The biodiversity hypothesis and allergic disease: world allergy organization position statement.

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by  Haahtela, Tari

Haahtelaetal.WorldAllergyOrganizationJournal2013,6:3 journal
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POSITION ARTICLE AND GUIDELINES Open Access
The biodiversity hypothesis and allergic disease:
world allergy organization position statement
Tari Haahtela1*, Stephen Holgate2, Ruby Pawankar3, Cezmi A Akdis4, Suwat Benjaponpitak5, Luis Caraballo6,
Jeffrey Demain7, Jay Portnoy8, Leena von Hertzen1, and WAO Special Committee on Climate Change
and Biodiversity
Abstract
Biodiversity loss and climate change secondary to human activities are now being associated with various adverse
health effects. However, less attention is being paid to the effects ofbiodiversity loss onenvironmental and
commensal (indigenous) microbiotas. Metagenomic and other studies of healthy and diseased individuals reveal
that reduced biodiversity and alterations in the composition of the gutand skin microbiota are associated with
various inflammatoryconditions, including asthma, allergic and inflammatory bowel diseases(IBD), type1 diabetes,
and obesity. Altered indigenous microbiota and the general microbial deprivation characterizing the lifestyle of
urban peoplein affluent countries appear to be risk factors for immune dysregulation and impaired tolerance. The
risk is further enhanced by physical inactivity and a westerndiet poor in fresh fruit and vegetables, which may act
insynergy with dysbiosis of thegut flora. Studies of immigrants moving from non-affluent to affluentregions
indicate that tolerance mechanisms can rapidly become impaired inmicrobe-poor environments. The data on
microbial deprivation and immune dysfunction as they relate to biodiversity loss are evaluated inthis Statement of
World Allergy Organization(WAO). We propose that biodiversity, the variability among living organismsfrom all
sources are closelyrelated, atboth the macro- and micro-levels. Loss ofthemacrodiversity is associated with
shrinking ofthe microdiversity,which is associated with alterations of theindigenous microbiota. Data on
behavioural means to induce tolerance are outlined and a proposal made for a Global Allergy Plan to prevent and
reduce the global allergy burden for affected individuals and thesocieties inwhich they live.
Keywords: Allergy plan, Biodiversity, Civilizationdisease,Epigenetics, Immunedysfunction,Microbiota, Microbiome,
Urbanization
Introduction mucosal inflammatory diseases, may be more closely
Biodiversity loss is a global concern with a variety of linked than iscommonlyrecognized(Figure 1).
possible adverse consequences for humanity. The rea- Inflammation is a cardinal feature of asthma and al-
sons for this loss are complex and are in large part due lergic diseases, autoimmune diseases, and many forms
to the consequence of industrialization, pollution and of cancer [1], but more recently less tangible associa-
utilization of chemicals, which impact the environment tions have been linked to these trends such as an
and the microorganisms with which humans have lived increased incidence of depression associated with
since time immemorial. In recent years, attention has inflammatory markers [2]. Thus far, the increase
been paid to the potential health effects of this altered in the prevalence of inflammatory disorders is a
biosphere. Indeed, the two globalmegatrends, one in the phenomenon largely restricted to the developed
state of biodiversity and the other in the prevalence of world, while such disorders are still uncommon
among populations in non-affluent regions, i.e. those
regions, which still have more traditional non-urban
lifestyles [3,4]. Adoption of cultural patterns and nu-
*Correspondence:[email protected]
1SkinandAllergyHospital,HelsinkiUniversityHospital,POBox160,Helsinki tritional habits from affluent countries, together with
00029,HUCH,Finland declining frequency and severity of intestinal parasitic
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a b
% Asthma ( ) Allergic rhinitis ( )
100 WPSI 3.5 9
LPI 8
3.0
90 7
2.5
6
80 2.0 5
1.5 4
70 3
1.0
2
60 0.5 1
0.0 0
1970 1980 1990 2000 2010 1960 1970 1980 1990 2000
Year Year
Figure1Twoglobalmegatrendsinbiodiversityandpublichealth.(a)Decliningbiodiversity(percentagechange)since1970asmeasured
bytwoindices.WPSI=WaterbirdPopulationStatusIndex;LPI=LivingPlanetIndex[14].(b)Increasingtrendsintheprevalenceofinflammatory
civilizationdiseases,asthmaandallergicrhinitisamongmilitaryconscriptsin1966-2003[165]asanexample(modifiedfromref.[14]).
infections,arerapidlychangingtheallergytrendsupwards Increasedattentionisnowfocusedoncriticalenvironmen-
also in many developing countries [5]. Not unexpectedly, tal factors in the search for the origins of these diseases.
loss of traditional cultures and loss of biodiversity are Studies of immigrants, epigenetic studies and mapping of
likely linkedand as such,drivenbyshared factorssuch as thegutmicrobiotahaveprovidedcompellingevidencethat
increasedurbanization,commercializationandwidespread the environment can fundamentally modulate immune
useofchemicals[6]. functioninhumans(Table1).Poorlydevelopedorbroken
Previous studies reveal that microbe-rich environments immunetoleranceplaysaroleinthepathogenesisofmany
confer protection against allergic and autoimmune dis- diseasessuchasallergyandasthma,autoimmunity,cancer,
eases [3,4,7], but it is likely that declining biodiversity is chronicinfections,abortions[10].
more generally responsible for human immune dysfunc- Living in urban environments with higher exposure to
tion.Hanskietal.[8]showedrecently,thatcomparedwith chemicals and with reduced green space with the conse-
healthyadolescentstheatopicindividualshadlowerenvir- quence of limited plant, animal and microbial life is
onmental biodiversity – in the form ofspeciesrichness of associated with immune dysfunction and impaired tole-
native flowering plants and in the land use type – in the rance in humans [11]. Reduced contact with nature and
surroundings of their homes. The atopic adolescents also environmental microbiota appears to be linked with a
had significantly lower generic diversity of Gram-negative range of civilization diseases, including allergy and type
gammaproteobacteria on their skin. Furthermore, the 1 diabetes [12]. Of considerable concern is that these
abundance of the genus Acinetobacteria on the skin was chronic inflammatory diseases are becoming increas-
positively correlated with the peripheral mononuclear cell ingly prevalent in low and middle income countries in
expression of IL-10, a key anti-inflammatory cytokine in parallel to their improving economic development and
immunological tolerance. Gammaproteobacteria are com- adoptionofwestern-typeurbanization.Itispossiblethata
mon in the soil, but are particularly dominant in above- more biodiverse exposure confers more protection, not
groundvegetation,suchasfloweringplants. only against infectious diseases [13], but also against
The line of evidence that the declining biodiversity of chronicinflammatory(andpossiblymalignant)diseases.
plants, animals, and their natural habitats is associated Novel methodologies now allow accurate determi-
with changes in the interactions between humans and nation of microbial communities in various ecosystems.
microbes, and that these interactions might be causally Despite this advance in technology, hardly anything is
related to the increasing prevalence of asthma and allergy known about the interactions between environmental and
as well as other inflammatory disorders, is reviewed in indigenous microbiotas. How are reduced biodiversity and
thispaper. the change in the micro-organism profile found in urban
andmoreaffluentenvironmentsreflectedintheindigenous
Focusonenvironmentalfactors human microbiotas? What are the effects of biodiversity
Irrespective of major efforts to clarify the genetic causes, lossofplantsandanimalsonenvironmentalmicrobiota?
which predispose to the onset of asthma and allergic We propose that biodiversity at the level of macrobiota
diseases, theresultsremain rathermodest [9], underscor- and microbiota are interrelated in thatbiodiversity loss of
ing the genetic complexity of these multi-trait diseases. the former is likely to be associated with loss of diversity
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Table1Evidenceoftheimmunomodulatorycapacityofthelivingenvironmentinhumans
Evidencefrom Alteredsusceptibilityto References
Immigrantstudies Allergicdiseases [74,75,77,78]
Type1diabetes [73]
Multiplesclerosis [76]
Obesity,type2diabetes [79]
Depression [80]
Cancers [81]
Epigeneticstudies
Microbialdeprivation Allergicdiseases [111,117,118]
Airpollution Asthmadeterioration [119]
Studiesonthegutandskinmicrobiota
Microbialdeprivation,alteredcomposition Allergicdiseases [8,51-54]
Dataonalteredsusceptibilitytoinflammatorydiseasesareforimmigrantsmovingfromlessaffluenttoaffluentcountries,exceptinref[76].
of the latter [14]. Moreover, biodiversity loss leads to Biodiversityandhumanhealth
reduced interaction between environmental and human There is a rich literature to demonstrate that natural
microbiotas.Thisinturnmayleadtoimmunedysfunction environments are of vital importance to the physical and
andimpairedtolerancemechanismsinhumans. mental health of humans [19], and as a consequence,
biodiversity should be integrated into the conventional
measures of well-beingand recognized as a global public
Conceptsofbiodiversity goodrequiringconsciouscollective choices[20].
By definition, biodiversity is ‘the variability among living A recent large study found that the annual preva-
organisms from all sources, including, inter alia, terres- lence rate of most disease clusters was lower in envi-
trial, marine and other aquatic ecosystems and the eco- ronments where people were living with more green
logical complexes of which they are part. This includes space (10% or more than the average) within a 1 km
diversity within species, between species and of ecosys- radius. This effect was most pronounced for depression
tems’[15].Inpractice,thekeyelementsof biodiversityin- and anxiety, but also significant for asthma/COPD,
clude genetic diversity of populations and species; the diabetes and coronary heart disease [21]. Green space,
richness of local and global species; the spatial extent and including forests and natural areas as well as parks,
thestateofnaturalhabitats;andthefunctioningofecosys- may act as a buffer between stressful life-events and
temsthatprovidevariousessentialservicestomankind. health [22]. Aligned to this concept, better self-reported
The year 2010, the United Nations’ International Year health and lower stress scores also have been reported
of Biodiversity, was to be the turning point for biodiver- to be inversely associated with the distance to green
sity decline, but a recent comprehensive report shows space[23].
that this target has not yet been met; the rate of bio- A meta-analysis of 10 intervention studies reveal that
diversity loss does not show signs of decreasing, and ‘green exercise’ (activities in natural environments), even
worryingly, the indicators which reflect the various pres- of short duration, significantly improved the physical
sures on biodiversity continue to increase [16]. For and mental health [24]. Of importance, physical activity
example, one-third of the sufficiently well-defined spe- in a natural environment versus other settings, appears
cies of animals and plants are currently classified as tohavemorebeneficialhealtheffects[25].
threatened(56000 species) [17]. Severalon-goingstudieshaveexaminedthehealtheffects
Although the Convention of Biological Diversity [15] of forests [26]. Compared with urban settings, forest
isprimarilyconcernedwithplantsandanimals,biodiver- environments are associated with lower cortisol level,
sity also includes micro-organisms, which are less visible lowerpulserateandbloodpressureaswellaswithhigher
but comprisethe bulk ofliving matter on ourEarth [18]. parasympathetic and lower sympathetic nerve activity in
Biodiversity, according to the definition, concerns both healthy individuals [27]. It is increasingly recognized
environmental and commensal microbiota. Thus far, thatexposuretonature,andforestenvironmentsinpar-
little attention has been paid to the biodiversity of en- ticularhasthepotentialtosubstantiallyimprovehuman
vironmental microbiota. health[26].
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The health effects of natural environments are obvious, inflammatorydiseasestates[38].Theindigenousfloramay
but difficult to examine experimentally. Accumulating not only comprise bacteria and fungi, but also viruses and
evidence underlines the critical role for micro-organisms microscopic protozoans, although hardly any data on the
in the normal development and maintenance of mucosal latterareavailable.
integrity and tolerance [28,29]. Urbanization and general This paper focuses on the gut and skin bacterial flora,
loss of biodiversity, combined with sedentary indoor life- the two microbiotas that have been studied in greatest
styles have been a principle driving factor leading to detail. Although the current literature is dominated by
microbial deprivation [14,30] and may play a significant data about the gut flora to maintain immune tolerance
role in the epidemics of inflammatory diseases. Neverthe- andhealth,theon-goingmetagenomicstudiesmaydem-
less, more data and better understanding of the relevant onstrate a significant role for microbiotas at other sites,
mechanisms underlying the ‘nature effect’ at the cellular includingtherespiratorytract [39]andskin[40].
andmolecularlevelsarenecessary.
Gutmicrobiotaandinflammatorydiseases
Immuneregulation–mechanismsoftissueintegrityand Thehumangutfloraisthought tobeanessential‘organ’,
homeostasis which not only provides nutrients, but also regulates
Various immune cells must interact with microbes for epithelial development and orchestrates innate immun-
normal development and function. Protective mechan- ity [41]. The gut community is dominated by only two
isms against inflammatory diseases involve the activation phyla, Firmicutes and Bacteroidetes, and to a lesser ex-
of the innate and regulatory networks by continuous tent by Acinobacteria and Proteobacteria, even though
exposure to microbial components via the skin, gut and the populations of bacteria in the gut are huge and
respiratory tract. Humans have evolved with these micro- diverse at both the genus and species levels [41-43].
organisms,whichdonotelicitdefensiveimmuneresponses, Recent metagenomic data indicate that any one individ-
but rather induce immune regulatory circuits. A suddenly ual harbours an assemblage of at least 160 species,
reduced abundance or diversity of these micro-organisms, whicharepartlysharedwithotherindividuals.Thetotal
previously ubiquitous, may have led to failures to regu- numberof bacterialspeciesidentifiedinasampleof124
late and restore appropriate immune and inflammatory Europeans was 1000 to 1150 [44], suggesting a rather
responses[11]. distinctcompositionofflorapresentineachindividual.
Signaling via Toll-like receptors (TLRs) and other The microbiota is variable and shows temporal fluctu-
conserved pattern-recognizing molecules [31,32] that ation in early life. When a steady state is reached, the
are present on/in various cells play a decisive role, not composition of the gut flora remains relatively stable
only in host defense against pathogens, but also to main- overtime, providing thatnomajorchangesinlifestyle or
tainepithelialcellhomeostasisandtissuerepair[28].This environment occur [45]. Early environmental exposures
apparently universal phenomenon has been shown in are thus considered the key determinant of adult gut
various tissues and occurs in wound healing [33]. Evi- microbiota [46], as is the type of diet consumed [47-50].
dence from mice highlights the role of TLR stimulation Clues about the influence of environmental factors on
to confer protection against inflammatory conditions, the development of the gut microbiota have been
supporting the epidemiological studies of human popu- obtained from studies of infants in Estonia and Sweden
lationslivinginamicrobe-richenvironment.Theeffects and provide some of the first evidence that the compos-
were mediated by induction of regulatory circuits [34,35] ition of gut microflora between non-western and western
andbystimulatinginnateimmunemechanismsinepithe- childreninearlylifediffersandthatthesedisparitiescould
lialcells[36]. beassociatedwiththemanifestationofallergicdiseasesin
laterlife [51-53].Usingnovel molecular-based methods, a
Alterationsinhumanmicrobiota–implicationsfor Swedishstudyrevealedthatamorediversegutmicrobiota
immunedysregulationandinflammatorydisorders early in life is associated with protection against allergy at
A fundamental role for micro-organisms in human health, theageof5years[54].
whetherindigenousorenvironmental,isbecomingincreas- Dysbiosis, the reduced diversity and disturbed com-
ingly evident. Commensals are no longer considered as position of the gut microbial community, not only has
passivebystandersortransientpassengers,butincreasingly an influence on the occurrence of asthma and allergies,
asactiveandessentialparticipantsinthedevelopmentand but also on other chronic and relapsing inflammatory
maintenance of barrier function and immunological toler- conditions that include type 1 diabetes [55], inflamma-
ance [37]. They are also involved in the programming of tory bowel disease (IBD) [56,57], obesity [42], and even
many aspects of Tcell differentiation in co-operation with psychiatric disorders, such as depression [58]. Studies in
the host genome [29]. Mounting evidence also shows that both mice and humans indicate that some common
alterations in the indigenous microbiota correlate with members of the normal microbiota could exert a special
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role in maintaining homeostasis and immune health factors that determine these complex communities and
[29,45,56,57]. A decrease or absence of these microbes their relationship to the host both to maintain health
in the colon has been shown to lead to impaired deve- and predispose to disease open up a whole new field of
lopment of regulatory T lymphocytes (T reg cells), the inquiry into human homeostasis and its potential link to
TcellsubsetthatmediatessuppressionofT-cellmediated thewiderenvironment.
inflammatory responses. Moreover, an imbalance of ‘pro- As in the gastrointestinal tract, the skin microbial
inflammatory’ and ‘anti-inflammatory’ microbes may also community includes both transient and resident micro-
result in an increased susceptibility of the host to inflam- biota [66,67], suggesting that at least a part of the skin
matory diseases [29] and could explain the increase in flora is in a dynamic interaction with the environment.
paediatric inflammatory bowel disease (IBD) [59], one of Toprobetheseinteractions,long-term studiesareneeded
the many inflammatory diseases being reported with in- over lifetime, on the intensity and composition of the
creasingfrequencyinwesternizedcountries(Figure2). skin flora in people living in contrasting environments
Although it is unclear what is the cause and effect, the in different countries and socioeconomic conditions and
rich literature on the mechanisms for the development theirassociationswithhealthanddisease.
of epithelial cell tolerance and homeostasis referred to
above and the experimental models using transfer of Effectofantibiotics
gut microbiota [55,60] support the concept of alterna- Antibiotics modulate microbiota, and the effect may be
tive stable states. Altered environmental microbiota and long-term. One-week course affected the gut microbiota
reduced signaling of TLR and other receptors cause im- even for three years [68]. Recent systematic review by
munedysfunction,enhancingthecolonizationandgrowth Murk et al. [69] indicated a slight increase in the risk of
of a biased microbiota, thus creating a self-perpetuating asthma, if antibiotic were used during pregnancy or in
circle to push the host-microbe interaction toward an the first year of life. Hill et al. [70] showed how in anti-
‘unhealthy’ state [14]. Collectively, sedentary lifestyle in biotic treated mice commensal-derived signals influenced
affluent urban environments does not provide adequate basophilhematopoiesisandsusceptibilitytoTH2cytokine-
microbial exposure to develop ‘healthy’ microbiota, an dependentinflammationandallergicdisease.Choetal.[71]
essential part of the immune system closely linked to increased adiposity in young mice by administering sub-
the development and maintenance of epithelial cell tol- therapeutic doses of antibiotics. Changes were observed in
erance and homeostasis. An indirect illustration of this the gut microbiota as well as in copies of key genes
concept is that faecal microbiota transplant has been involvedinthemetabolismofcarbohydratestoshort-chain
successfully used to restore the microbiota balance in fattyacids.
severeClostridiumdifficileinfections[61]. Altogether, antibiotic manipulation seems to alter, es-
pecially in early-life, metabolic homeostasis and increase
Skinmicrobiota riskofallergicandotherinflammatoryconditions.
Skinflora,similarlytogutflora,can be viewed asacom-
munity or an organ composed of various cell lines that Immigrationreshapingimmuneregulation
communicate with each other and with host cells. The Immigrant studies have provided invaluable evidence for
use of global metagenomic approaches reveals that the the immunoregulatory capacity of the living environ-
microbial diversity of the skin is comparable to that in ment. When immigrants move from areas of low to high
the gut [44,62], giving credence to the fact that the skin prevalence of disease, they have a good health status at
flora is a part of the immune system and able to shape the time of arrival (healthy immigrant effect), but this
the responses. In genetically predisposed individuals, declines thereafter and converges to that of the natives
various environmental factors may lead to inflammatory [72] or even becomes worse. The immunomodulatory
skin responses and impaired barrier function as seen changes appear to occur within 10 years after arrival
with chronic eczema [63]. A good example is the pos- [72-75], and these changes are not restricted to young
sible role of staphylococci in predisposing to atopic people only but also occur in adults as well [76,77]. This
eczema [40], but on a larger scale, the role of skin immunomodulation by “cultural adaptation”, which leads
microbiotainbarrierfunction isnot yetfully elucidated. tochangesindiseasesusceptibility,appearstobeuniversal
Several metagenomic studies [62,64-66] demonstrate and has been reported for various inflammatory diseases,
thattheskinmicrobiotaiscomposedmainlyofmembers including asthma and allergic diseases [74,75,77,78],
of the same four phyla that comprise the gut microbiota, autoimmune diseases, such as type 1 diabetes [73] and
although with dissimilar relative abundances [64-66]. An multiple sclerosis [76], obesity and type 2 diabetes [79],
exciting and highly relevant study shows that each of depression[80]andcivilizationcancers[81].
these two body sites harbour its own characteristic Of note, this list of disorders is almost identical to the
microbiota, with little temporal variation [64,65]. The disease spectrum associated with altered gut microbiota
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a) b) Incidence of pediatric inflammatory
bowel diseases (IBD)
18
Asthma ( ) Allergic rhinitis ( )
3.5 9 s)16
ar
3.0 8 ye14
s
7 on12
2.5 s
6 er
p10
2.0 5 00
0 8
1.5 4 00
1 6
3 n/
1.0 e ( 4 Total
2 nc Male
0.5 1 cide 2 Female
n
0.0 0 I 0
1960 1970 1980 1990 2000 1987 1989 1991 1993 1995 1997 1999 2001 2003
Lehtinen P, et al. Inflamm Bowel Dis 2010
c) d) Prevalences of coeliac disease
and type 1 diabetes
0.35 2.5
Total %) Type 1 diabetes %)
3 000 Rectum cancer s (0.30 Coeliac disease e (
Colon cancer e s
2 500 bet 2.0sea
2 000 e 1 dia00..2250 1.5eliac di
p o
1 500 e of ty0.15 1.0e of c
c c
1 000 alen0.10 alen
ev 0.5ev
500 Pr0.05 Pr
0 0.00 0.0
1962–1967–1972–1977–1982–1987–1992–1997–2002–20072008 1950 1960 1970 1980 1990 2000
1966 19711976 19811986 1991 199620012006
Lohi S, et al. Aliment Pharmacol Ther 2007
e) Incidence of Wegener’s granulomatosis f) Incidence of Non-Hodgkin’s lymphoma
11
Male 16 Male
10 Female s Female
9 ear 14
atio 8 on y 12
ate r 7 pers 10
ence r 65 0 000 8
d 0
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3 e 4
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1981- 1986- 1991- 1996- 1963-1968-1973-1978-1983-1988-1993-1998-2003-20082009
1985 1990 1995 2000 1967 19721977198219871992199720022007
Takala J, et al. 2008 Finnish Cancer Register 2010
Figure2Trendsina)prevalenceofasthmaandallergicrhinitis[165],b)incidenceofpediatricinflammatoryboweldisease[59],c)
incidenceofcolonandrectumcancer[168],d)prevalenceofcoeliacdiseaseandtype1diabetes[166],e)incidenceofWegener’s
granulomatosis[167],andf)incidenceofnon-Hodgkin’slymphomainFinlandin1950-2009[168].
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as discussed above. Recently-arrived individuals may well as rising sea levels [86]. Climate change is resulting
experience a particularly dramatic reduction in health in chemical, physical and biologic stressors that have far
status, even if they are younger than the native residents reachingconsequences tohealth [87].
and earlier immigrants. The relatively rapid change in Theprevalenceofasthmaandallergicrhinitishasmark-
health status is best explained by the dietary factors edly increased globally since the 1960s [88,89]. Pollen is
affecting gut microbiota. In addition to dietary factors an important trigger in many patients with allergies and
and environmental exposures, psychological factors, such asthma. Air pollution and higher concentrations of CO2-
as loss of socioeconomic status contributing to stress and induced increases in levels and allergenicity of allergenic
depression[72],arelikelytoplayakeyroleintheimmune pollens may be contributing to increasing prevalence of
modulationobservedinimmigrants. allergic disease and asthma, with climate change a plaus-
ibleexplanationforboth[90].
Additionalriskfactors Climate change has direct impacts on aeroallergens, in
Airpollution particular pollens and mold spores and allergic diseases
Indoor and outdoor pollution is a major environmental [90-92]. Pre-Industrial CO2 levels in 1870 were 280
risk factor for asthma and allergy not only increasing the ppm, followed by a steady increase of 35% by 2005 to
prevalencesoflong-termsymptomsbutalsoacuteattacks 379 ppm, with urban areas exhibiting the highest levels
[82]. The association studies indicate that ambient air [87]. Several studies have demonstrated direct correla-
pollution is connected to asthma, rhinitis, rhinocon- tions between rising CO2 and increases in both pollen
junctivitis,acuterespiratoryinfections,theneedforasthma and biomass levels, as well as increased allergenicity of
drugs,andhospitaladmissionsbecauseofrespiratorysymp- the pollen [93,94]. Ziska, et al. [94] tested the hypothesis
toms.Indoortobaccosmokeisthemostobviousriskfactor, that ragweed pollen levels were impacted by pre-
which can be reduced by legislation and education. In industrial revolution CO2 level (280 ppm), current CO2
Turkeyatobaccobaninitiatedin2009resultedina24% levels (370 ppm) and CO2 levels (600 ppm), projected
decrease in respiratory emergency visits in Istanbul in level for the year 2100. All variables remained constant
oneyear[83]. using a greenhouse environment, with the exception of
The main ambient air pollutants are derived from fuel rising CO2 levels. There was a 132% increase in ragweed
combustion (traffic and various industrial sources like pollen from pre-industrial to current and an additional
power plants and refineries). Fine particulate matter, 90% increase in pollen level at projected 2100 levels. In
nitrogen and sulphur compounds (NOx, SOx) are the the greater Baltimore area between 2000 and2001, Ziska
most important pollutantsemitted directly tothe atmos- demonstrated that the urban levels of CO2 were 30%
phere. Ozone(O3)isproducedbythereactionofsunlight higher and temperature 2 degrees Celsius higher than
with air containing hydrocarbons and NOx. In China, surrounding rural areas. A fundamental aspect of climate
ambient air pollution is associated with 300000 deaths change is the potential shift in flowering phenology and
and20millioncasesofrespiratoryillnessesannually[84]. pollen initiation associated with milder winters and
The most important sources of indoor air pollutants, warmer seasonal air temperature. Earlier floral anthesis
in addition to tobacco smoke are biomass fuels, like hasbeensuggested,inturn,tohavearoleinhumandis-
wood and coal, for heating and cooking, cleaning and ease by increasing the time of exposure to pollen that
washing products and mold/dampness. Conservative cause allergic rhinitis and related asthma.In the urban
estimates indicate that indoor air pollution may be re- area, the ragweed plants produced 189% more pollen,
sponsible for nearly two million deaths per year in deve- comparedwiththesurroundingruralarea[95].
loping countries [85]. Correlation between earlier ragweed pollen start dates,
prolonged pollination cycles and increasing latitudes of
Climatechange ragweedgrowthinNorthAmericahasalsobeenreported,
TheIntergovernmental Panel onClimate Change(IPCC) with a nearly linear increase from Oklahoma City with
defines climate change as a “change in the state of the 1 day earlier from 1995 to 2009 to a high of 27 days
climate that can be identified (e.g. using statistical tests) earlierinSaskatoon,Canada [96].In additionto increases
by changes in the mean and/or the variability of its in pollen levels and prolonged pollination cycles, there is
properties and that persists for an extended period, typ- also evidence of an impact on pollen spatial distribution,
ically decades or longer. It refers to any change in cli- dispersal of pollen and increased allergenicity of the
mate over time, whether due to natural variability or as pollens [97,98].
a result of human activity.” The IPCC further states that D´Amato et al. [99] have described the potential of cli-
warming of our climate system is unequivocal, demon- mate change to alter atmospheric circulation patterns,
strated byincreases in global air and ocean temperatures which contribute to long distance transport of allergenic
in addition to widespread melting of snow and ice as pollen. Extreme events like thunderstorms and cyclones
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have an impact on aeroallergens increasing the risk of aspects of Western lifestyles, but what these factors are
suddenexposure. have so far eluded definition. The genetic changes in
In high CO2 environments, birch pollen exhibited populations over the time when these trends have oc-
increased bet-v-1 specific IgE binding compared to curred cannot account for the rise in allergic disease
baseline levels, p<0.05 [100]. Interestingly, similar fin- associated with socioeconomic gradients. As discussed
dings have been demonstrated with molds, specifically earlier, changes in microbial exposure, diet and expos-
Alternaria alternata, with a significant increase in spore ure to pollutants and chemicals (not discussed further
production as well as an increase in allergenicity in high in the present paper) are all being pursued as possibil-
CO2 environments compared to low [92]. These effects ities. Most likely, it will be multiple environmental
do not seem limited to pollen and spores. Increased to- changes interacting at different time points across the
xicity (allergenicity) has also been demonstrated in poi- life course(includingpregnancy)thatinteracttopredis-
sonivysubjected toelevatedatmosphericCO2[101]. posetoallergicsensitisationandatopicdisease.
Arecentretrospectivestudylookedat27yearsofpollen Although there have been many examples of genetic
counts compared withcorrelatingprevalence ofthe deve- mutations of pathogen recognition receptors (PRR),
lopment of allergen sensitivity. Significant increases in especially toll-like receptors influencing the association
pollen levels and duration of the pollen season of cypress between atopic disease including asthma, genome- wide
(+18days),olive(+18days)andparietaria(+85days)were association studies (GWAS) have in this respect been
demonstrated,withnosignificantchangeinbirchorgrass. disappointing[106].
The percentage of patients sensitized to those pollens This is especially the case in the protective influence of
significantlyincreased(p<0.05),whiletherewasnochange early life microbial exposure in farming and related envi-
in the prevalence of dust mite sensitivity (used as a con- ronments and anthroposophic lifestyles, and novel genes
trol). The authors went on to look at climate variables, associatedwithasthmaandatopy.Theexceptionisexpos-
finding significant correlations with rising levels and pro- ure to maternal and environmental tobacco smoke that
longedseasonwithincreasingtemperaturesandincreased has been reported to increase the strength of association
solarirradiation[102]. between some novel genes and asthma e.g. the ORMDL3
Impact of climate change on indoor aeroallergens, locuson17q21andPCDH1on5q31-q33[107].Whatare
such as molds, house dust mites, cockroaches, rodents, nowneededareGWASinwhichenvironmentalmeasures
and others pests have received less attention than those and individual responses are incorporated at the start in
on outdoor allergens. For example, increased relative order to uncover those disease-related genes that are
humidity will increase the risk for mold growth and most sensitive to particular environmental exposures.
heavy periodic rainfalls stress the buildings to manage Anotherwayofseekingsuchgenesistoexploreepigenetic
excesswater flow[103]. influences.
Gene–environmentinteraction Epigeneticmodulation
Disposition to atopy and associated allergic disorders Epigenetic changes, functionally relevant, environmen-
are strongly heritable. In addition, most atopic diseases tally induced genome modifications that can be heri-
coexist in the same patients suggesting overlapping table, but are unrelated to DNA sequence changes [108],
mechanismsthatinvolveinlargepartTh2-relatedinflam- has received much attention over the past few years as
matory mechanisms. Atopy that predisposes to enhanced an explanation of immune modulation by environmental
sensitisation to common allergens is only one genetic exposure. Environmental factors are key players in
factor driving the heritability of allergic disease, another activating or silencing genes by altering DNA (CpG is-
are genes that predispose to expression of the atopic land) and chromatin histone acetylation, methylation
phenotypeinaparticularorgan.Agoodexampleisatopic and phosphorylation thereby altering chromatin struc-
dermatitis (eczema). The mutations of the filaggrin gene ture, or through the inhibitory effects of microRNAs on
may increase skin permeability and predispose to allergen gene translation, thus modifying disease susceptibility in
penetration and sensitisation of the skin (also upper air- individuals.
ways) and are closely associated withseveredisease[104]. Epigenetic changes are likely to be of major impor-
Abreakdownofepithelialbarrierfunctionisalsoanemer- tance in contributing to phenotypic expression of com-
ging factor in other allergic diseases such as food allergy, plex disease and are highly disease- and organ- specific.
rhinosinusitis and asthma although other defects beyond GWAS of several complex diseases have identified a
filaggrinareinvolved[105]. number of genetic variants, but these variants only
The large geographic variations in the prevalence of explain a minor part of disease susceptibility. For ex-
allergic diseases and rising trends reported in the low ample, over 45 single nucleotide polymorphisms (SNP)
and middle income countries have been linked to some associated with Type 2 diabetes account for only 10% of
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the phenotype. In the case of asthma, the EU GABRIEL inhaled antigen, maternal TLR signalling appears crucial
collaboration reported highly significant genome-wide for mediating the transfer of this transgenerational pro-
associations with loci on chromosomes-17 (ORMDL3/ tective effect. Most recently, the inhibitory effect of A.
GSDMB), -2 (IL1RL1/IL18R, -6 (HLA-DQ gene cluster), lwoffii F78 on the development of an allergic lung
-9(IL33),-15(SMAD3)and-22(IL2RB)thatisclaimedto phenotype in the offspring has been shown to be IFN-γ
accountforupto50%ofasthmariskacrossthelifecourse -dependent and epigenetically controlled through chro-
[109]. Nevertheless, only a small proportion of the herit- matin histone 4 (H4) acetylation of the IFNG promoter
ability of asthma can be accounted for by novel genes of CD4+ T cells with inhibition of H4 acetylation abo-
identified by GWAS. The missing heritability may in part lishingtheTh2-protectivephenotype[117,118].
result from non-synonymous variants with high pene- Traffic-related air pollution is an example of an envi-
trance as has been reported in some cases of extreme ronmental factor that may increase disease susceptibility
obesity. due to epigenetic changes. A study among school chil-
The involvement of epigenetic changes in this ‘missing dren with and without asthma living in areas with
heritability’ [108] is also apparent, but still needs to be contrasting levels of ambient air pollution showed that
verified. Studies of disease discordance in monozygotic pollution is associated with increased methylation of
(MZ)twinsindicatethatsignificantepigeneticmodulation CpG islandsin the Foxp3 locus, reduced T reg cell func-
occurs in utero. A study among newborn twins highlights tion and increased asthma severity scores. A dose-
the importance of the intrauterine period for establishing dependent relationship between the exposure to air
epigenetic variability in humans [110]. It is likely that pollution and Treg cell function and/or Foxp3 methyla-
many factors will influence epigenetic expression of spe- tion has been reported [119]. However, complete
cific genes beyond disease including, but not limited to, demethylation of the regulatory regions of the Foxp3
age,sex,sharedenvironments,dietandsmoking. gene is required for stable Foxp3 expression linked to
A microbe-rich environment has been shown to Treg cell function [120]. Traffic-related particles have
induce both pro-inflammatory and regulatory circuits been found to exert epigenetic modulation even when
very early in life [111], indicating early activation of the exposureoccursviatheplacenta [121].
relevant genes. Prenatal exposure to high levels of Though early life is important for epigenetic modula-
microbial products e.g. milking parlours and cow sheds tion, such changes also occur in adults [122], which is
is especially protective. Such exposures lead to high cir- not unexpected, given the inherent plasticity of the epi-
culating levels of Tregs, so that in mice, selective deple- genetic mechanisms. This plasticity also provides for an
tion of Tregs during the allergen sensitisation phase opportunity for environmental/behavioural strategies in
dramatically enhances experimental allergic lung inflam- diseaseprevention[123].
mation [112]. One study in humans has shown that Although the imbalance in regulatory versus inflam-
maternal cells have the capacity to traverse the placenta matory circuits is a universal feature in various inflam-
and enter fetal lymph nodes to induce Tregs with sup- matory conditions, the basic mechanisms have been
pressive functions to prevent anti-maternal immunity examined in greatest detail in allergic diseases, the focus
[113]. Recently, reduced human placental Foxp3 has ofthefollowing discussion.
been shown to be associated with subsequent infant
developmentofallergicdisease[114].
Further support for maternal programming to protect Tolerance–thekeyissueinallergyprevention
againstinfantallergen sensitisation comes from exposing The concept of induction of immune tolerance has
pregnant mice to the Gram-negative, non-pathogenic become a prime target for prevention and treatment
bacterium Acinetobacter lwoffii F78 found in cow sheds strategies for many diseases such as allergy, asthma,
and which has been shown to activateTLR2, 3, 4, 7, and autoimmunity, organ transplantation and infertility in
9. Combining prenatal exposure to A. lwoffii F78 with a which dysregulation of the immune system plays an
mouse model of Th2-mediated airway inflammation essential role. In addition to various modes of allergen-
leads to protection from development of an allergic lung SIT, healthy immune response development during high
phenotype in the offspring [115,116]. The mechanism dose of allergen exposure in beekeepers and cat owners
involves up-regulation of maternal lung TLR expression, have been intensively studied to understand mechanisms
initiation of a transient acute local Th1-like inflamma- of allergen tolerance in humans [124,125]. Mechanisms
tory response, systemic release of inflammatory cyto- include changes in the profile of allergen-specific me-
kines and a down-regulation of TLR and cytokine mory Tand B cell responses, and specific antibody iso-
expression in the placenta. As the offspring from A. types towards a non inflammatory direction, as well as
lwoffii F78-treated TLR2/3/4/7/9−/−mothers were no decreased activation, tissue migration and degranulation
longer protected from Th2-type airway responses to ofmastcells,basophilsandeosinophils[10,126,127].
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In different guidelines and consensus reports little Practicalactionstopromoteallergyhealth
attention is devoted to immunological tolerance and There are no clearly established guidelines for primary
how to strengthen this in the prevention and manage- prevention of allergic disease or any established methods
ment of allergic diseases. This is the case in spite of the to non-specifically strengthen tolerance in established
fact that basic immunological mechanisms of tolerance disease. However, data have accumulated to indicate that
have largely been unravelled and the commonly used some simple behavioral activities can confer some pro-
strategy to reduce allergen exposure at different stages tection against or alleviate allergic diseases, providing
from the inception of an allergic disease to its life-long indirect evidence of their beneficial effects on tolerance.
expression (allergen avoidance) is of questionable effi- Not unexpectedly, such interventions include physical
cacy. With the possible exception of occupational expo- exercise, a healthy diet and connection with the natural
sures, effective allergen avoidance is difficult, if not world and countryside. Acting in synergy with specific
impossible, and the results from the avoidance trials immunotherapy, enhancing tolerance by these means is
havebeenmostlydiscouraging[128,129].Althoughthere importantalso insecondaryprevention(Figure 3).
is some evidence that multiple allergen reduction strat- In Western societies, chronic inflammatory diseases
egies are more successful,at leastfor primary prevention affectanincreasing proportion ofthepopulation.In pre-
[130], complex and multifaceted avoidance procedures vention and disease management, studies that highlight
cannot be seen as a long term solution for a common the immunological and anti-inflammatory effects of
public healthproblem[131]. environmental-andlife-stylefactorsareurgentlyneeded,
It has been generally thought that the dose-response particularly in view of this increased inflammatory bur-
curve for gaining immunological tolerance to different den(Tables 2,3).
allergens/ bioparticles is different. However, the emer-
ging picture is that a non-linear bell-shaped dose- Physicalactivity
response curve is a universal phenomenon, shown at Several outlines of evidence emphasize the risks of a
least for endotoxin, fungal 1-3-beta-glucans, cat and dog sedentary lifestyle for health. Physical inactivity increases
allergens, rat and mouse allergens and house dust mite the inflammatory burden, independently of obesity, and,
allergens (reviewed in [128]). In several recent reviews, conversely, exercise programs decrease systemic low-
the mechanisms in the development of tolerance have level inflammation in various patient groups and healthy
been comprehensively considered [132-134]. adults (reviewed in [136]). The anti-inflammatory effects
Clinical tolerance in its broadest terms comprises of physical exercise seem to be mediated by activating
not only immunological tolerance, but also tolerance the regulatory circuits, including regulatory T cells. For
affecting tissues and cells other than the immune sys- example, in healthy adults, a 12 week program of mode-
tem, including psychological tolerance. Mild, intermit- rate exercise 3 times per week significantly improved
tent allergy can be viewed as a trait or characteristic regulatory Tcell numbers and function [137]. Moderate
rather than a state requiring regular treatment or strict exercise for 12 weeks in patients with type 2 diabetes,
instructions for allergen avoidance. Mild allergy does significantly decreased HbA1c levels while increasing
not necessarily worsen with time [135], but often, par- IL-12 levels and the expression of transcription factors
ticularly in children, wanes naturally through child- T-bet and Fox3p+, indicating improvements both in the
hood and adolescence. metabolic and the immune systems [138]. In asthmatic
Acquired immunity
(cid:129) SLIT
(cid:129) specific
(cid:129) SIT T cells
(cid:129) memory
B cells
(cid:129) rearranged receptors
(cid:129) Healthy diet NKT NK
(cid:129) Probiotics Innate immunity
(cid:129) Physical exercise DCs, macrophages, (cid:129) unspecific
(cid:129) Connection monocytes, neutrophils, (cid:129) no conventional memory
with nature mast cells, eosinophils, basophils (cid:129) germline-encoded receptors
Figure3Tolerancecanbeendorsedbybehavioralmeansincludingphysicaltraining,consumptionofhealthydietanddoingactivities
innaturalenvironments.Thesethingsshouldbeincludedalsoinsecondarypreventiontogetherwithspecificimmunotherapy.Unspecificand
specificmeanstoendorsetoleranceactinsynergy.NaturalKiller(NK)cellsandNaturalKillerT(NKT)cellssharecharacteristicsofbothinnateand
acquiredimmunity.SIT=SpecificImmunotherapy,SLIT=SpecificOralImmunotherapy.