age and lasting
for decades if not for a lifetime.6,7 And to add insult to
injury, research shows that the incidence of allergies is
on the rise in most developed countries. Thankfully, as
our understanding of allergic disorders improves, new
treatment and preventive approaches emerge, because
at times, scratching an itch truly makes it worse.
Allergies and the Immune System
Allergies are a disorder of the immune system that is
caused by the improper activation of the immune
response. Allergies are almost always linked to the
presence of an excessive amount of allergic antibodies
known as IgE. Allergies occur because a substance
present in the environment that is normally harmless
enters our body and is mistakenly identified as a
threat. Most pathogens that we are exposed to, from
bacteria to viruses, are proteins and are eliminated
through the activation of the immune system. In the
case of harmless proteins, like proteins from food, the
immune response must be suppressed through a
process known as oral tolerance. Inducing oral
tolerance has been used as a strategy to prevent
allergies for years. For instance, Native Americans
used to eat poison ivy leaves to prevent contact
Volume 3 Issue 5
dermatitis associated with skin exposure to the plant.8
Understanding the process of oral tolerance is
essential for the prevention and treatment of allergies.
Although true or immediate allergies are mediated by
IgE, other antibodies and immune cells have also been
linked to allergic diseases. Contact dermatitis for
instance occurs through the effect of T-cells and IgM or
IgG are often responsible for drug allergies or what is
known as cytotoxic allergies.9
Food intolerances are also probably allergies since
significant immune factors are involved in the process.
Infants with milk, soy and egg intolerance were found
to have IgG levels significantly higher than the control
group.10 Trials in animals also show a clear
involvement of IgG immunoglobulins when peanut
sensitivities are present.11 Other studies point to a clear
immunological link in irritable bowel syndrome, with
results showing that elimination diets that focus on the
foods which elicit an IgG response in IBS patients lead
to significant improvements of the disease in a
majority of patients.12,13 IgG immune reactions are
delayed occurring several hours after exposure to the
offender and are often not immediately identified as
allergies.14
When Intolerance Sets In
The immune system is designed to protect our body
from pathogens and must respond and eliminate
threats. On the other hand, the immune system must
also be able to tolerate the cells of our body, the
proteins from food as well as the bacteria naturally
present on our body. Most of the interaction with
foreign proteins occurs in the intestine which explains
why the gastrointestinal tract is the largest immune
organ in the body. Given the complexities of the
immune response and the abundance of proteins and
bacteria in our diet, it is not surprising that allergies
are common. There are two important immune
reactions occurring in our intestines, the activation of
the immune system when pathogens are present in the
gastrointestinal tract and the suppression of the
immune response when food proteins are digested.
If tolerance fails, which means that the immune system
is inappropriately activated, B cells produce antibodies
specific to the antigen and antibody’s known as IgE
are produced to neutralize the perceived threat. This
leads to the release of histamines, leukotrienes,
tryptase, chemokines, cytokines and prostaglandins
from mast cells. These in turn lead to inflammation
through the recruitment of basophils, eosinophils and
leukocytes. These cells increase the blood flow to the
ADVANCES in orthomolecular research
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area which accentuates symptoms such as swelling
and itching. There are two main phases to allergies,
the first phase is the immediate phase characterized by
the release of histamine and vasodilators. The second
phase is mediated by the mobilization of immune cells
and occurs 4 to 6 hours after the initial reaction.15
Immune tolerance is a process that begins during
pregnancy, as early as 20 weeks of age through
transfer of immune factors from the mother.16 Several
researchers have focused on the age at which
exposure to a protein first occurs and its consequence
on allergies. Experiments in mice have shown that
when the exposure occurs at a younger age, especially
when exposure occurs prior to the normal weaning
time, allergies are more likely to occur. For many of
these mice tolerance develops with age.17
More than an Inconvenience
Although the symptoms of allergies are often seen as
a mere nuisance, they have been shown to cause
headaches, fatigue, difficulty learning, loss of sleep,
and reduced productivity.18,19 There are also several
associated problems such as headaches, loss of smell
and taste, cough, wheezing, snoring, ear infections
and nasal polyps.20 The most severe kind of allergic
reaction, known as anaphylaxis, is very serious, can
progress very quickly and can be lethal due to the
involvement of several body systems. Other allergies
such as seasonal allergies, which affect up to 35% of
the North American population, are not life
threatening but lead to seriously unpleasant side
effects. By far the most common symptoms associated
with air borne allergies are a runny nose and itchy
eyes. The eyes are typically quite inflamed in seasonal
allergy sufferers as allergens can impact the eye
surface directly.21 Severe allergies are often
overwhelming because avoidance strategies are
needed. The most common kind of this type of allergy
is peanut or tree nut allergy, which affects roughly 1%
of children under the age of 5.22,23 In Canada, peanut
allergy affects 1.34% of children.24 Food allergies in
general affect 6-8% of children and 4% of the United
States population older than 10 years of age. Every
year in the US alone, 30 000 anaphylactic reactions
are caused by allergies, of those, 2000 lead to
hospitalization and 200 are lethal.
25,26
Diagnosis of Allergies
Appropriate history of exacerbating
factors
Perennial or seasonal symptoms, with
timing correlated to specific pollen or mold
spore exposure
Symptom triggering with identifiable
agents such as animals
Familial history of asthma, allergic rhinitis,
or atopic eczema
2
Physical findings
Rhinorrhea, clear or mucoid discharge
Erythema of nasal mucosa
Nasal congestion
“Allergic facies”
Collaborative findings
Immediate hypersensitivity skin testing
Serum specific IgE
Medication and medical history
Comorbid conditions
Oral aggravators such as acetylsalicylic
acid, nonsteroidal anti-inflammatory
drugs, anti-hypertensive agents
Topical aggravators such as alpha agonists
Hypothyroidism
Pregnancy
Sinusitis
Nasal polyposis
Asthma
Eustachian tube dysfunction
Serous otitis media
ADVANCES in orthomolecular research
Volume 3 Issue 5
Some allergies take a long time to develop, while
others appear very quickly.
Generally, allergies are more likely to be a problem
for foods that are introduced early in life and that are
eaten more commonly. Delaying the introduction of
potential allergens may be a good idea and studies
have demonstrated that exclusive breast feeding for
the first 4 months of life reduces the risk of developing
atopic dermatitis, a hereditary inflammatory skin
condition.33
Some allergies are life-long while others lessen
with time.
Figure 1. Skin prick testing remains the most specific
and most cost effective way to diagnose allergies.
An Inborn Predisposition
Allergies are still poorly understood. We know that they
tend to run in families, which indicates a genetic bias.
Most allergy sufferers have inherited their allergies
through an immune predisposition to a Th2 immunity
profile (mediated by antibodies) which is often seen in
autoimmune disorders. Allergies are therefore linked
to an abnormal immune system, tend to occur in
clusters and are often associated with other
hypersensitivity reactions. 27
Allergies, genes and the
immune system
Women suffering from allergic symptoms early
in their pregnancy are 6 times more likely to
have children who also have allergies.28
Animal studies have demonstrated that in the
most susceptible strain 87-100% of the animals
developed allergies to milk or peanut while the
least susceptible animals did not develop
allergies.29
A very clear indication of the central role the
immune system plays in allergic disease is that
bone marrow recipients develop the allergies of
their donor.30
Children with egg allergies and eczema have a
20% chance of having peanut allergy.31
There is a concordance between allergies and
asthma.32
Volume 3 Issue 5
For all allergies, there seems to be a tendency towards
eventual tolerance. 20% of children with peanut
allergies will eventually outgrow them.34 For egg
allergy, which affects 1-2% of children, 4% develop
tolerance 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 the
children on an elimination diet developing tolerance
without any other form of treatment.36 However, severe
allergies are less likely to subside and patients with IgE
levels to egg exceeding 50 ku/L and patients with
multiple food allergies are less likely to see their
allergies subside.37
Potential Determinants
of Allergic Disease38
Genetics
Family history
Low birth weight
Exposure to pets
Exposure to allergens
Infections
Exposure to parasites
Obesity
Dietary fatty acids
Dietary antioxidants
Exposure to tobacco smoke
Exposure to pollutants
ADVANCES in orthomolecular research
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Avoidance as a Stratagem
The best way to control allergies once they have
developed is to prevent exposure to the allergen.
Unfortunately, as seasonal allergy sufferers know too
well, avoidance is not always a possibility. While most
of us rejoice once spring has arrived, for seasonal
allergy sufferers, the powdery grains released from
trees and grasses can wreak havoc on their immune
system. Pollens from trees and grasses that are carried
by the wind to pollinate other plants can cause an
allergic reaction if the person is sensitive to pollen.
Springtime allergies are typically caused by pollen
from trees, summertime allergies are a result of pollen
from grass and fall allergies are caused by weed
pollen. Unlike avoidance to dust or pet dander,
allergies to pollen or mold spores are more difficult to
avoid. This problem is made worse by the “priming
effect”, which results in progressively worsening
symptoms as the inflammation from the initial allergic
reaction is made worst by subsequent exposure.39
Typical prescription medications for the treatment of
allergies include antihistamines, which prevent the
release or action of histamine. Histamine can cause
sneezing, itchiness, irritation and excess mucous
production. One major inconvenience to prescribed
antihistamines is that they have a sedative effect and
can lead to drowsiness, increasing the risk for
accidents and injuries. Antihistamines are also typically
ineffectual for nasal congestion and other treatment
options often need to be considered in allergy
sufferers.
countries. The theory’s basic premise is that limited
exposure to microbes in early childhood increases the
susceptibility to allergic disease and other immune
disorders such as asthma. Such exposure would be
important to educate the immune system and a sterile
environment would predispose to immune dysfunction
and autoimmune diseases.44,45 This may also explain
why certain strains of probiotics seem to have a
protective role in immune diseases.46 This also explains
why children who grow up with dogs in their home are
less likely to suffer from allergies.47 Surprisingly,
children born through C-section were also more likely
to develop food sensitivities. It has been speculated
that contact with the bacteria in the birth canal may
reduce the risk of allergy. It is also possible that the
presence of antibiotics in the mother to prevent
infections post surgery may predispose to the
development of allergies.48 Studies looking at the
importance of early exposure to specific bacteria have
shown that children who develop allergies are
significantly less likely to have been exposed to S.
aureus, a bacteria that has a strong stimulatory effect
on T-cells, another indication that exposure to
microbes in early childhood is important for the proper
development of the immune system.49 This would also
explain why children drinking milk fortified with
probiotics missed fewer days from day care due to
sickness and were less likely to receive antibiotic
therapy.50,51
A commonly used treatment for allergy sufferers is
cutaneous allergen immunotherapy, a technique
where allergens are periodically injected under the
skin in gradually increasing quantities. If successful the
technique eventually leads to desensitization.
Unfortunately, this technique is not used for food
allergies as the risk of adverse reactions is too great.40
Several studies have reported an increase in the
prevalence of allergies in recent decades. In the UK for
instance, the prevalence of peanut allergy has risen
from 1.3% of 3 year olds to 3.2% of 3 year olds in
1995.41,42 These increases are common throughout the
developed world with several European countries now
reporting one in ten children suffering from asthma
and one in three affected by allergies. Such increases
are unlikely to be caused by genetic factors alone.43
Possible explanations have included the “hygiene
theory” and an increase in air pollution. The hygiene
theory has been put forth to explain the rise in
incidence of several immune disorders in developed
4
Figure 2. Peanut Allergy - A problem on the rise.
ADVANCES in orthomolecular research
Volume 3 Issue 5
Observational studies continue to strengthen the link
between air pollution and allergic conditions. Pollution
has long been known to induce asthma and to
acerbate inhaled allergens in asthmatics.52 The link
between pollution and allergies has been explained by
an increase in oxidative stress and free radicals in
people that are more likely to suffer from allergies.
People with allergies would be more sensitive to
pollution due to a lessened ability to detoxify
pollutants.53 Other possible explanations for the
increase in allergic disorders have included the
manner in which foods are prepared. For instance, in
the case of peanut allergies, it has been postulated
that the formation of advanced glycation end products
in roasted peanuts may increase the susceptibility of
developing peanut allergies. The presence of
advanced glycation end-products in heat treated
peanuts could therefore increase their allergenicity
and previously non-allergenic raw peanut proteins
have been shown to trigger an immune reaction once
heated.54 However, more research is needed to
confirm those results as they have not been
reproduced by other researchers.55
Since foods that are introduced at a young age are
more likely to be candidates for allergies, the
American Academy of Pediatrics has recommended
that children should not consume peanuts for the first
three years of their life to help prevent the
development of allergies.56 Others have suggested that
this measure is counterproductive and that the
consumption of peanuts at an early age may actually
prevent allergies and countries where peanut snacks
are available for infants have lower rates of allergies
to peanuts.58,59
It has also been postulated that skin exposure to
peanut oil may contribute to allergies but those
findings remain tenuous and are only based on
population studies.61 More work is needed to
determine the role exposure plays in the development
of allergies.
Other work in the prevention of allergies has looked at
producing transgenic plants that are free of the
proteins that lead to the allergy.62
Newer research has revealed ways of reducing the
likeliness of developing allergies. Probiotics for
instance have demonstrated promise in this new field.
Vitamin D has also been portrayed to be a significant
factor in allergies and epidemiological studies
demonstrate that there is a very strong North-South
gradient for the sales of EpiPen prescription in the
United States. This may point to a link between vitamin
Volume 3 Issue 5
D and allergies, an interesting finding given new
research showing that vitamin D is important for self
tolerance. Other possibilities include the shift in dietary
lipid consumption with a significant decline in the
consumption of Omega 3 fatty acids. It has been
proposed that omega 3 fatty acid consumption would
have a protective effect against allergic disease due to
the anti-inflammatory effect of those oils. Higher
omega 3 fatty acid levels in the breast milk decreased
the risk of allergic disease in infants.63 Increased
maternal consumption of omega 3 fatty acids during
pregnancy may have even greater health benefits for
the infant, with studies suggesting a long term immune
effect associated with early exposure to omega 3 fatty
acids.64 Several mechanisms have been identified as
far as how these fatty acids can influence the function
of the immune system (see figure 6 from65). Omega 3
fatty acids may also have a direct effect on the immune
system and on the structure and function of cellular
membranes. The effect of omega 3 long chain
polyunsaturated fatty acids on cellular membranes
reduces T-cell signaling and activation.66 The
prevention of T-cell proliferation and the inhibition of
the production of immune messengers such as IL-2
and IFN-by omega 3 fatty acids are key to their
beneficial effects for allergy sufferers.
Figure 3. EpiPen, the treatment for anaphylaxis
You wouldn’t play the piano with a mallet, or swat a fly
with a bat… unfortunately, that is what your body is
doing if you experience allergies. Instead of
addressing a problem by eradicating a pathogen, it
creates havoc by unleashing an array of immune cells
and their mediators, creating inflammation, swelling
and itchiness. Most of us will experience allergies,
which is not surprising given the difficult task of
separating threatening substances from harmless
ones. As more research surfaces on allergies, our
understanding of the disease process will improve. For
the time being, suffice it to say that when we stray from
the natural way and the natural environment we
evolved in, problems arise. For example, although
growing up in a cleaner and more germ-free
environment seems like a good way to prevent
ADVANCES in orthomolecular research
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infection and disease, in reality it also predisposes to
autoimmune diseases. We evolved with germs and
bacteria and it seems that this interaction is needed for
the proper development and maturation of the
immune system. Exposure to the sun is another key
factor in the prevention or allergies. Our ancestors
would have spent most of their time in the sun and
would have had much higher vitamin D levels than
most of us do. Since vitamin D is extremely important
for immune tolerance, it is not surprising to see such a
strong North-South gradient for immune diseases.
Despite all of modern medicine’s advancements,
Mother Nature still knows best.
References
1 K. Singh and L. Bielory, Epidemiology of ocular allergy symptoms
in United States adults (1988–1994), Ann Allergy (1) (2007).
2 K. Singh and L. Bielory, Epidemiology of ocular allergy symptoms
in 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 epidemiologic
study, J Allergy Clin Immunol 119 (1 Suppl 1) (2007), p. S154.
4 Savage JH, Matsui EC, Skripak JM, Wood RA. The natural history
of 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’s
7 Weber RW. Allergic rhinitis.Prim Care. 2008 Mar;35(1):1-10, v.
8 Dakin R.Remarks on a cutaneous affection produced by certain
poisonous vegetables. Am J Med Sci, 1829;4:98-100. J Dtsch
Dermatol 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. Food
protein-induced enterocolitis: altered antibody response to ingested
antigen. 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. Modulation
of mucosal immunity in a murine model of food-induced intestinal
inflammation. Clin Exp Allergy. 2008 Feb;38(2):338-49.
12 Yang CM, Li YQ. [The therapeutic effects of eliminating allergic
foods according to food-specific IgG antibodies in irritable bowel
syndrome][Article in Chinese]. Zhonghua Nei Ke Za Zhi. 2007
Aug;46(8):641-3.
13 Atkinson W, Sheldon TA, Shaath N, Whorwell PJ. Food
elimination based on IgG antibodies in irritable bowel syndrome: a
randomised controlled trial. Gut. 2004 Oct;53(10):1459-64.
14 Crowe SE, Perdue MH. Gastrointestinal food hypersensitivity:
basic
mechanisms
of
pathophysiology.
Gastroenterol
1992;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, Wold
AE, Koletzko B. Early nutrition and immunity - progress and
perspectives. Br J Nutr. 2006 Oct;96(4):774-90.
6
17 Strobel S, Ferguson A. Immune responses to fed protein antigens
in mice. 3. Systemic tolerance or priming is related to age at which
antigen is first encountered. Pediatr Res 1984; 18:588-94.
18 E.F. Juniper, A.K. Thompson and P.J. Ferrie et al., Validation of
the standardized version of the Rhinoconjunctivitis Quality of Life
Questionnaire, 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., Measuring
quality of life in children with rhinoconjunctivitis, J Allergy Clin
Immunol 101 (2 Pt 1) (1998), pp. 163–170
20 Weber RW. Allergic rhinitis.Prim Care. 2008 Mar;35(1):1-10, v.
21 Bielory L. Ocular allergy overview. Immunol Allergy Clin North
Am. 2008 Feb;28(1):1-23, v.
22 HA Sampson, Update on food allergy, J Allergy Clin Immunol
113 (2004), pp. 805–819.
23 SH Sicherer and HA Sampson, 9. Food allergy, J Allergy Clin
Immunol 117 (Suppl 2) (2006), pp. S470–S475.
24 RS Kagan, L Joseph and C Dufresne et al., Prevalence of peanut
allergy in primary-school children in Montreal, Canada, J Allergy
Clin Immunol 112 (2003), pp. 1223–1228.
25 Ferri’s
26 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. Allergol
Int. 2008 Jun;57(2):121-34.
28 Shinohara M, Wakiguchi H, Saito H, Matsumoto K. Symptoms of
allergic rhinitis in women during early pregnancy are associated
with higher prevalence of allergic rhinitis in their offspring. Allergol
Int. 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 allergic
sensitization
caused 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 allergenspecific IgE-mediated hypersensitivity with allogeneic bone marrow
transplantation. N. Engl. J. Med. 1988; 319: 1623-1628.
31 Burks AW, Laubach S, Jones SM. J Allergy Clin Immunol. 2008
Jun;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, von
Berg A, Filipiak-Pittroff B, Berdel D, Bauer CP, Reinhardt D, Heinrich
J, Wichmann HE; GINI Study Group. Effect of breast-feeding on the
development of atopic dermatitis during the first 3 years of life-results from the GINI-birth cohort study. J Pediatr. 2004
May;144(5):602-7.
34 DM Fleischer, MK Conover-Walker, L Christie, AW Burks and RA
Wood, The natural progression of peanut allergy: resolution and
thepossibility of recurrence, J Allergy Clin Immunol 112 (2003), pp.
183–189.
35 Savage JH, Matsui EC, Skripak JM, Wood RA. The natural
history of egg allergy. J Allergy Clin Immunol. 2007
Dec;120(6):1413-7.
36 Staden U, Rolinck-Werninghaus C, Brewe F, Wahn U,
Niggemann B, Beyer K. Specific oral tolerance induction in food
allergy 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 natural
history of egg allergy. J Allergy Clin Immunol. 2007
Dec;120(6):1413-7.
ADVANCES in orthomolecular research
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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, Wold
AE, Koletzko B. Early nutrition and immunity - progress and
perspectives. 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 of
anaphylactic sensitivity to peanuts by immunotherapy with
injections of aqueous peanut extract. J Allergy Clin Immunol.
1997;99:744-51
41 J Grundy, S Matthews, B Bateman, T Dean and SH Arshad,
Rising prevalence of allergy to peanut in children: data from 2
sequential cohorts, J Allergy Clin Immunol 110 (2002), pp.
784–789.
42 Kabesch M, Schaal W, Nicolai T, von Mutius E. Lower
prevalence of asthma and atopy in Turkish children living in
Germany. 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, Wold
AE, Koletzko B. Early nutrition and immunity - progress and
perspectives. 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 immunological
basis of the hygiene hypothesis. Chem Immunol Allergy.
2006;91:30-48.
46 Isolauri E, Salminen S. Probiotics: Use in Allergic Disorders: A
Nutrition, 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, Bauer
CP, 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, Reinhardt
D, Wichmann HE, Koletzko S; GINI Study Group. Caesarean
section and gastrointestinal symptoms, atopic dermatitis, and
sensitisation during the first year of life. Arch Dis Child. 2004
Nov;89(11):993-7.
49 Adlerberth I, Lindberg E, Aberg N, Hesselmar B, Saalman R,
Strannegård IL, Wold AE. Reduced enterobacterial and increased
staphylococcal colonization of the infantile bowel: an effect of
hygienic lifestyle? Pediatr Res. 2006 Jan;59(1):96-101.
50 Hatakka K, Savilahti E, Pönkä A, Meurman JH, Poussa T, Näse
L, Saxelin M, Korpela R. Effect of long term consumption of
probiotic 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 infant
formula on infections in child care centers: comparison of two
probiotic agents. Pediatrics. 2005 Jan;115(1):5-9.
52 Peden DB. Effect of air pollution in asthma and respiratory
allergy. Otolaryngol Head Neck Surg. 1996 Feb;114(2):242-7.
53 Riedl MA. The effect of air pollution on asthma and allergy. Curr
Allergy Asthma Rep. 2008 Apr;8(2):139-46.
54 SY Chung and ET Champagne, Allergenicity of Maillard reaction
products from peanut proteins, J Agric Food Chem 47 (1999), pp.
5227–5231.
55 L Mondoulet, E Paty and MF Drumare et al., Influence of thermal
processing on the allergenicity of peanut proteins, J Agric Food
Chem 53 (2005), pp. 4547–4553.
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56 HA Sampson, Update on food allergy, J Allergy Clin Immunol
113 (2004), pp. 805–819.
57 G Lack, D Fox, K Northstone and J Golding, Factors associated
with the development of peanut allergy in childhood, N Engl J Med
348 (2003), pp. 977–985.
58 A Khakoo and G Lack, Preventing food allergy, Curr Allergy
Asthma Rep 4 (2004), pp. 36–42.
59 Yeh KW. Allergens and allergic diseases in children. Acta
Paediatr Taiwan. 2006 Jul-Aug;47(4):169-74.
60 Levy Y, Broides A, Segal N, Danon YL. Peanut and tree nut
allergy in children: role of peanut snacks in Israel? Allergy. 2003
Nov;58(11):1206-7.
61 J Strid, J Hourihane, I Kimber, R Callard and S Strobel,
Epicutaneous exposure to peanut protein prevents oral tolerance
and enhances allergic sensitization, Clin Exp Allergy 35 (2005), pp.
757–766.
62 BE Moseley, How to make foods safer—genetically modified
foods, Allergy 56 (suppl 67) (2001), pp. 61–63.
63 Yu G, Kjellman NI, Björkstén B. Phospholipid fatty acids in cord
blood: 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 cytokine
production 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, Wold
AE, Koletzko B. Early nutrition and immunity - progress and
perspectives. Br J Nutr. 2006 Oct;96(4):774-90.
66 Zeyda M, Stulnig TM. Lipid rafts& co.: An Integrated Model of
Membrane Organization in T cell Activation. Progr Lipid Res. 2006
45, 187-202
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Sensitization
Dendritic cells
Peanut - specific
T-cells
Allergic Reaction
The Allergic Reaction:
8
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Volume 3 Issue 5
Th2
B cells
IL-4
IL-5
IL-13
Peanut-specific
lgE
Mast cells
FcERI
Antigens from allergens like peanuts are engulfed and then presented by immune cells called
dendritic cells that in turn activate T-cells, causing a Th2 immune response. This causes the
release of cell signaling molecules called cytokines (IL-4, IL-5 and IL-13), triggering the
production of antibodies specifically matched to the antigen. Antibodies then activate Mast
cells, causing the release of histamines and pro-inflammatory molecules, this in turn produces
the symptoms of allergies.
Volume 3 Issue 5
ADVANCES in orthomolecular research
9
Q&A
Vitamin D
What is the optimal vitamin D3 dosage?
An abundance of clinical information is now showing
that the current intake recommendations are far too
restrictive and are detrimental to the health of the
populations they are meant to protect. There is good
evidence showing that dosages up to 10,000 IU of
vitamin D are safe for long term use and that single
dosages of up to 5 times this amount are not
harmful.4,5
Studies also point to natural physiological levels of
vitamin D that are far greater than what can be
obtained from the current recommended intake levels.
The maximum amount of vitamin D produced in the
skin is similar to that obtained from an oral dose of
10,000 IU, ten times the maximum allowed by Health
Canada.6
To prevent immune dysfunction, when should
vitamin D3 therapy be initiated?
All of the research on vitamin D clearly points to the
need for a complete overhaul of the current
recommendations for vitamin D supplementation. The
Canadian government recommends a minimum of
0.2 mcg (8 IU) of vitamin D up to 13 years of age and
0.8 mcg (32 IU) per day thereafter. The current
maximum allowed by Health Canada remains at 25
mcg (1000 IU) per day for all age groups.1
The situation is very similar in the United States, with
the National Institute of Health establishing Adequate
Intakes of 200 IU from birth until 50 years of age, 400
IU per day from 51-70 years and 600 IU afterwards.2
The Tolerable Upper Intake levels for vitamin D have
been set at 1000 IU for the first year of life and 2000
IU for all other age groups.3
These recommendations were established in 1997
and therein lies the problem. There have been almost
20,000 medical publications on vitamin D since that
time. To put this number in perspective, Lipitor®, the
prescription medication with the highest dollar volume
of sales in the US, has a total of less than 3700
publications under its name. Needless to say that our
knowledge and understanding of the amounts of
vitamin D required for health has significantly
improved since the establishment of the Adequate
Intake guidelines.
The last ten years of research into the health benefits
associated with vitamin D have shown that vitamin D
possesses greater than expected health benefits. The
vitamin has been shown to reduce the risk of
developing cancer, help lower blood pressure, help
maintain physical strength and reduces bone fractures.
10
Breast feeding does not provide infants with the
amount of vitamin D they require. Breast milk,
although the preferred food for newborn infants, is
quite low in vitamin D (roughly 25 IU of vitamin D per
liter). Infants can produce additional vitamin D when
exposed to sunlight but some reports of rickets have
been documented in exclusively breastfed infants. The
American Academy of Pediatrics recommends a
minimum of 400 IU of vitamin D per day for all
breastfed infants.7 The same recommendations of
400 IU per day have been made by Health Canada8
and the Canadian Pediatric Society advocates up to
800 IU per day for children in Northern Native
communities which are more prone to vitamin D
deficiency.9
Research has shown that supplementation with vitamin
D during infancy and pregnancy is associated with a
decreased risk of type 1 diabetes, allergies and
multiple sclerosis.10-13 Vitamin D supplementation
should start at birth and dosages should vary from
400 IU to 2000 IU per day depending on whether or
not there is a vitamin D deficiency to begin with.14
References: see page 20
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Volume 3 Issue 5
Quercetin:
Sweet Allergy
Relief
Quercetin: ubiquitous in the world of botanicals
and the most abundant of polyphenolic
flavonoids, this vibrantly colored substance is
making quite the name for itself in health
circles. With the benefits of being an antiinflammatory, anti-proliferative, anti-oxidant,
anti-bacterial,
anti-atherogenic,
antihypertensive, and of course anti-allergenic1-5
it’s lucky for us that 70% of flavonoid
consumption in the diet is actually quercetin.6
Apples and onions are the most well known
sources of quercetin but there are also healthy
doses of this flavonoid favorite in kale, broccoli,
green and black teas, berries, and even red
wine.7-9
2’
8
7
6
A
5
C
4
3’
B
4’
5’
6’
3
Figure 1: The Chemical Structure of Quercetin
Of the 5000 different flavonoids discovered, with
more being added to this count everyday, quercetin is
stealing the show as studies are demonstrating again
and again how it is one of the most potent and
effective of the polyphenolic flavonoids.1 Flavonoids in
Volume 3 Issue 5
general are composed of a three-ringed structure that
allows for the antioxidant and anti-inflammatory
actions they are famous for. Quercetin in particular
contains a catechol group (B ring) and a strategically
placed hydroxy group (at position 3) that contribute to
its more potent antioxidative actions, allowing it to
scavenge free radicals more efficiently.10
The antioxidant action of quercetin, that is its ability to
scavenge reactive oxygen species (ROS), is
hypothesized to be the source of its beneficial effects,
and particularly its anti-inflammatory properties.1 This
is mediated through the actions of a regulatory
molecule called Nuclear factor kappa beta (NF-kB)
which, when stimulated, promotes production of
inflammatory molecules including tumour necrosis
factor (TNF)-alpha and others.11 ROS increase NF-kB
stimulation, which through TNF-alpha leads to
inflammatory cytokines, which leads to the production
of ROS and the cycle continues.12 Quercetin acts to
both inhibit NF-kB13 and neutralize the ROS
produced14, thus breaking the cycle of oxidative stress
and down regulating the progression of disease
processes.
This effect leads to the many benefits associated with
this flavonoid powerhouse. Quercetin is used in the
management of pain and inflammation as it works to
block the action of lipoxygenases and cycloxygenases,
enzymes that produce proinflammatory, and thus pain
producing, mediators.15,16 Quercetin inhibits aldose
reductase, an enzyme that promotes the formation of
fructose and sorbitol from circulating glucose,
suggesting a use in diabetes related conditions such as
cataracts, glaucoma, nephropathy and neuropathy.17
Quercetin is also showing great promise in
cardiovascular health, including a recent double-blind
placebo controlled trial, which demonstrated that
quercetin supplementation at 730mg/day for 28 days
ADVANCES in orthomolecular research
11
was effective in reducing blood pressure in stage I
hypertensive patients.18 Due to its free-radical
scavenging structure quercetin also has a role in
cancer prevention and treatment, particularly colon
and lung cancers.19 Interestingly, quercetin has also
shown benefit in the treatment of chronic prostatitis
specifically in treating the associated pelvic pain,
which can be attributed to the anti-inflammatory and
analgesic properties of quercetin.20
several Interleukin (IL) molecules: IL-6, IL-8, and IL13.20,23 It’s these contents that, once released when
mast cells ‘degranulate’, lead to the symptoms seen in
allergies. The antibody IgE is an important player in
mast cell degranulation, and is found in higher
amounts in allergy sufferers.20 Quercetin’s claim to
allergy fame is indeed its ability to stabilize these mast
cells, leading to less degranulation episodes and
subsequently, lower occurrence of allergy symptoms.
Studies show that quercetin inhibits IgE mediated
histamine release from mast cells to have an overall
effect of down-regulating mast cell activation.21 Mast
cell activation doesn’t only result in degranulation, but
also results in the production of more inflammatory
cytokines through the action of NF-kB, thereby
perpetuating the allergic cycle.24,25 Quercetin not only
works to stabilize the mast cells and inhibit NF-kB, but
also down-regulates the production of inflammatory
mediators such as tryptase, IL-6, histidine
decarboxylase, and TNF-alpha.26,27
Figure 2: The antioxidant and anti-inflammatory
actions of quercetin
The list of benefits goes on, but the topic of interest this
season is, of course, quercetin’s ability to ease the
woes of allergy sufferers. Both seasonal and chronic
allergies are associated with debilitating symptoms
such as itchy, watery eyes, nasal congestion, hives,
atopic dermatitis, asthma and in severe cases of
allergen exposure, anaphylaxis. Fortunately for those
afflicted, one of quercetin’s most well known effects is
that of allergy relief. Since the early 1980’s quercetin
has been studied for its effects on allergy related
immune cells in the body.21 These immune cells, most
notably basophils, mast cells, eosinophils, and Thelper cells, are part of the intricate network in the
body that works to prevent invasion by infectious
offenders, however they can become part of an
overactive response leading to allergic reactions,
autoimmunity and inflammation.22
Mast Cell Stabilizer
Mast cells and basophils are at the root of allergic
symptoms. Found in numerous tissue locations
throughout the body, they house inflammatory
mediators such as histamine as well as proinflammatory cytokines like TNF-alpha, tryptase and
12
Figure 3. Quercetin is a flavonoid found in many
common foods including apples and onions
Th-1/Th-2 Balance
In light of this it may be tempting to see the mast cell
as an immune enemy, however they are important
inflammatory cells of the immune system that respond
to danger signals; it is the moderation of their action
that is of concern. This is where the T-helper (Th) cells
play an important role in what is called the Th-1/Th-2
balance. Th-2 immune cells are associated with
cytokines that encourage the development of mast
cells, basophils and eosinophils, all of which are
implicated in allergies.28 Allergy sufferers are thought
to have a dominance of Th-2 to Th-1 immune cells.
Thankfully quercetin acts on this level as well to
moderate the actions of the immune system, lessening
the effects of allergic symptoms. Quercetin has been
shown in vitro to reduce the expression of Th-2 derived
ADVANCES in orthomolecular research
Volume 3 Issue 5
cytokine IL-4 and increase the expression and
production 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/Th2
balance through this decrease in IL-4 and increase in
IFN-γ: The result was a decrease in allergic airway
constriction and airway hyper responsiveness, as seen
in allergic asthma.30
Another group of allergy associated immune cells,
eosinophils, are found in the blood of allergy and
allergic asthma sufferers.31 Eosinophils are a source of
cytokines and chemokines and are known to produce
leukotrienes, inflammatory products that cause
bronchoconstriction, and mucus hypersecretion
associated with allergic asthma.32-35 Quercetin has
been shown in animal models of asthma to decrease
eosinophils in lung tissue thereby reducing asthmatic
symptoms. This effect was demonstrated both with oral
supplementation and with an inhaled application of
quercetin.29,36,37 Once again, researchers are looking at
quercetin’s ability to inhibit NF-kB in order to explain
this decrease in eosinophil levels, since it is known that
NF-kB is associated with eosinophil recruitment to
allergy sites.38
Many of these studies are test tube or animal model
studies, and although these have shown promising
results, the need for more human studies is apparent.
However, research is surfacing in human trials. A very
recent double-blind randomized placebo controlled
trial looked at the effect of an enzymatically modified
quercetin glycoside on symptoms of cedar pollinosis
common in Japan.39 20 subjects positive for Japanese
cedar pollen IgE were assigned either 100mg twice
daily of the quercetin glycoside or placebo for 8 weeks
in the pollen season.37 The effect was a significant
reduction in ocular symptoms, that is a decrease in the
symptoms of itchy watery eyes associated with
seasonal pollen allergies.37
With the research results so far it’s no wonder
quercetin is gaining a name in anti-allergy treatment,
not to mention the plethora of benefits being shown to
result from its consumption. Of course eating a diet
high in flavonoids will benefit overall health, but often
the body needs an extra kick of flavonoid action to
support the immune system against an oncoming
allergy season. And with quercetin in the allergy
arsenal, this pollen season just got better.
made it less available for use in the body.40 This
led to the belief that supplementation with a
digestive enzyme such as bromelain would
result in better availability of quercetin both
intestinally and in the serum.
Bioavailability of Quercetin
Quercetin is most commonly found in nature as
a glycoside, meaning that there is a sugar
group in place of one of the OH (hydroxy)
groups. Quercetin glycosides include rutin,
quercitrin, isoquercitrin and hyperoside. Due to
it’s structure, the aglycone form of quercetin is
the most effective antioxidant and antiinflammatory.
Quercetin was previously thought to have a
very low bioavailability, and it’s obsorption in
the intestines was questioned. In addition to
this, because quercetin is bound by albumin (a
blood protein) in the body, some thought this
Volume 3 Issue 5
However, research is lacking to support this
claim. The aglycone has actually been shown to
have an absorption rate of 24%, and the
glycosidic forms (those with a sugar molecule
attached) have an absorption rate of 52%.41 It is
also now understood that quercetin is converted
by enzymes in the intestinal tract to glycosidic
forms to be absorbed,42,43 suggesting an even
higher absorption rate. In addition to this,
quercetin has a relatively long half-life, and on
repeated supplementation of the pure
aglycone, quercetin blood levels increase
significantly.44 This suggests that concurrent
supplementation with digestive enzymes is
unnecessary to absorb and utilize the quercetin
aglycone.
ADVANCES in orthomolecular research
13
References
1 Boots, A.W., Haenen, G., Bast, A. Health effect of quercetin: from
antioxidant to nutraceutical. (2008) 585: 325-337.
2 Cushnie, T.P., Lamb, A.J., Antimicrobial activity of flavonoids. Int. J.
Antimicrob. Agents (2005) 26: 343–356
3 Perez-Vizcaino, F., Bishop-Bailley, D., Lodi, F., Duarte, J., Cogolludo, A.,
Moreno, L., Bosca, L., Mitchell, J.A., Warner, T.D.,The flavonoid quercetin
induces apoptosis and inhibits JNK activation in intimal vascular smooth
muscle cells. Biochem. Biophys. Res. Commun. (2006) 346: 919–925
4 Perez-Vizcaino, F., Duarte, J., Jimenez, R., Santos-Buelga, C., & Osuna, A.
Antihypertensive effects of the flavonoid quercetin. Pharmac Rep. (2009)
61:67-75
5 Gulati, N., Laudet, B., Zohrabian, V.M., Murali, R., Jhanwar-Uniyal,
M.,The antiproliferative effect of quercetin in cancer cells is mediated via
inhibition of the PI3K-Akt/PKB pathway. Anticancer Res. (2006) 26:
1177–1181
6 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 subjects
eating a variety of diets. Cancer Lett. (1997) 114: 141-144
7 Hertog, MGL, Hollman PCH, Katan MB. Content of potentially
anticarcinogenic flavonoids of 28 vegetables and 9 fruits commonly
consumed in The Netherlands. J Agric Food Chem (1992) 40:2379.
8 Hertog, MGL, Hollman PCH, van de Putte B. Content of potentially
anticarcinogenic flavonoids of tea infusions, wines and fruit juices. J Agric
Food Chem (1993) 41:1242.
9 Aherne, S.A & O’Brien N.M. Dietary flavonols: chemistry, food content
and 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 structure
activity relationship revisited. Free Radic. Res. 36: 575–581.
11 Sarkar, F.H., Li, Y., Wang, Z., & Kong, D. NF-kB signaling pathway and
its therapeutic implications in human disease. Int Rev immunol. (2008).
27:293-319
12 Rahman, I., Gilmour, P.S., Jimenez, L.A., MacNee, W., Oxidative stress
and TNF alpha induce histone acetylation and NF-kappaB/AP-1 activation
in alveolar epithelial cells: potential mechanism in gene transcription in lung
inflammation. 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 of
quercetin, which inhibits inflammation through down-regulation of the NFkappaB pathway. Eur J Immunol. (2005) 35:584–92.
14 Hanasaki, Y., Ogawa, S., Fukui, S., The correlation between active
oxygens 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 of
arachidonic 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 in
galactosemic 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. Quercetin
reduces blood pressure in hypertensive subjects. J Nutr. (2007)
137(11):2405-11.
19 Murakami, A., Ashida, H., Terao, J. Multitargeted cancer prevention by
quercetin. Canc Lett. (2008) 269:315-325.
20 Shoskes, D.A., Zeitlin, S.I., Shahed, A. & Rajfer, J. Quercetin in men with
category III chronic prostatitis: a preliminary, prospective, placebo
controlled trial. Urol. (1999) 54:960-963.
21 Middleton, E. Et al. Quercetin: an inhibitor of antigen-induced human
basophil histamine release. J. Immunol. (1981) 127(2): 546-550
22 Prussin, C. & Metcalfe, D. IgE, mast cells, basophils, and eosinophils. J
Allergy Clin Immunol. (2003) 111(2): S486-S494
23 Park, H. Et al. Flavonoids inhibit histamine release and expression of
pro-inflammatory cytokines in mast cells. Arch Pharm Res (2008) 31(10):
1303-1311.
14
24 Min, Y. Et al. Quercetin inhibits expression of inflammatory cytokines
through attenuation of NK-kB and p38 MAPK in HMC-1 human mast cell
line. 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 human
mast cells (HMC-1). Pharmacol. Res. (2007) 55:31-37.
26 Ruiz, P.A Et al. Quercetin inhibits TNF-induced NF-kB transcription factor
recruitement to proinflammatory gene promotors in murine intestinal
epithelial cells. J.Nutr. (2007) 137: 1208-1215.
27 Kempuraj, D. Et al. Inhibitory effect of quercetin on tryptase and
interleukin-6 release, and histidine decarboxylase mRNA transcription by
human mast cell-1. Clin Exp Med; (2006) 6:150-156.
28
Miller,
A.
The
etiologies,
pathophysiology,
and
alternative/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 blood
mononuclear cells. Biochimica et Biophysica Acta (2002) 1593:29-36.
30 Park, H., Et al. Quercetin regulates Th1/Th2 balance in a murine model
of asthma. Int. Immunopharm. (2008) 9:261-267.
31 Rogerio, A.P Et al. Anti-inflammatory activity of quercetin and
isoquercitrin 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 by
human eosinophils: predominant production of leukotriene C4. Proc Natl
Acad 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 Respir
Crit Care Med (1998) 158: S193–200.
35 Holgate ST, Sampson AP. Antileukotriene therapy. Future directions. Am
J Respir Crit Care Med (2000) 161: 147–53.
36 Moon, H. Et al. Quercetin inhalation inhibits the asthmatic responses by
exposure to aerosolized-ovalbumin in conscious guinea pigs. Arch Pharm
Res. (2008) 31(6): 771-778.
37 Jung, C. H., Lee, J. Y., Cho, C. H., and Kim, C. J., Antiasthmatic action
of quercetin and rutin in conscious guineapigs challenged with aerosolized
ovalbumin. Ach. Pharm. Res. (2007) 30, 1599-1607.
38 Jia GQ, Gonzalo JA, Hidalgo A, Wagner D, Cybulsky M, Gutierrez‐Jia
GQ et al. Selective eosinophil transendothelial migration triggered by
eotaxin 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, a
flavonoid, on symptoms of Japanese cedar pollinosis: A randomized
double-blind placebo controlled trial. Int Arch Allergy Immunol (2009)
149:359-368.
40 Boulton DW, Walle UK, and Walle T: Extensive binding of the
bioflavonoid 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 in
healthy ileostomy volunteers. Am. J. Clin. Nutr. (1995) 62, 1276–1282.
42 Sesink, A.L., Arts, I.C., Faassen‐Peters, M., Hollman, P.C., Intestinal
uptake of quercetin-3-glucoside in rats involves hydrolysis by lactase
phlorizin 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 small
intestinal epithelial cell beta-glucosidases is a critical step in the absorption
and metabolism of dietary flavonoid glycosides in humans. Eur. J. Nutr.
(2003) 42: 29–42.
44 Egert, S. Et al. Daily quercetin supplementation dose dependently
increases plasma quercetin concentrations in healthy humans. J Nutr.
(2008) 138:1615-1621.
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Rosemary:
Where tradition
meets science
Rosemary is a bushy shrub with whitish blue flowers
that grows wildly along the coasts of the
Mediterranean.1 It has been cultivated since ancient
days in Europe, Central America, and other regions2.
Now it is a common household plant that is used for
flavoring and in cosmetics, and whose fragrant
needle-like leaves are used in cooking.3 Rosemary has
been used in folk medicine as an antispasmodic, for
relief of respiratory disorders, and for stimulating hair
growth. It has also been used as a pain killer, a
diuretic, and for human fertility. Its extracts relax the
smooth muscles of the trachea and intestine and have
antioxidant, liver protective and tumour fighting
activities.2 One of the ancient cult plants, it is closely
associated with love and marriage, birth and death,
and is still used in bridal bouquets in England and
Germany as a symbol of remembrance. Rosemary
was also traditionally put in the cradles of infants to
guard against harm.2 Modern science is now showing
that rosemary extracts can indeed guard against
certain kinds of harm, including the damage caused
by allergies and inflammation.
Dealing with Allergies
Studies of rosemary have found that its major chemical
components are polyphenolics with antioxidant
activities. 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 block
inflammation. Allergies are inextricably linked with
inflammatory processes since inflammation is the
mechanism behind most of the unpleasant and
potentially dangerous allergic symptoms. Inflammatory
events involve very complex pathways, and can be
blocked at a number of steps in a variety of ways. The
initiation and continuation of inflammation is caused
by inflammatory signaling mediators such as
prostaglandins, leukotrienes, chemokines and
Volume 3 Issue 5
cytokines. Histamine is another signaling molecule
whose effects contribute to a number of allergic
symptoms. Anti-inflammatory compounds often work
by blocking such mediators. Immune cells such as
macrophages, eosinophils and basophils play an
important part in the pathogenesis of allergic disease
by releasing inflammatory mediators. Mast cells are
particularly detrimental because they store histamine
and other agents of allergy inside granules, all ready
to be released as soon as the signal is given.
Blocking the activation of these cells can reduce
allergic responses. Inflammation can also be
modulated by preventing the recruitment of
inflammatory cells to the tissues being targeted for an
allergic response, and blocking their infiltration into
these tissues.5
Rosemary’s Anti-inflammatory Team
One of rosemary’s key components, rosmarinic acid,
is a substance that is well absorbed from the
gastrointestinal tract and that has therapeutic potential
in the treatment and prevention of bronchial asthma,
spasmogenic disorders, peptic ulcers, inflammatory
diseases, liver toxicity, atherosclerosis, ischemic heart
disease, and even cancer.2 In the inflammatory
process, rosmarinic acid increases the production of
anti-inflammatory signaling molecules while reducing
the production of pro-inflammatory leukotrienes. It
also inhibits a key step of the complement system.6
This system is a biological cascade that provides an
alternate pathway of inflammation, eventually leading
to increased blood vessel permeability, recruitment of
inflammatory cells, enhancement of platelet activation
and aggregation, and an enhancement of
proinflammatory signal molecule production.2
Another of rosemary’s main components, caffeic acid,
also has benefits in inflammatory conditions. When
tested against various anti-inflammatory plant
polyphenols, caffeic acid showed the most potent
inhibition of tumour necrosis factor alpha, a major
pro-inflammatory cytokine.7
Carnosic acid also has anti-inflammatory actions. In
chronic inflammation, cytokines induce the production
of nitric oxide (NO), which shifts the balance of the
immune system to favor inflammation. Elevated levels
of NO are found in patients with allergic diseases such
as asthma.8 A study of rosemary extract found that it
was able to suppress the production of NO. This
activity was attributed to carnosic acid and carnosol.3
Furthermore, the antioxidant properties of rosemary’s
extracts can help reduce the cellular damage caused
by free radicals that are released during the
inflammatory process.2
ADVANCES in orthomolecular research
15
Outside the Test Tube
While the anti-allergic and anti-inflammatory
properties of rosemary’s components have been well
tested in cell studies, they also hold up in vivo. One
study found that rosemary’s volatile oil inhibited the
contraction of tracheal smooth muscle induced by
acetylcholine and histamine in rabbits and guinea
pigs.9 Rosemary also blocked the complement system
in various animal models6, and inhibited cutaneous
anaphylaxis (a severe allergic reaction) in rats, blocked
the activation of macrophages in mice, and reduced
paw swelling in rats.2
Another study tested the effects of a rosemary extract
in mice that were exposed to diesel exhaust particles.
These pollutants exaggerate the severity of allergic
conditions and are involved in increased morbidity
and mortality from lung diseases10. In this study, lung
inflammation in mice was characterized by the
infiltration of immune cells into lung tissue, by the
cellular profile of bronchoalveolar lavage fluid, and by
histological examination. Mice that were exposed to
diesel exhaust particles and given rosemary extract
had significantly less lung inflammation and
suppressed expression of proinflammatory signaling
molecules compared to mice that were only exposed to
the exhaust. Rosemary also inhibited the increase in
numbers of inflammatory cells.11
Rosmarinus is Latin for “dew of the sea”. While not
quite accurate, the name evokes entirely appropriate
images of refreshment. By blocking inflammation at a
number of levels, rosemary helps to cool the heat of
inflammation and sooth the irritation of allergies.
Therapeutic Potentials of the Rosemary Plant2
Pharmacological Actions
Therapeutic Potential
1. Relaxation of bronchial smooth muscle
Bronchial asthma
2. Relaxation of intestinal smooth muscle
Antispasmodic
3. Reduction of leukotrienes and increased
PGE2 production
Bronchial asthma, Peptic ulcer, Inflammatory
diseases
4. Inhibition of lipid peroxidation
Hepatotoxicity, Atherosclerosis and Ischaemic
heart disease, Inflammatory diseases,
Asthenozoospermia
5. Inhibition of the complement pathway
Inflammatory diseases
6. Prevention of carcinogen-DNA adduct
formation
Cancer (protection)
References
1. 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 Journal
of 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 antiinflammation and anti-tumor effects. Biosci. Biotechnol. Biochem.
2007;71(9):2223-2232.
4. Hoefler C, Fleurentin J, Mortier F, Pelt JM and Guillemain J. Comparative
choleretic and hepatoprotective properties of young sprouts and total plant
extracts of Rosmarinus officinalis in rats. J Ethnopharmacol.
1987;19(2):133-143.
5. Kindt TJ, Goldby RA and Osborne BA. Kuby Immunology 6th Ed. WH
Freeman and Company. NY 2007.
6. Englberger W, Hadding U, Etchenberg E, Graf E, Leyck S, Winkelmann J
and Parnham MJ. Rosmarinic acid: A new inhibitor of complement C3convertase with anti-inflammatory activity. Int J Immunopharmacol.
1988;10(6):639-784
16
7. Molna V, Gray J. Plant-derived anti-inflammatory compounds affect MIF
tautomerase activity. International Immunopharmacology. 2005;5:849856.
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 on
tracheal smooth muscle. J Ethnopharmacol. 1991;33:57-62.
10. Sagai M, Furuyama A and Ichinose T. Biological effects of diesel
exhause 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, Kato
Y and Yoshikawa T. Effects of volatile constituents of rosemary extract on
lung inflammation induced by diesel exhaust particles. Basic & Clinical
Pharmacology & Toxicology. 2006;99:52-57.
ADVANCES in orthomolecular research
Volume 3 Issue 5
Perilla
An Allergy Fighting Herb
Perilla frutescens is a plant whose leaves are
commonly used as a garnish with raw fish in Japan. It
is also used in Chinese herbal medicine1, and its
leaves are used medicinally as a sedative, for
indigestion, and for food poisoning treatment.2 The
functional components of perilla are flavonoid
aglycones such as luteolin, apigenin, and rosmarinic
acid. These substances have been studied for their
anti-allergic and anti-inflammatory potential.
Perilla’s Mechanisms at all 3 Levels of Study
Inhibitory ratio (%)
In cell studies, perilla effectively inhibits mast cells from
“degranulating” and releasing histamine, which is one
of the principle mechanisms behind allergic
symptoms. One study found that perilla not only dosedependently inhibited the release of histamine from
mast cells, but also significantly inhibited the
production of a main pro-inflammatory cytokine.3
Perilla also selectively blocks the activity of 5lipoxygenase, a key enzyme in one of the pathways of
inflammation.4
100
80
60
40
20
0
0
200
400
600
Perilla Seed Extract (µg/ml)
Figure 1. Inhibitory effect of Perilla on histamine
release
Volume 3 Issue 5
The effects of perilla extracts have also been tested in
animal models of allergy. In rats, Perilla frutescens
extract inhibited mast cell-mediated allergic reactions.
It dose-dependently decreased plasma levels of
histamine and inhibited systemic and local allergic
reactions.3 In another study, a perilla extract containing
luteolin, scutellarin, apigenin and rosmarinic acid
significantly suppressed cutaneous anaphylaxis, a
severe allergic reaction, in mice. This type of reaction
is related to the second and third stages of common
allergic responses, when mast cells are activated to
release mediators such as histamine, serotonin and
leukotrienes, and when these mediators cause
inflammatory reactions such as enhancing vascular
permeability and causing smooth muscle to constrict.2
This then leads to allergic symptoms such as swelling
and redness. A second trial confirmed the ability of
perilla extracts to suppress cutaneous anaphylaxis.5
Other studies have indicated that perilla extracts may
inhibit the production of immunoglobulin E (IgE).6 IgE
is the antibody that is responsible for recognizing
“allergens”, which are proteins from substances such
as food, plant pollens, latex, animal hair, etc. and
priming the immune system for an allergic reaction.
Total serum levels of IgE have been roughly correlated
with the severity of allergic disease.7 Blocking IgE
production is therefore an effective way to block an
allergic reaction at the first step.
In humans, perilla has been found to reduce the
severity of asthma. One trial compared the clinical
features of patients with asthma who had been given
perilla seed oil for 4 weeks to those of asthmatics who
had not been given perilla extracts. In the group given
perilla seed oil, pro-inflammatory leukotriene synthesis
was significantly decreased, whereas it increased
significantly in the control group. Perilla seed oil also
significantly increased breathing measurements such
as peak expiratory flow, forced vital capacity and
forced expiratory volume in one second.8 Another
study observed the effects of perilla seed extracts in
volunteers with allergic symptoms such as sneezing,
nasal obstruction, and itchy skin and eyes. 20
participants were given perilla seed extracts for 2-4
weeks, and their change in symptoms was evaluated.
Symptoms were improved in all 20 patients, with
significant improvements in sneezing (almost 40%),
stuffed nose (over 60%) and itchy eyes (50%). Two of
the patients had blood samples taken to determine the
effect of the extract on IgE concentrations. IgE levels
were significantly lower in both patients, without any
change in other antibody levels.9
ADVANCES in orthomolecular research
17
Effect on Patient with Allergy
Sneeze
Cured
Significantly
Improved
Stuffed Nose
Blow Nose
Improved
Eye Itchy
Unchanged
Skin Itchy
0
20
40
60
80
100
(%)
Figure 2. Effect of Perilla seed extract on a patient with
allergy
Luteolin
Luteolin is considered by many scientists to be the
major active constituent in Perilla frutescens. Studies of
this component have found that it exerts antimutagenic
and anti-inflammatory-allergic effects. It is also
recognized as an antioxidant scavenger of damaging
free radicals, and as an inhibitor of protein kinase C,
which is a key regulator in the initiation of
inflammatory events such as smooth muscle
constriction.9 Luteolin has been shown to be a potent
inhibitor of human mast cell activation.10,11 One study
compared the effects of luteolin, baicalein and
quercetin on the inhibition of the release
of histamine, leukotrienes, cytokines and other
inflammatory factors from human mast cells, and
found that luteolin was the most effective at inhibiting
the release of these components.10 Another study
found that luteolin could completely block the
stimulation of mast cells, inhibiting the IgE-mediated
release of histamine and pro-inflammatory cytokines.11
Luteolin is effective at preventing the production of
proinflammatory cytokines.3,12 Some of the cytokines
that are primarily responsible for allergic diseases
include interleukin (IL)-4 and IL-5. IL-4 is one of the
most important cytokines in the production of IgE and
allergic inflammation.12 IL-5 is responsible for
recruiting eosinophils.13 Eosinophils are immune cells
that assist in priming the immune system for an
allergic response. When they infiltrate the inflamed
tissue, eosinophils become activated and release
mediators such as histamines, cytokines, leukotrienes
and other pro-inflammatory mediators.14 Eosinophil
accumulation is a distinctive feature of allergic
inflammation.14 One study compared the antiinflammatory activities of 37 flavonoids and related
compounds, and found that luteolin and compounds
with a similar structure were the strongest inhibitors of
18
interleukin-4 production by basophils.12 Other studies
have 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 significantly
inhibited production of the cytokine tumour necrosis
factor alpha. Luteolin also inhibited ear swelling in
mice that was induced by pro-inflammatory
molecules.1
Luteolin has shown benefits in models of asthma.
Asthma is an inflammatory disease of the airways
which is characterized by difficulty in breathing due to
inflammation which causes smooth muscles in the
bronchi to constrict. It is also characterized by elevated
levels of IgE in the blood, and infiltration of eosinophils
into the airways.15 The development of asthma is
mediated 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 airway
hyperactivity which mimics
some of the characteristic features of asthma, orally
administered luteolin significantly decreased airway
hyperreactivity and blood levels of IgE. It also reduced
levels of IL-4 and IL-5 in the bronchoalveolar lavage
fluid while increasing levels of IFN-y.15
Rosmarinic Relief
Like rosemary, one of perilla’s active constituents is
rosmarinic acid. This compound’s antioxidant and
anti-inflammatory properties have been shown to help
with allergic disease in several studies. One study
observed a mouse model in which an allergic reaction
was induced using a dust mite allergen. Mice that were
given rosmarinic acid in a perilla extract had strongly
inhibited recruitment of inflammatory cells. Rosmarinic
acid also decreased the numbers of mucus-containing
airway cells and significantly prevented the intensity of
infiltration of eosinophils and other inflammatory cells
into tissues, and it prevented the allergy-induced
increase in the production of IL-4 and IL-5.
Furthermore, rosmarinic acid reduced the production
of antibodies that react to allergens. All of these results
indicate that rosmarinic acid is capable of strongly
blocking allergic inflammation14.
Rosmarinic acid has also proved its worth in helping
with human allergies. In one randomized, doubleblind, age-matched placebo-controlled parallel group
study, 30 patients with seasonal allergic
rhinoconjunctivitis (SAR) were given either a low or
high dose of Perilla frutescens extract enriched with
ADVANCES in orthomolecular research
Volume 3 Issue 5
rosmarinic acid or a placebo for 21 days. Their
symptoms were recorded, and their levels of infiltrating
inflammatory cells and histamine in the nasal lavage
fluid were measured. Serum levels of IgE were also
measured. At the end of the trial period, there was a
significant increase in responder rates for itchy nose,
watery eyes, itchy eyes and total symptoms. 55.6% of
patients given a lower dose of the extract and 70% of
patients given the higher dose reported global
symptom relief, compared to only 30% of the placebo
group. The extract also significantly decreased the
number of eosinophils and other inflammatory cells in
the nasal lavage fluid at both doses. These results were
suggested to be due to the inhibition of immune cells
from infiltrating into the nostrils. Since there were no
adverse effects or significant abnormalities in blood
tests, the study concluded that rosmarinic acid from
perilla extract is an effective intervention for SAR.16
placebo
No Change
rosmarinic
acid 50mg
Partial Relief
P=0.284 vs. placebo
rosmarinic
acid 200mg
Complete Relief
P=0.05 vs. placebo
0
25
50
75
100
(%)
Figure 3. Patients’ evaluations of global symptoms
using the health-related quality of life questionnaire.
Patients’ assessments of global symptoms at study
endpoint relative to prestudy levels are shown for each
group.16
Apigenin vs IgE
Apigenin is another flavonoid constituent of perilla
with anti-allergic activity. Studies have found that it
blocks the expression of the receptor on basophil cells
that IgE antibodies bind to, thereby preventing IgE
from stimulating these cells to release proinflammatory mediators.17 Dietary apigenin also
decreases serum levels of IgE in mice.18 Another study
found that mice fed apigenin for 3 weeks and
sensitized to develop an allergic reaction had
suppressed levels of IgE, while other antibody levels
were unaffected. Apigenin also blocked the production
of IL-4.19
An Effective Way to Scratch the Allergy Itch
Overall, Perilla frutescens is full of anti-allergic
potential. By blocking the production and release of
pro-inflammatory mediators, reducing levels of IgE,
and reducing the infiltration of inflammatory cells,
luteolin, rosmarinic acid and apigenin help prevent the
misery of a full-blown allergic reaction.
Volume 3 Issue 5
References
1. Ueda H, Yamazaki C and Yamazaki M. Luteolin as an anti-inflammatory
and 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 of
oral treatment of Perilla frutescens and its constituents on type-I allergy in
mice. 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 in
rats by Perilla frutescens. Immunopharmacol Immunotoxicol
2000;22(3);489-500.
4. Oryza oil&fat chemical co., LTD. Anti-allergic effects of perilla seed
extract in patient with allergy. 1997.
5. Makino T, Furuta Y, Wakushima H, Fujii H, Saito K and Kano Y. Antiallergic effect of Perilla frutescens and its active constituents. Phytotherapy
Research. 2004;17:240-243.
6. Imaoka K, Inoue S, Takahashi T, Ojima Y. 1993. Effect of Perilla
frutescens extract on anti-DNP IgE antibody production in mice. Jpn J
Allergol 42: 74–80.
7. Mosmann TR and Coffman RL. Heterogeneity of cytokine secretion
patterns 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 seed
oil supplementation on leukotriene generation by leukocytes in patients with
asthma associated with lipometabolism. Int Arch Allergy Immunol. 2000
Jun;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-mediated
mediator release from human cultured mast cells. Clinical and Experimental
Allergy. 2000;30:501-508.
11. Theoharides TC, Kempuraj D and Iliopoulou BP. Mast cells, T cells, and
inhibition by luteolin: implications for the pathogenesis and treatment of
multiple 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, Yoshikawa
M, Maezaki N, Tanaka T, Kawase I, Tanaka T. Luteolin, a flavonoid, inhibits
AP-1 activation by basophils. Biochemical and Biophysical Research
Communications. 2006;340:1-7.
13. Kindt TJ, Goldby RA and Osborne BA. Kuby Immunology 6th Ed. WH
Freeman and Company. NY 2007.
14. Sanbongi C, Takano H, Osakabe N, Sasa N, Natsume M, Yanagisawa
R, Inoue K-I, Sadakane K, Icinose T and Yoshikawa T. Rosmarinic acid in
perilla extract inhibits allergic inflammation induced by mite allergen, in a
mouse model. Clin Exp Allergy. 2004;34:971-977.
15. Das M, Ram A and Ghosh B. Luteolin alleviates bronchoconstriction and
airway hyperreactivity in ovalbumin sensitized mice. Inflammation Research.
2003;52:101-106.
16. Takano H, Osakabe N, Sanbongi C, Yanagisawa R, Inoue K-I, Yasuda
A, Natsume M, Baba S, Ichiishi E-I and Yoshikawa T. Extract of Perilla
frutescens 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 expression
of the high-affinity IgE receptor Fc‐RI in human basophilic KU812 cells. J
Agric 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 in
C57BL/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 Th2
cytokines in OVA-immunized BALB/c mice. European Journal of Nutrition.
2007;46:257-263.
ADVANCES in orthomolecular research
19
Q&A
AllerControl™
At what age can children start using AllerControl™?
Allercontrol™ is a multi-ingredient formula that
contains Perilla seed extract, Butterbur Extract,
Quercetin, Luteolin, Rosmarinic acid and Mangiferin.
Although most of the ingredients have a long history of
use as spices or food, some of the ingredients found in
the formula have not been clinically tested in young
children. There is no reason to expect any side effects
or adverse reaction for AllerControl™ but it is best to
avoid using the product without medical supervision in
children younger than 12 years of age.
Is AllerControl™ effective for asthmatics?
Absolutely, several of the ingredients have been shown
to improve the symptoms associated with asthma. In
one study, supplementation with Butterbur, one of the
ingredients found in AllerControl™ was shown to
improve several of the symptoms related to asthma
and also decreased the frequency and duration of
attacks. Furthermore, 40 percent of the patients who
were using medication to help control their symptoms
were able to reduce their intake of those medications
after using butterbur for two months.15
Probiotics
Can probiotics also decrease the risk of allergies in
children?
The list of health benefits associated with the use of
probiotics never ceases to grow. Over the past
decades, research on probiotics has focused on their
beneficial effects on the immune system. Trials have
demonstrated that probiotics improve the function of
the gut barrier, help to regulate the immune system
and reduce the inflammatory response.16 The initial
trials looking into the link between probiotic
supplementation and the risk of atopic eczema were
20
very encouraging and showed that infants who had
received probiotics were less likely to develop eczema
than children who had received the placebo.17
However, such results have not been confirmed in
follow up trials and no benefits were seen for other
conditions related to the immune system such as
allergic rhinitis and asthma.18,19
Quercetin
I am allergic to citrus, can I use quercetin?
Although most quercetin supplements available to
Canadians are extracted from citrus, AOR is proud to
offer a quercetin product that is derived from the seeds
of Dimorphandra mollis and therefore, citrus free.
Q & A References
1. Health Canada, Vitamin D Monograph, August 2007
2. NIH, Office of Dietary Supplements, Dietary Supplement Fact Sheet:
Vitamin D
3. Institute of Medicine, Food and Nutrition Board. Dietary Reference
Intakes: 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. Vitamin
D and its major metabolites: serum levels after graded oral dosing in
healthy men. Osteoporos Int 1998;8:222–30.
5. Heaney RP, DaviesKM,Chen TC, HolickMF,Barger-Lux MJ.Human
serum 25-hydroxycholecalciferol response to extended oral dosing
with cholecalciferol. Am J Clin Nutr 2003;77:204 –10.
6. Holick MF. Vitamin D. The underappreciated D-lightful hormone that
is important for skeletal and cellular health. Curr Op Endocrinol Diabetes
2002;9:87–98.
7. Centers for Disease Control and Prevention. Breastfeeding. Vitamin D
Supplementation, American Academy of Pediatrics, Nov 2008
8. Health Canada. Vitamin D supplementation for breastfed infants – 2004
Health Canada recommendation.
9. Canadian Paediatric Society, First Nations and Inuit Health Committee
[Principal author: J Godel]. Vitamin D supplementation in northern Native
communities. Paediatr Child Health 2002;7:459-63.
10. Hypponen E, Laara E, Reunanen A et al. Intake of vitamin D and risk of
type 1 diabetes: a birth cohort study. Lancet 2001; 358:1500-3.
11. Brekke HK, Ludvigsson J. Vitamin D supplementation and diabetesrelated autoimmunity in the ABIS study. Pediatr Diabetes. 2007
Feb;8(1):11-4.
12. Annesi-Maesano I. Perinatal events, vitamin D, and the development of
allergy. Pediatr Res 2002; 52:3-5
13. Hypponen E, Laara E, Reunanen A et al. Intake of vitamin D and risk of
type 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 Clin
Endocrinol Metab. 2008 Jul;93(7):2716-21.
15. Danesch UC. Petasites hybridus (Butterbur root) extract in the treatment
of asthma--an open trial. Altern Med Rev. 2004 Mar;9(1):54-62.
16. Kalliomäki MA, Isolauri E. Probiotics and down-regulation of the allergic
response. Immunol Allergy Clin North Am. 2004 Nov;24(4):739-52, viii.
17. Kalliomäki M, Salminen S, Poussa T, Arvilommi H, Isolauri E. Probiotics
and prevention of atopic disease: 4-year follow-up of a randomised
placebo-controlled trial. Lancet. 2003 May 31;361(9372):1869-71.
18. Kopp MV, Salfeld P. Probiotics and prevention of allergic disease. Curr
Opin Clin Nutr Metab Care. 2009 May;12(3):298-303.
19. Niers LE, Rijkers G, Knol EF, Meijer Y, Hoekstra MO. Probiotics for
prevention of atopic disease? Lancet. 2003 Aug 9;362(9382):496; author
reply 496.
ADVANCES in orthomolecular research
Volume 3 Issue 5
Butterbur:
Beyond Migraines
Introduction
Butterbur (genus Petasites) is a Eurasian plant that
grows mainly along the damp, marsh areas and
riverbanks of Europe and Northern Asia. Upon
ripening, it bears a strong resemblance to rhubarb,
and it has been utilized as part of the folk medicine of
various Eurasian cultures for at least two millennia.
One of its earliest recorded uses was by the Greek
physician Dioscorides, who prescribed using its
grinded leaves to treat skin ulcers in the first century
AD. In northern Europe during the Middle Ages, it was
used to treat the feverish symptoms of the infamous
Black Death, the ominous name given to the plague
that wiped out a third of the continent. In the 17th
century, butterbur’s use was also noted for treating
coughs and asthma. Since then, it has consolidated a
reputation as an anti-spasmodic and an analgesic,
with the latter gaining particular acceptance and
recognition in the treatment of migraines. The former,
however, holds promise for the treatment of allergies.
In fact, butterbur has been clinically tested among
patients with seasonal allergic rhinitis, bronchitis and
asthma. This research has led to a renewed interest in
butterbur, particularly in the Far East and Japan (where
pollinosis affects 10% of the population), as a
preventative treatment for common allergies.
How Does Butterbur Work?
Researchers in Japan have identified within Japanese
Butterbur (Petasites Japonicus) specific sesquiterpenes
– biologically active fractions – with demonstrated
anti-allergenic activity.1 The full biological activity of
Japanese butterbur is actually quite diverse, with antioxidative2, anti-inflammatory3, and vasodilative4
capabilities (among others) being well documented.
Volume 3 Issue 5
While all of these activities contribute indirectly to the
alleviation of allergy symptoms, there are some very
specific parameters for measuring the inhibition of the
allergic response itself, as well as identifying which
sesquiterpenes within butterbur affect those
parameters.
A primary parameter of the allergic response is
degranulation. This happens when the body of an
allergy-prone individual produces excess IgE, or
Immunoglobin E (a type of antibody meant to protect
against infections), which in turn attaches itself to mast
cells, causing degranulation. Degranulation is the
release of granules from the mast cells in an immune
response process called exocytosis. Granules are
cytotoxic, antimicrobial molecules whose release is
accompanied by a corresponding synthesis and
release of histamine, cytokines, and leukotrienes, all of
which launch an inflammatory cascade leading to the
standard symptoms of an allergic reaction (mucous
buildup, runny nose, irritated eyes, etc). Anaphylaxis
represents the most severe form of such a reaction.
Defusing Degranulation
Japanese scientists have identified those biologically
active sesquiterpenes within butterbur that are most
effective in their inhibition of degranulation. The most
potent is a particularly novel sesquiterpine glycoside
sulfate called fukinolic acid.5 Fukinolic acid’s antidegranulation effects have been evaluated in both invitro and in-vivo (animal) studies by measuring its
impact on beta-hexosaminidase, an antigendependent enzyme central to degranulation. These
studies reveal that while many fractions of Japanese
Butterbur (Petasites Japonicus) suppress this enzyme,
fukinolic acid does so at a rate that is more than twice
as effective as butterbur extract as a whole.6 It is
important to appreciate that degranulation from the
mast cells is an early and primary initiator of the
allergic reaction (after elevated IgE production) and
precedes the release of histamines – which are the
point of intervention for most prescribed anti-allergy
medications. This helps to define the role of butterbur
extract as a natural remedy, which (in general) differ
from their pharmaceutical counterparts by eliciting
their effects in a manner that is more fundamentally
preventative than interventionist.
The biological course of events that follow
degranulation is a familiar one: inflammation caused
by an increase in leukotriene and TNF-alpha
production, leading to the previously mentioned and
all too-familiar symptoms of an allergic reaction.
ADVANCES in orthomolecular research
21
who were using asthma medications at the beginning
of the study had reduced the intake of these
medications by the study’s end.9 In yet another study,
this one conducted in 2002 with 131 seasonal allergic
rhinitis patients as subjects, butterbur extract was
found to be as effective as the commonly prescribed
antihistamine cetirizine in the treatment of symptoms
associated with seasonal allergic rhinitis. In addition,
about two-thirds of those receiving cetirizine reported
symptoms of drowsiness and fatigue (in spite of the
fact that cetirizine is not considered a sedative
antihistamine), while no such sedative effects were
reported in the butterbur group.10
In Conclusion
Japanese butterbur extract has also been shown to
inhibit both leukotriene release and TNF-alpha
production over and above its concurrent inhibition of
degranulation.7
Real World Results
The clinical studies that have examined butterbur’s
effectiveness in alleviating the symptoms of allergic
rhinitis, asthma and bronchitis have been known for
about a decade now. A 1998 Polish study examined
the effect of butterbur on the lung ventilation and
bronchial reactivity in chronic obstructive bronchitis or
asthma patients. Some patients reported ‘significant
decreases’ in bronchial reactivity within just two hours
of receiving an oral dose of 600 mg of butterbur
extract. Some patients were also given corticosteroids
to reduce severity, yet those patients given butterbur
extract without concurrent corticosteroid treatment
experienced the most pronounced improvements. This
led the scientists to conclude that “Petasites might be
helpful in improving lung ventilation in patients with
asthma or chronic obstructive bronchitis.”8 Suffice to
say, the symptomatic overlap between these conditions
and common allergies is significant.
In a more recent 2004 trial in Germany, 80 subjects
diagnosed with asthma (including 16 children) were
given butterbur extract in a prospective, nonrandomized, open trial. The study permitted the
concomitant use of asthma medications. At the end of
the study, the number, duration, and severity of asthma
attacks decreased, while pulmonary functions
improved. Furthermore, more than 40% of the subjects
22
Extracts of the genus Petasites have been associated
with reports of the potential for hepatic damage and
carcinogenic activity due to the plant’s pyrrolizidine
alkaloids. However, commercial extracts are available
that have these alkaloids removed, especially in
Europe where the pharmaceutical giant Weber &
Weber ® have a patented procedure to remove such
alkaloids from their own finished butterbur extract
known as Petadolex®. The commercially available
Japanese subspecies of butterbur (Petasites japonicus)
do not contain these alkaloids at all.
References
1 Tobinaga S, et al. Anti-histaminic and anti-allergic principles of Petasites
japonicus Maxim. Chem Pharm Bull (Tokyo) 1983 Feb;31(2):745-8.
2 Watanabe S, et al. Proceeding of general meeting of Japan Society for
Bioscience, Biotechnology, and Agrochemistry in 2004. Pp. 87 (2004).
3 Lee DK, et al. Butterbur, an herbal remedy, confers complementary antiinflammatory 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, and
fukinolic acid in cimicifuga rhizome. Biol Pharm Bull. 1998
Nov;21(11):1163-8.
5 Yoshikawa M, et al. Medicinal Foodstuffs. XXXII. Novel Sesquiterpene
Glycoside Sulfate, Fukinoside A, with Antiallergic Activity from Japanese
Butterbur (Petasites Japonicus).
6 Shimoda H, et al. Anti type I allergic property of Japanese butterbur
extract and its mast cell degranulation inhibitory ingredients. J AgricFood
Chem. 2006 Apr 19;54(8):2915-20.
7 Ibid.
8 Ziolo G, Samochowiec L. “Study on clinical properties and mechanism of
action 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 treatment
of asthma--an open trial.” Altern Med Rev. 2004 Mar;9(1):54-62.
10 Schapowal A. “On behalf of Petasites Study Group: Randomised
controlled trial of butterbur and ceterizine for treating seasonal allergic
rhinitis.” BMJ 2002;324:144–146.What Is Mangifera indica L. Extract ?
ADVANCES in orthomolecular research
Volume 3 Issue 5
Anti-Allergen
Therapy from the
Mango Tree
What Is: Mangifera indica L. Extract ?
The mango tree has been a rich source of medicinal
folk remedies in many traditional societies. One part
of the mango tree, namely the stem bark (known as
Mangifera indica L.) has been used by such societies
for the treatment of a variety of ailments ranging from
anaemia to scabies to diarrhea.
Mangifera indica extract contains an impressive array
of phytonutrients, of which mangiferin (a
glucosylxanthone) is the largest as well as the greatest
single source of biological activity. Other constitiuents
of Mangifera indica extract include gallates, catechins,
epicatechins, benzoic acid, triterpenes, phytosterols,
fatty acids and trace amounts of vitamins and
minerals. This diverse profile is reflected in the
biological activity of Mangifera indica, which in both
in-vitro and in-vivo studies has demonstrated
antioxidant, analgesic, anti-inflammatory and
immunomodulating properties. From such a broad
spectrum of benefits, Mangifera indica extract seems
to have found a practical application as an antiallergen.
The Allergic Reaction and Mangifera Indica’s Role
Within It
The aforementioned spectrum of pharmacokinetic
activity, aside from the indication of the potency and
potential of its source, also relates – to varying degrees
– to how the body deals with an allergy. Antioxidants,
for example, can inhibit the generation of reactive
oxygen species (ROS-free radicals that can exacerbate
an allergic reaction).1 Analgesics can provide relief
from the pain and discomfort caused by allergic
reactions2, while the importance of antiinflammatories cannot be overstated. This is because
Volume 3 Issue 5
an allergic reaction is essentially an inflammatory
response, with cytokines such as TNFα, IL-1, IL-4, IL12, IL-13, IL-15, and IL-16 playing highly significant
Antioxidants,
analgesics
and
antiroles.3
inflammatories all serve to strengthen the immune
system as a whole.
Again, in the face of a spectrum of biological activity
so broad that the risk of descending into ambiguity is
very real, how does Mangifera indica extract
specifically elicit an anti-allergy effect?
A Proactive Approach: IgE
IgE, or immunoglobulin E, is a type of antibody meant
to protect against infections. However, allergy sufferers
tend to produce IgE in excessive amounts, which is in
response to their IgE recognizing a common allergen
(i.e. pollens) as a threat. The IgE levels of non-allergy
sufferers are much lower because their IgE only
recognizes parasites in such a manner. IgE then
attaches itself to mast cells, and when it does this in
excessive amounts, the mast cells respond by
granulating and releasing excessive amounts of
histamines and cytokines. Very succinctly, the former
leads to increased mucous production and the latter to
inflammation, resulting in the most common
symptoms of an allergic reaction, namely congestion,
eye irritation, skin rashes and lung spasms, among
others.
Supplements, unlike drugs, are more often than not
proactive rather than reactive. They do not attack
afflictions so much as they strengthen the defenses
against them. Such a simplistic interpretation is more
of a principle than a rule, with a more concise
definition being that supplements elicit their effects on
a more preliminary metabolic level than their
pharmaceutical counterparts. In the case of allergic
reactions, the standard pharmaceutical route of
intervention is anti-histamines, which as their name
implies, inhibits the action of histamine - usually by
targeting the H1 histamine receptor.
Mangifera Indica: IgE Inhibitor
Since excessive IgE activity is a root cause of allergic
reactions, inhibiting its production is a proactive way of
limiting the frequency and effect of such reactions. This
precedes the actions of standard allergy medications
(anti-histamines) by one key biological step, since the
adhesion of excessive IgE to the mast cells is what
leads to the release of histamine in the first place, not
to mention cytokines with subsequent inflammation and
associated symptoms (irritated eyes, congestion, etc.).
ADVANCES in orthomolecular research
23
In-vivo studies have demonstrated that Mangifera
Indica extract (standardized for 10% mangiferin) can
indeed inhibit IgE production by more than 22%.4
Mangiferin as an isolate has also been studied, and it
was determined to lower IgE production by nearly
52%.5 These studies – conducted on laboratory
mice–determined (predictably) that histamine release
was also inhibited by both Mangifera indica and
mangiferin supplementation, theoretically due to the
precursory effect of lower IgE production. Ironically,
however, Mangifera indica extract was slightly more
effective than mangiferin in lowering both histamine
levels and histamine-induced skin reactions.
Mangifera indica lowered the latter by 66%, compared
with 63% for mangiferin.6 Similar results were also
seen when the two compounds were tested for their
ability to inhibit the most severe allergic reactions of
anaphylaxis.7
It must be noted that an extract offering advantages
over its isolated main medicinal ingredient is nothing
new. This has been seen with whole extracts and their
respective isolates from grape seed, green tea,
curcumin, and numerous others. While conclusive
evidence is scarce, it would seem that whole extracts
can offer a broader spectrum of support while isolates
can provide a more concentrated potency within
specifically set targets. In the case of Mangifera indica
and mangiferin, it would appear that the most effective
compromise is a Mangifera indica. extract
standardized to a degree higher than 10% mangiferin.
Other Benefits of Mangifera Indica
Like many natural ingredients, the beneficial
applications of Mangifera indica extract are relatively
widespread and cannot always be neatly categorized.
One recent study indicates that the extract may also
possess the ability to alleviate iron-induced oxidative
damage by increasing iron excretion from the liver.8 It
does this in part due to an electrochemical capacity to
bind to iron (as a chelator), and while this protects
against iron-overload, Mangifera indica also acts
synergistically with iron for an enhanced anti-oxidant
effect,
particularly
against
2,2-diphenyl-1picrylhydrazyl (DPPH) and superoxide free radicals.9
Mangifera indica also protects against lipid
peroxidation and increases glutathione levels, leading
researchers to suggest that it may provide
‘therapeutically useful effects in iron overload
diseases.’10
References
1 Szlagatys-Sidorkiewicz A, et al. Reactive oxygen species and antioxidative
barrier in asthma. Pneumonol Alergol Pol. 2007;75(2):158-62.
2 George RB, et al. Brief Report: A randomized controlled trial of SyneraTM
versus lidocaine for epidural needle insertion in labouring parturients:
[Compte-rendu court : Une etude randomisee controlee du SyneraTM vs
lidocaine dans l'insertion de l'aiguille peridurale chez les parturientes en
travail]. 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. 389
7 Ibid. P. 388
8 Pardo-Andreu GL, et al. Protective effects of Mangifera indica L extract
(Vimang), and its major component mangiferin, on iron-induced oxidative
damage 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 oxidative
damage to rat serum and liver. Pharmacol Res. 2008 Jan;57(1):79-86.
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Volume 3 Issue 5
The Role of
Vitamin D in
Immunity
Vitamin D is well-known for the important role it plays
in calcium utilization and the proper development of
bones. For example, most people are aware that
vitamin D deficiency in young children can lead to
rickets, a condition where the bones become weak
and soft.1 More recently, however, vitamin D has
gained attention for a plethora of other important
benefits, and low levels of vitamin D have now been
linked to increased hypertension, increased
autoimmune diseases, an increased risk for various
forms of cancer including breast, prostate and skin,
chronic pain, premenstrual syndrome (PMS), poor
immune system, diabetes, seasonally affective
disorders and even an increased risk of mortality by all
causes.2-7
Immune System Modulation
Many of the benefits of vitamin D relate to the very
important role the vitamin plays in the normal
functioning of the immune system. The immune system
is made up of a number of different types of cells that
work together to protect the body from threats.
Dendritic cells are important for activating the rest of
the immune system, and are specialized in antigen
presentation. 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 then
stimulate other cells including killer T-cells, which
attack and kill cells infected by the invader, and Bcells, which produce antibodies that identify and attach
to the invader, marking it for elimination.
This is an extremely complicated process, and requires
a delicate balance for proper functioning. The immune
system is critical for protecting our bodies from foreign
pathogens and invaders. However, it must also be able
to distinguish between a dangerous invader and
harmless food proteins, friendly bacteria and cells of
the body. In other words, the immune system must
Volume 3 Issue 5
develop “tolerance” for these types of proteins and
cells. When tolerance fails, an inappropriate immune
response occurs – resulting in allergies, where the
immune system reacts to normally harmless molecules
as if they were dangerous invaders, or even
autoimmunity, where the body attacks its own cells.
This delicate balance is mostly established by the
helper T-cells, which are responsible for the
moderation and regulation of the immune response.
There are two types of helper T-cells– Th1 and Th2.
Autoimmunity seems to be related to an
overabundance of Th1, whereas allergies have been
linked to an overactive Th2 response.8 The active
metabolite of vitamin D3, 1,25(OH)2D3, has been
shown to affect both the Th1 and Th2 responses, and
plays a very important role in immune system
regulation.
The Regulatory Role of Vitamin D
Firstly, vitamin D inhibits the formation of dendritic
cells, which in turn reduces the activation of T-cells,
and the T-cell mediated immune response.8,9 Vitamin
D also acts on T-cells themselves, regulating the
differentiation and activation of Th1 and Th2. Studies
have shown that vitamin D3 down-regulates Th1,
whose expression is related to autoimmunity. Vitamin
D’s actions on Th2 are less certain, with some studies
showing increased Th2 function and others showing
suppressed function.8,9 Vitamin D has also been shown
to increase the production of regulatory T-cells, which
play a very important role in self-tolerance, and
therefore in the prevention of autoimmunity.8
In addition to the regulation of T-cells, vitamin D also
has an effect on the actions of B-cells. It seems to act
on them in two primary ways; first, it stimulates
increased production of interleukin (IL)-10, which
inhibits antigen presentation by dendritic cells and
prevents T-cell activation, and second, it inhibits the
production of IgE antibodies, the primary antibody
associated with the allergic response.10
Overall, vitamin D is critical for the regulation and
proper functioning of the immune system, and may act
to prevent inappropriate immune system responses
and help to restore proper immune system balance.
Innate Immunity
Beyond its role in immune system modulation, vitamin
D is also critically involved in the body’s innate
immune response. Specifically, vitamin D has been
shown to activate important antibacterial proteins
called defensin and cathelicidin.8 Researchers have
related these actions to numerous beneficial effects,
including a reduction in the risk of skin infection in
individuals with atopic dermatitis11, a reduced risk of
placental infections during pregnancy12, and even a
reduction in the occurrence of the common cold.13
ADVANCES in orthomolecular research
25
Figure 1. Asthma is a chronic inflammatory disease of the airways that is
often associated with allergies. Asthma affects 8.4% of Canadians and 12%
of Canadian children (Statistics Canada, 2001).
The Link to Allergies and Asthma
Recent research on vitamin D has established a clear
link between vitamin D and autoimmune disorders,
and with self-tolerance. For example, low vitamin D
levels have been related to the occurrence of
autoimmune diseases including multiple sclerosis (MS)
and inflammatory bowel disease (IBD).8,14,15
Furthermore, studies in mice have suggested that
treatment with vitamin D could be beneficial for a wide
range of autoimmune diseases including MS, IBD and
rheumatoid arthritis.8
With vitamin D playing such a major role in the
function of the human immune system, it seems
evident that there must also be some link to allergies,
and indeed this seems to be the case. However, the
role of vitamin D in the allergic response has not yet
been fully clarified. For example, one study in mice has
suggested potentially dual influences of vitamin D on
allergies, with administration of active vitamin D
resulting in increased T-cell activation and cytokine
production in the mice, while at the same time
reducing airway eosinophilia – a key pathological
feature of asthma.14
Studies in humans have also demonstrated an
important link between vitamin D levels and the
development of asthma. Two recently published
studies have reported that children under the age of 5,
whose mothers had higher vitamin D intakes during
pregnancy, had a reduced incidence of wheezing
symptoms.17,18 In fact, it has been demonstrated that
higher vitamin D intakes during pregnancy may
reduce the risk of childhood asthma by as much as
40%, and suggest a dose of 2000 IU daily during
pregnancy to achieve adequate levels.19 In yet another
study involving 616 asthmatic children, low serum
vitamin D levels were associated with increased levels
of well-known markers of asthma and allergy severity,
including IgE and eosinophil levels.20
26
The association between asthma and vitamin D is also
supported by genetic studies, which have revealed
variations in the vitamin D receptor in asthmatic
individuals.21,22 Furthermore, research has indicated
that 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 the
other 14901 adults, found that higher vitamin D intake
is associated with improved lung function.24,25
Another interesting link between vitamin D and
allergies was established by a group of American
researchers examining the prevalence of EpiPen
prescriptions across the United States.26 EpiPens are
autoinjectors that administer epinephrine as an
emergency treatment for severe and potentially deadly
allergic reactions called anaphylaxis. The study
revealed a strong north-south gradient in EpiPen
prescriptions, with northern states having a
significantly higher number of prescriptions than
southern states. The Researchers inferred that this
gradient is related to sunshine exposure, and thus
vitamin D levels.26
Figure 2. Regional Difference in EpiPen prescriptions per 1000 persons.26
How it works
The mechanism by which vitamin D influences
allergies and asthma is quite complex. Vitamin D has
been shown to influence IgE levels, which is highly
significant as IgE is the main antibody involved in the
initiation of the allergic response. There have,
however, been some conflicting results regarding
vitamin D’s influence on IgE. A recent study conducted
in Europe offers some potential insight into this
conflict. Scientists in Europe and the UK examined
both the IgE and serum vitamin D levels of 7288
individuals and found that those with both extremely
low (< 25 nmol/L) and extremely high (> 135 nmol/L)
vitamin D levels in the blood expressed elevated IgE
levels, and thus a higher potential for allergies.28 These
results indicate the importance of balanced vitamin D
ADVANCES in orthomolecular research
Volume 3 Issue 5
levels, and are consistent with other studies suggesting
a lower threshold of 75-100 nmo/L for serum vitamin
D levels.28
More and more evidence suggests, however, that the
most important role of vitamin D may be during early
development, especially before birth.19 As mentioned
above, vitamin D’s effects on Th2 are inconsistent, with
some studies showing upregulation of Th2 cytokines
associated with allergies, and others showing their
suppression.8,9 Researchers have suggested that these
seemingly contradictory effects may relate to the
timing 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 also
to increase the secretion of IL-10. Both of these actions
have been shown to benefit individuals with steroidresistant asthma – a well-established Th2 disorder.27
Achieving Balance
Vitamin D3 has wide-ranging effects on the immune
system. Due to its actions on both Th1 and Th2
mediated immune responses, vitamin D deficiency has
been purported as a potential unifying factor in the
rise of the prevalence of both Th1 disorders
(autoimmunity) and Th2 disorders (allergies) over a
similar time span.19 Vitamin D may be of particularly
critical importance at early stages of development to
ensure proper immune function later in life. It has
been hypothesized that vitamin D is essential for
normal Treg development, and in turn the suppression
of improper Th1 and Th2 responses and a more
balanced immune response.19 Although more research
and clinical trials are required, it is clear that the
“Sunshine” vitamin is an essential component of good
health and in the development and maintenance of a
healthy, balanced immune system.
References:
1 Ward LM, Gaboury I, Ladhani M, Zlotkin S. Vitamin D-deficiency rickets
among children in Canada. CMAJ. 2007 Jun 28.
2 Melamed ML, Michos ED, Post W, Astor B. 25-Hydroxyvitamin D Levels
and 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, Erik
Ingelsson, Katherine Lanier, Emelia J. Benjamin, Ralph B. DAgostino, Myles
Wolf and Ramachandran S. Vasan. Vitamin D Deficiency and Risk of
Cardiovascular 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 a
randomized trial. Am J Clin Nutr. 2007 Jun;85(6):1586-91.
Volume 3 Issue 5
5 Bailey R, Cooper JD, Zeitels L, Smyth DJ, Yang JH, Walker NM, Hyppönen
E, Dunger DB, Ramos-Lopez E, Badenhoop K, Nejentsev S, Todd JA.
Association of the vitamin D metabolism gene CYP27B1 with type 1
diabetes. Diabetes. 2007 Jul 2.
6 Svoren BM, Volkenning LK, Wood JR, Laffel LMB. Significant Vitamin D
Deficiency 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 British
population: evidence from a cross-sectional population survey. Ann Rheum
Dis. 2008; Early online publication
8 Hyppönen E, Berry DJ, Wjst M and Power C. Serum 25-hydroxyvitamin D
and IgE – a significant but non-linear relationship. 2009. Allergy. 64: 613-620.
9 Cantorna MT and Mahon BD. Mounting evidence for vitamin D as an
environmental factor affecting autoimmune disease prevalence. Exp Biol
Med. 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 production
in human B-cells. Eur J Immunol. 2008. 38: 2210-2218.
11. Hata TR et al. Administration of oral vitamin D induces cathelicidin
production 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 via
an intracrine pathway. Biology of Reproduction. Published online November
12, 2008.
13 Ginde AA, Mansbach JM, Camargo CA. Association between serum 25hydroxyvitamin D level and upper respiratory tract infection in the third
national health and nutrition examination survey. Arch Intern Med. 2009;
169(4): 384-390.
14 Ramagopalan SV et al. Expression of the Multiple Sclerosis-Asscoiated
MHC Class II Allele of HLA-DRB1*1501 is Regulated by Vitamin D. PLoS
Genetics. 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 of
vitamin D-induced alteration of TH1/TH2 cytokine expression: enhancing
IgE production and decreasing airway eosinophilia in murine allergic airway
disease. J Allergy Clin Immunol 2003; 112:585–592.
17 Devereux G, Litonjua AA, Turner SW, Craig LC, McNeill G, Martindale S
et al. Maternal vitamin D intake during pregnancy and early childhood
wheezing. Am J Clin Nutr 2007;85: 853–859.
18 Camargo CA Jr, Rifas-Shiman SL, Litonjua AA, Rich-Edwards JW, Weiss
ST, Gold DR et al. Maternal intake of vitamin D during pregnancy and risk
of recurrent wheeze in children at 3 y of age. Am J Clin Nutr
2007;85:788–795.
19 Litonjua AA and Weiss ST. Is vitamin D deficiency to blame for the
asthma 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. Serum
Vitamin D Levels and Markers of Severity of Childhood Asthma in Costa
Rica. AJRCCM. 2009. doi:10.1164/rccm.200808-1361OC
21 Poon AH, Laprise C, Lemire M, Montpetit A, Sinnett D, Schurr E, Hudson
TJ. Association of vitamin D receptor genetic variants with susceptibility to
asthma 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 and
adult 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: immunogold
detection of VDR expression in pneumocytes type II cells and effect on
fructose 1,6 bisphosphatase. J Steroid Biochem Mol Biol 2004;89-90:93-7
24 Burns JS, Dockery DW, Speizer FE. Low levels of dietary vitamin D intake
and pulmonary function in adolescents. Proc Am Thoracic Soc
2006;3:A526.
25 Black PN, Scragg R. Relationship between serum 25-hydroxyvitamin D
and pulmonary function in the third national health and nutrition
examination survey. Chest 2005;128:3792-8.
26 Camargo CA, Clark S, Kaplan MS, Lieberman P, Wood RA. Regional
differences in EpiPen prescriptions in the United States: The potential role of
vitamin 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 in
glucocorticoid-resistant asthma patients. J Clin Invest 2006;116:146-55.
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27
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Alimentin
Unique blend of enzymes, anti‑inflammatory Boswellia, adaptogenic Withania and immune modulating
Vitamin D to provide relief for IBD and Celiac disease sufferers.
Butyrate Enema
Provides butyrate in a convenient applicator to feed the colonocytes, reducing cancer risk and controlling
IBD associated inflammation.
D‑Tox‑2
Supports phase 2 detoxification, providing protection against cancer, cardiovascular disease and
hypertension; features isothiocyanates from SGS and wasabi.
Fem‑Adapt
Advanced combination of flax lignans, soy isoflavonoids, and botanicals that work to reduce menopausal
symptoms, as well as provide protection against cardiovascular disease, osteoporosis and cancer.
Infla‑Min
Botanical anti‑inflammation formula for osteoarthritis associated joint pain, featuring a highly bioavailable
nano‑delivery system.
Lycopene 30mg
A higher dose of the antioxidant carotenoid lycopene. Supports prostate health and helps protect against
prostate cancer and atherosclerosis.
AORPro.ca
MecoFolate
Advanced forms of folate and vitamin B12 in higher dosages to reduce homocysteine and support
cardiovascular and neurological health.
NeuroPro
Unique formulation of several well researched nutrients for the treatment of autistic spectrum disorders in a
convenient powdered form for easy ingestion.
ProBiotic 3
Well researched blend of probiotic microorganisms, featuring B.mesentericus that supports the growth of two
human strains resulting in higher numbers surviving and taking up residence in the gastrointestinal tract.
ProCardio
Cardiovascular supporting combination of botanicals, soy isoflavones and CoQ10, that increases cardiac
performance and contributes to a healthier lipoprotein balance.
ProChondria
Unique combination of nutrients and botanicals designed to enhance mitochondrial activity and thus is
beneficial in most disease processes.
ProGastrin
Provides protection against gastric ulcers by increasing gastric lining thickness, inhibiting H.pylori growth,
and maintaining health stomach acidity.
ProMethyl
Potent methylation promoting blend of B vitamins and TMG to lower homocysteine levels, protecting
against cardiovascular disease, inflammation, and osteoporosis as well as being useful in the treatment of
autoimmune disease.
Prostectin
Advanced anti‑prostatic formula including ingredients shown to lower PSA levels, relieve BPH symptoms
and provide protection against prostate cancer.
VascuPress
Blood pressure lowering blend featuring several key botanicals known to prevent ischemic damage and
protect vasculature from hypertensive damage.