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Review article: Current opinion | Published 24 December 2014, doi:10.4414/smw.2014.14036
Cite this as: Swiss Med Wkly. 2014;144:w14036
Childhood asthma: causes, risks, and protective factors;
a role of innate immunity
Georgios T. Noutsiosa, Joanna Florosa,b
aCenter for Host Defense, Inflammation, and Lung Disease (CHILD) Research Department of Pediatrics, College of Medicine The Pennsylvania State
University, Hershey, Pennsylvania, USA
bDepartment of Obstetrics and Gynecology, College of Medicine The Pennsylvania State University, Hershey, Pennsylvania, USA
Summary
Childhood asthma is an umbrella of multifactorial diseases
with similar clinical features such as mast cell and eos-
inophil infiltration causing airway hyper responsiveness,
inflammation, and airway obstruction. There are various
factors that are implicated in childhood asthma pathogenes-
is. A combined contribution of genetic predisposition, en-
vironmental insults, and epigenetic changes account for po-
larisation of the immune system towards T helper (Th) type
2 cell responses that include production of pro-inflammat-
ory cytokines, IgE, and eosinophil infiltrates, shown to as-
sociate with asthma. Environmental cues in prenatal, peri-
natal, and early childhood seem to determine development
of asthma incidence or protection against it. Mode of birth
delivery, use of antibiotics, oxidative stress, exposure to
tobacco smoke and an industrialised lifestyle are signific-
ant contributors to childhood asthma exacerbation. Envir-
onmental stimuli such as exposure to maternal antibodies
through breast milk, and certain early infections favour Th1
cell responses, leading to the production of anti-inflammat-
ory cytokines that protect from asthma. Aside from the Th
cell responses the role of innate immunity in the context of
alveolar macrophages, dendritic cells, and surfactant pro-
tein A (SP-A) and SP-D is discussed. SP-A and SP-D en-
hance pathogen phagocytosis and cytokine production by
alveolar macrophages, bind and clear pathogens, and inter-
act with dendritic cells to mediate adaptive immunity re-
sponses. Further study of the interactions between genet-
ic variants of genes of interest (SP-A and SP-D) and the
environment may provide valuable knowledge about the
underlying mechanisms of various interactions that differ-
entially affect asthma susceptibility, disease severity, and
reveal potential points for therapeutic interventions.
Key words:childhood asthma; pulmonary surfactant
proteins; SP-A; innate immunity; alveolar macrophages;
dendritic cells; T-helper cells; respiratory distress
syndrome; epigenetics; preterm delivery
Definition – problem
Childhood asthma is one of the most common respiratory
disorders worldwide with increased prevalence in Western
industrialised societies where they inflict a high economic
burden. In America more than 7.1 million children have
asthma (National Center for Health Statistics, 2011) and
this translates to thousands of annual hospitalisations or
774,000 emergency room visits due to severe asthma at-
tacks in children under 15 years old. In 2009, 3,388 people
died from asthma and out of these 157 were children under
15 years old. The health care expenditures for asthma are
estimated to be more than $50.1 billion per year in the
USA, while the impact on the productivity of working par-
ents rises to $5.9 billion loss per year (2007 report) [1].
Also, asthma is responsible for 10 million missed school
days per year. According to World Health Organization
(WHO) (2011), 235 million people worldwide suffer from
asthma, and it is the most common chronic disease among
children. The economic cost for the UK is estimated to be
$1.8 billion and for Australia $460 million (WHO, 2013).
Worldwide, the economic burden of asthma exceeds those
of HIV/AIDS and TB combined. Childhood asthma is a
complex syndrome composed of different phenotypes (i.e.,
observable biochemical, clinical, morphological, and
physiological characteristics) and endotypes (i.e., subtypes
of asthma), each with a distinct pathophysiology. The dif-
ferent phenotypes of childhood asthma, their clinical ap-
pearance and symptoms, the current diagnostic procedures
and therapeutic regimens have been described previously
by Wenzel [2]. Moreover, it has been noted that exhaled
nitric oxide can help to distinguish the asthma phenotypes
[3]. The five different phenotypes include early-onset al-
lergic, late-onset eosinophilic, exercise induced, obesity
related and neutrophilic asthma. The endotypes of child-
hood asthma define distinct pathophysiological and func-
tional characteristics of the disease. There have been four
different endotypes identified: early-on set severe allergic
asthma, late-onset persistent eosinophilic asthma, aspirin-
exacerbated airway disease, and allergic bronchopulmon-
ary mycosal asthma [4]. The pathogenetic sources of
asthma remain unknown and although genetic, environ-
Swiss Medical Weekly · PDF of the online version · www.smw.ch Page 1 of 14
mental, and epigenetic factors have been identified, an ef-
fective therapeutic intervention is yet to be established.
Importance of sex prematurity
interactions
Males are more susceptible to asthma in early childhood
than females, but later on females are more prone to the dis-
ease in conjunction with other contributing factors such as
weight gain, obesity, and hormonal changes [5]. It is known
that the menstrual cycle, pregnancy, and menopause cause
dramatic fluctuation in oestrogen levels and this fluctuation
activates proteins that can produce inflammatory responses
in the airways and impact the risk of asthma. Male preterm
List of abbreviations
Afu aspergillus fumigatus
AhR arylhydrocarbon receptor
AHR bronchial airway hyper-responsiveness
AMs alveolar macrophages
AP-1 activator protein 1
BDNF brain-delivered neurotrophin factor
BPD bronchopulmonary dysplasia
BT bronchial thermoplasty
CS Cesarean section
DCs dendritic cells
DEPs diesel exhaust particles
ETS environmental tobacco smoke
FcεRI-β high affinity receptor IgE
GBS group B streptococcal
GM-CSF granulocyte- macrophage colony-stimulating factor
GSDM Gasdermin-B
GSTM1 glutathione S-transferase M1
GSTP1 glutathione S-transferase pi 1
GWAS genome wide association studies
HLA-G human leukocyte antigen gene
HPA hypothalamic-pituitary-adrenal infantile axis
hTG humanised transgenic
ICAM-1 serum soluble intracellular adhesion molecule 1
IL interleukin
INF-β Interferon-beta
ΙNF-γ interferon-γ
LRIs lower respiratory viral infections
miRNAs microRNAs
MMP-9 matrix metalloproteinase 9
NF-κB nuclear factor kappa-light-chain-enhancer of activated B
cells
NQ01 quinoneoxidoreductase 1
ORMDL3 sphingolipid biosynthesis regulator 3
OxS oxidative stress
PAH polyaromatic hydrocarbons
PM particulate matter
RDS respiratory distress syndrome
ROS reactive oxygen species
RSV respiratory syncytial virus
SCIT subcutaneously administered immunotherapy
SNPs single nucleotide polymorphisms
SP-A surfactant protein A
TB tuberculosis
TGF-β transforming growth factor β
Th T helper
TIMP-1 tissue inhibitor of matrix metalloproteinase 1
TLR toll-like receptors
Tregs T regulatory cells
TSLP genes thymic stromal lymphoprotein
WHO World Health Organization
WTC World Trade Center
infants have higher rates of asthma incidence and chronic
lung diseases than females [6]. The basis for sex-based dif-
ferences in asthma is not entirely known. However, females
appear to have higher airflow rates (i.e., volume of air that
passes through lungs per unit time) and forced expiratory
volumes (i.e., vital capacity or the volume of air that is ex-
pelled from the lung during a maximally forced expiratory
effort after taking the deepest possible breath) than males
possibly due to differences in airway smooth muscle and
wall diameters [7].
Nowadays, the “male disadvantage” hypothesis for the pre-
maturely born infant is well established [8]. Males in com-
parison to females show higher frequency of RDS, asthma
and/or other lung related injuries. Sex differences in gon-
adal steroid production in utero and increased cerebrospin-
al levels of IL-8 and leptin in females in comparison to
males [9] have been discussed as plausible reason for in-
creased asthma occurrence in males. Moreover, it has been
demonstrated that maternal stress factors during pregnancy
(such as maternal smoking and obesity) increase the vul-
nerability to lung diseases in males compared to females
[10]. Also, a difference has been observed in intrauterine
fetal growth retardation between sexes, with males show-
ing greater fetal retardation, as well as slower lung matur-
ation than females [11]. In preterm females some in utero
prenatal infections have a protective effect against asthma
while males tend to be more susceptible to them [12].
These fetal stresses (in utero bacterial infections) in fe-
males may result in acceleration of maturation of lung de-
velopment and immune system responses and this may not
happen in males.
Prematurity is often accompanied with therapies such as
mechanical ventilation and postnatal corticosteroids, both
of which are shown to strongly associate with an increased
incidence of childhood asthma. The barotrauma caused by
mechanical ventilation and the corticosteroids effect on in-
fantile lung development and bronchial remodelling are
most likely the underlying contributors to the increased
childhood asthma incidence [13]. Postnatally preterm fe-
males in comparison to males have an extremely active
thymus [14] that may be particularly responsive to cy-
tokines that modulate immune regulatory functions, thus
rendering protection against asthma in females.
The parental contribution to childhood asthma is rather
complex and not fully understood. For example in the 1989
Isle of Wight Birth Cohort (n = 1,456) maternal asthma was
associated with asthma in girls but not in boys; paternal
asthma was associated with asthma in boys but not in girls.
Maternal eczema was associated with increased risk of
eczema in girls only, whereas paternal eczema did the same
for boys [15]. Others have shown that maternal asthma
more than paternal asthma is associated with early child-
hood asthma [16]. However, the prevalence of asthma later
in puberty and adolescence seems to depend on the sex of
the child, with girls being more susceptible to asthma [17].
These indicate that further studies are needed to unravel the
observed complexity of childhood asthma.
Review article: Current opinion Swiss Med Wkly. 2014;144:w14036
Swiss Medical Weekly · PDF of the online version · www.smw.ch Page 2 of 14
Causes and risk factors of childhood
asthma
A number of diverse factors have been implicated in
asthma pathogenesis in children. These include genetic pre-
disposition (asthmatic parents), environmental stimuli dur-
ing prenatal and early childhood that include allergens
(mite, cat, dog, grass, pollen, and mould) [18], maternal in-
fection and smoking during pregnancy, environmental to-
bacco smoke, mode of birth delivery (i.e., Casearean sec-
tion), viral respiratory illnesses, obesity, diet, hygiene, and
toxic exposures, fig. 1.
No single factor can account for the rapidly increasing in-
cidence of childhood asthma during the last two decades.
Genetic changes alone should be excluded because the
gene pool does not change rapidly enough to explain this
increase. It is assumed that a combined contribution of en-
vironmental and epigenetic (the result of environmental in-
sults) changes, accounts for the increased prevalence of this
emerging health risk. Because childhood asthma is correl-
ated with chronic comorbid diseases [19] such as increased
respiratory infections, bronchitis, cystic fibrosis, pneumo-
nia, atopic dermatitis, otitis media (middle ear effusion), ol-
factory disorders and lung cancer, it is possible that preven-
tion and treatment of childhood asthma will eliminate and/
or benefit a great number of significant life-long health bur-
dens.
Genetic and epigenetic factors
Increasing evidence supports the notion that in children, an
early onset of allergic immune response might be a trigger-
ing factor for the physiological lung remodelling process.
This in turn may lead to a lower lung function, bronchial
airway hyper-responsiveness (AHR), and persistent asthma
Figure 1
Diagrammatic summary of childhood asthma causes, risks and
protective factors. The figure depicts the causes and the risk factors
of childhood asthma that include genetics, epigenetics and
environmental insults. These favour the Th2 biased cell response
and select against Th1 cell response leading to inflammation and
exacerbation of asthma (red arrows). The figure shows the factors
leading to the Th1 cell response that produces anti-inflammatory
cytokines and these in turn protect against asthma (blue arrows).
The role of innate immunity in asthma, as exemplified by AMs,
DCs, SP-A and SP-D is also noted with a broken line. The human
cartoons were taken from Google. (Infant cartoon:
http://123freevectors.com/black-baby/#.UVtFcFdyPfo, Asthmatic
child: http://krames.sjmctx.com/HealthSheets/3,S,88710, Healthy
child: http://www.wernerbaumgartner.info/)
into adolescence. In addition, childhood asthma has been
implicated in a predisposition toward developing certain
allergic hypersensitivity reactions. Asthma and allergies
run in parallel under certain genetic (i.e., asthmatic par-
ents) and perinatal influences [20] (such as in utero infec-
tions [12], antibiotics, and tobacco smoke exposure [21])
rather than being the stepping stones for a progressive atop-
ic march [19]. Atopy is defined as a genetic predisposition
toward the development of immediate hypersensitivity re-
actions against common environmental antigens.
Genetics: It has been found that children whose parents are
asthmatic are more likely to have asthma at school age.
Children sensitised to allergens, with strong family his-
tory of asthma, by the age of three years have signific-
antly lower airway conductance (i.e., lower instantaneous
rates of gas flow in the airway per unit of pressure differ-
ence between the mouth, the nose, and the alveoli) [22].
Specific asthma-associated gene polymorphisms have been
shown to be more likely to be passed down to children
from the mother than the father. For example polymorph-
isms in the high affinity receptor IgE (FcεRI-β) (L181I and
L183V on exon 6 and E237G on exon 7) [23] that increased
asthma risk, were transmitted from mother to offspring and
resulted in greater IgE levels and positive allergic skin
tests. Another example is that of glutathione S-transferase
pi 1 (GSTP1) locus polymorphisms [24], where genotypes
Val105/Val105 and Ala114/Val114 were associated with greater
Figure 2
Contributions of different immune system cells and molecules in
pathogenesis of childhood asthma. The solid lines describe the
T helper cells that have been associated with asthma in humans
whereas the broken lines represent asthma studies that have been
conducted in animal models and their role in human is yet to be
determined. Th2 responses lead to production of IL-4, IL-5, IL-9,
IL-13 which are associated with increased levels of IgE and
eosinophils leading to asthma. Th1 responses include anti-
inflammatory cytokine INF-γ, and early infant immune system
development (possibly by TLR-2, TLR-4, TLR-9). Th1 responses
render protection against asthma. Tregs inhibit the production of Th2
cells and Th2 cytokines, and are regulators of immune system self-
tolerance, prevent autoimmunity and suppress allergies. Th17 cells
produce pro-inflammatory cytokines IL-17A, IL-17F, IL-21, IL-22,
IL-26 and are associated with an increased number of neutrophils
and amount of inflammation. Th22 cells, which produce pro-
inflammatory IL-22, are believed to play an important role in asthma
pathogenesis. Th9 cells produce IL-9, which stimulates expression
of FcεRI-α and mast cell proteases. Th9 cells are also believed to
play an important role in asthma disease.
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Swiss Medical Weekly · PDF of the online version · www.smw.ch Page 3 of 14
lung function and their transmission was maternal rather
than paternal, fig 1.
Fetal programming of gene expression during development
is critical to the formation of a normal lung. Two large gen-
ome wide association studies (GWAS) in European [25]
and diverse US populations [26] produced remarkably sim-
ilar results. Single nucleotide polymorphisms (SNPs) in
or near seven loci were associated with asthma in both
studies, and SNPs in or near four of these loci had p-
values at or near genome wide levels of significance in
both studies, with contributions from ethnically diverse
samples. Variation at the 17q21 asthma locus that encodes
the GSDML [GSDML gene is predicted to be generated
due to a duplication of Gasdermin-B (GSDM) gene] and
ORMDL3 (sphingolipid biosynthesis regulator 3) genes, is
specifically associated with childhood onset asthma [27].
Moreover, variations have been found in epithelial cell-
derived cytokines genes, thymic stromal lymphoprotein
(TSLP), IL-33, IL1RL1 (that encodes the receptor of
IL-33) and ST2 (the receptor for IL-33 on mast cells, Th2
cells, Tregs and macrophages) [27]. All these associations
highlight the importance of epithelial cell-derived cy-
tokines that promote differentiation and activation of Th2
cells and their receptors. Despite the success of GWAS for
discovering common risk alleles for many complex dis-
eases and quantitative phenotypes, only a small proportion
of the heritability is accounted for by these variations, and
is now apparent for asthma. This has been termed as “the
dark matter” or “missing heritability”, and has been dis-
cussed extensively in the literature [28,29].
Epigenetics: The variability of asthma symptoms (i.e., in-
cidence and remittance) can be the result of epigenetic in-
fluences induced by early (perinatal) or later (infantile) en-
vironmental exposures. Epigenetics gene expression regu-
lation is a heritable change of gene expression that happens
without any alteration in the DNA sequences and involves
i) histone and chromatin modifications, ii) DNA methyla-
tion in the promoter regions, iii) imprinting (methylation of
DNA sequences that alter the binding of specific transcrip-
tion factor and/or enhancer elements), and iv) micro-RNA
(miRNA) changes in conjunction with environmental stim-
uli.
In vitro studies have demonstrated that environmental in-
sults such as in utero exposure to maternal tobacco smoke,
environmental tobacco smoke (ETS), oxidative stress, dies-
el exhaust particles (DEPs), polyaromatic hydrocarbons
(PAH), either during pregnancy or shortly after birth, me-
diate histone modification, and methylation of DNA se-
quences in T-helper cell genes that lead to induction of po-
larisation towards allergic type 2 (Th2) immune responses
associated with asthma versus Th1 responses that are in-
volved in atopic protection [30], fig. 1. T lymphocytes ex-
pressing CD4 glycoproteins on their surface are called T
helper (Th) cells and are the main factories of pro- and
anti- inflammatory cytokines; these cytokines are the hor-
monal messengers responsible for cell mediated immunity
and allergic responses. Th1 pro-inflammatory responses
mainly include production of interferon-γ (ΙNF-γ) (which
inhibits the synthesis of IgE and eosinophil degranulation)
and are mostly associated with intracellular elimination of
parasites. Th2 responses mainly include the production of
interleukin (IL)-4, IL-5, IL-9, and IL-13, and are associ-
ated with increased levels of IgE and eosinophil produc-
tion leading to atopy [31], fig. 1. Thus, the Th1 response
is considered protective for asthma and the Th2 response
is associated with severe airway inflammation and asthma
[32]. However, other studies have demonstrated contradict-
ing results. In particular, when Th1 cells were transferred
into naïve mouse recipients, the Th1 cells migrated to lungs
and although they secreted INF-γ, they failed to counterbal-
ance the Th2–cell-induced AHR and caused severe airway
inflammation [30]. It is postulated that environmental stim-
uli may render protection against asthma by additional non
Th1–Th2 regulatory mechanisms.
Aside from the well-established Th1–Th2 paradigm, nu-
merous studies show that the actual situation is much more
complicated and other Th cells such as Th17, Th22, Th9,
and T regulatory cells (Tregs) also play key roles in the
pathogenesis of childhood asthma [33] (fig. 2). For ex-
ample Th17 cells are identified as a new subset of Th
cells that are characterised mainly by the production of
IL-17A and other well-known pro-inflammatory mediators
such as IL-17F, IL-21, IL-22, and IL-26 that play a role in
the inflammatory processes [34,35]. These together, along
with the observation that increased IL-17A mRNA is cor-
related with an increased number of neutrophils in asth-
matic patients [36], suggest that Th17 plays an important
role in asthma aggravation by recruiting neutrophils to the
already inflamed bronchial airways (fig. 2). Moreover, in
the past decade a small subpopulation of Th cells that pro-
duce IL-22 but lack the production of IL-17A has been
identified as new subset of cells, namely Th22 cells [37].
These are believed to play an important role in asthma
pathogenesis albeit their function in asthmatic patients has
to be elucidated. Another distinct subset of Th cells in-
volved in asthma pathogenesis is Th9 cells, which produce
large amounts of IL-9 [38]. This cytokine is known to stim-
ulate the expression of FcεRI-α (in Th cells and neutro-
phils) and mast cell proteases, and it has been suggested
that IL-9 primes mast cells to respond to allergen challenge
with increased FcεRI-α and proteases. However, all studies
on Th9 cells have been conducted in mouse models and
the existence of Th9 in humans remains to be determined.
The Tregs have been suggested to play an important role in
the immunopathogenesis of allergic asthma. Tregs are reg-
ulators of the immune system’s self-tolerance, can prevent
autoimmunity, and suppress allergies. In several in vitro
studies Tregs have been reported to inhibit the production
of Th2 cells and the Th2 cytokines, and to suppress the de-
velopment of asthma [39]. The number of Tregs in allergic
subjects appears to be significantly decreased in the lung
airway tissue, BAL, and peripheral bood [40]. All the sub-
sets of T helper cells described above could help to explain
the existence and treatment of the different phenotypes and
endotypes of childhood asthma.
MicroRNAs (miRNAs) constitute one of the epigenetic
mechanisms regulating gene expression. These are a re-
cently discovered short (~22 nucleotide) non-coding RNA
sequences that bind to complementary sequences in the
3’UTR of multiple mRNAs, usually resulting in gene silen-
cing or suppression of gene expression. Differential expres-
sion of miRNAs has been shown to contribute to asthma
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Swiss Medical Weekly · PDF of the online version · www.smw.ch Page 4 of 14
and other diseases and hold the potential as valuable dia-
gnostic markers, fig. 1. For example, a single nucleotide
polymorphism in the 3’UTR of the asthma-susceptibility
human leukocyte antigen gene (HLA-G) affects the bind-
ing of three miRNAs. The binding of these regulatory
miRNAs most probably blocks the HLA-G mRNA trans-
lation or mediates the degradation of HLA-G mRNA [41].
HLA-G, which is expressed in the placental cells that con-
stitute the interface between the fetus and the mother, dis-
plays immunosuppressive properties. Reduced levels of
HLA-G have been associated with asthma.
In addition, it has been shown that the inheritance of child-
hood asthma can take place across multiple generations.
Grand maternal smoking has been linked with grandchild
asthma vulnerability independent of maternal smoking
[42], supporting further the notion that environmental chal-
lenges mediate heritable epigenetic modifications to im-
portant genes that can be passed on to the second offspring
generation.
Environmental stimuli
Infection and Immunity: During pregnancy in utero expos-
ures to infections, such as maternal vulvovaginitis (Can-
dida albicans), chorioamnionitis (bacterial infection of the
foetal membranes, amnion, and chorion), and Group B
streptococcal (GBS) bacterial infection, negatively affect
foetal pulmonary and immunological development and
have been shown to associate with bronchopulmonary dys-
plasia [43] (BPD) and potentially childhood asthma [12],
fig. 1. Furthermore, prescribed perinatal antibiotics to fight
maternal infections are known to cross the placenta, enter
the foetal bloodstream and cause alterations in the neonatal
microflora including the proliferation of resistant bacteria
and induction of immune developmental modifications
[44] that may lead to asthma. Also, a wide variety of insults
can alter or interfere with the foetal respiratory and/or im-
mune system maturation and thus can significantly impact
the risk of asthma, respiratory distress syndrome (RDS),
and/or other airway related diseases.
The mode of child delivery has been associated with risk of
childhood asthma. Over the past two decades in the west-
ern industrialised societies the prevalence of asthma runs in
parallel with increased rates of Cesarean section (CS) [45],
fig. 1. There are two plausible biological explanations for
this correlation. In the CS the newborn does not get ex-
posed to the maternal birth canal and perineum microbial
flora, and thus the infant’s sterile gut does not stimulate the
maturation of the immune system as would have been the
case in a normal vaginal delivery. Another possible biolo-
gical reason is that the CS in newborns may lead to RDS
and transient tachypnoea and both of these factors are re-
lated to increased asthma risk in the early childhood. A
limited number of studies have demonstrated that preterm
deliveries accompanied with neonatal respiratory morbid-
ity are associated with increased risk of childhood asthma
[46].
Early transient infant wheezing induced by lower respirat-
ory viral infections (LRIs) such as bronchiolitis appear to
stimulate the children’s immune system and protect them
against asthma, whereas persistent wheezing later in child-
hood is strongly associated with asthma and allergies [47].
Although it is known that respiratory syncytial virus (RSV)
is the most common trigger of bronchiolitis, it is well es-
tablished that rhinovirus is the bio-agent that is mostly as-
sociated with childhood asthma. Upregulation of ICAM-1
observed in children diagnosed with allergic asthma, fa-
cilitates the translocation of rhinovirus into epithelial cells
[18]. The subsequent upregulation of interferon-beta (INF-
β) that would normally induce rhinovirus clearance, via ap-
optosis, fails in asthmatic children allowing the virus to
further replicate leading to cell lysis and viral propagation
though the airways.
Nutrition also plays a role in childhood asthma pathogen-
esis. Especially vitamin D and folate (as methyl group
donors) seem to be important. Ten different large studies
reported conflicting results on the association of maternal
folate levels with childhood asthma risk [48–57]. The ma-
jority of studies reported no association albeit a few repor-
ted a transient in nature, early-onset childhood asthma risk
related with folic acid supplementation in late pregnancy.
Maternal folate and childhood asthma have been recently
reviewed [58].
Ozone: Exposure of children to ozone has been linked with
significantly increased levels of eosinophils, production of
pro-inflammatory cytokines IL-1, IL-6, IL-8, granulocyte-
macrophage colony-stimulating factor (GM-CSF), and
nuclear factor kappa-light-chain-enhancer of activated B
cells (NF-κB). These lead to airway inflammation, child-
hood asthma, and other deleterious effects on human lung
[59]. Oxidative stress differentially affects individuals
probably due to differences in genetic predisposition to
asthma. Ozone disrupts epithelial integrity, compromises
mucociliary clearance, impairs effective phagocytosis, ox-
idises biomolecules in the lung, generates free radicals and
activates inflammatory lung cells. Oxidative stress activ-
ates redox-sensitive transcription factors, such NF-κB and
activator protein 1 (AP-1), mediating thus inflammatory
cytokine production, and exacerbates asthma and allergic
disease. Major polymorphisms of the quinoneoxidore-
ductase 1 (NQ01) and glutathione S-transferase M1
(GSTM1) genes have been shown to differentially affect
asthma risk in children under oxidative stress [60], fig. 1.
Ozone and oxidative stress (OxS): OxS affects the function
of alveolar macrophages (AMs) that serve as the front line
of the innate lung cellular immune defense against respirat-
ory pathogens. Moreover, AMs’ dysfunction has been cor-
related with asthma in a rat model [61]. Specifically, OxS
affects protein expression and compromises the function
of specific proteins via oxidation. This happens by a vari-
ety of mechanisms that usually involve oxidation of spe-
cific reactive cysteines and/or modification of amino acids.
Carbonylation, one of the more widely characterised modi-
fication of proteins under OxS, has been implicated in the
pathogenesis and progression of a variety of diseases in-
cluding asthma [62]. Oxidation of proteins can interfere
with their function and their metabolism by either promot-
ing degradation or by forming protein aggregates that are
not readily degraded. In vivo mouse model studies have
demonstrated that OxS-dependent changes have an impact
on epithelial permeability, inflammatory mediators, and
lead to pneumonia vulnerability.
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Surfactant Protein A (SP-A), an innate immunity molecule
and a component of bronchoalveolar lavage, is an example
of a protein that its function is affected by OxS [63–65].
Oxidised SP-A may negatively impact the function of AMs
and this has been shown by several studies. For example,
our in vitro studies have shown that the ability of SP-A
to enhance phagocytosis by AMs is significantly reduced
after ozone-induced oxidation of SP-A [64,66,67].
Moreover, ozone-induced oxidation of SP-A in vivo altered
the proteomic expression profile of the bronchoalveolar
lavage proteins [68]. This included a decrease in the levels
of proteins involved in the redox balance and an increase
in the levels of proteins involved in metabolism, protein
modification and chaperons. Several important innate im-
mune functions have been ascribed to SP-A [69,70]: i) re-
cognition and opsonisation of some pathogens, ii) inflam-
matory mediator expression (TNF-α and interleukins) by
some immune cells, iii) maturation of dendritic cells, and
iv) regulation of reactive oxygen species (ROS) produc-
tion.
Particulate matter (PM): Many bio-agents such as carbon,
iron, nickel, copper, organic residues and endotoxins are in-
cluded in PM. In addition to PM, Diesel Exhaust Particles
(DEPs) contain polyaromatic hydrocarbons (PAH), which
are one of the ligands of the cytoplasmic arylhydrocarbon
receptor (AhR). Upon binding the AhR is activated, and is
translocated to the nucleus and this results into changes of
transcriptional programmes [71]. DEPs increase eosinophil
degranulation and eosinophil adhesion to nasal epithelial
cells. DEPs have also been shown to i) induce CD80 ex-
pression in AMs, ii) augment histamine release, and iii)
shift (in children) the primary immune system responses
to Th2 phenotype (and thus select against the Th1 protect-
ive responses) [72], fig. 1. As noted above the Th2 phen-
otype involves production of cytokines (IL-4, IL-5, GM-
CSF) and IgE known to associate with asthma.
The example of World Trade Center (WTC) towers col-
lapse on 9/11 highlights the importance of the environ-
mental exposure in the development of asthma. It is now
known that WTC responders suffered from asthma at more
than twice the rate of the general U.S. population as a result
of their exposure to the toxic dust [73]. Multiple airborne
pollutants increased lung inflammation and AHR, and in-
duced acute lung function reduction.
Tobacco smoke: In utero foetal exposure to maternal to-
bacco smoke is associated with increased rates of child-
hood asthma and wheezing, elevated IgE levels, and in-
creased bronchial activity [74]. It is noteworthy mentioning
that a null GSTM1 genotype (a mutant copy of GSTM1
that completely lacks function) in conjunction with mater-
nal smoking during pregnancy and/or involuntary infant-
ile passive smoking is strongly correlated with asthma pre-
valence, while children with GSTM1 (+) genotype are less
likely to develop asthma [24], fig. 1. The GSTM1 enzyme
is involved in detoxification of the ROS and the tobacco
metabolic intermediates. While the gene is polymorphic, in
smokers the very common null genotype is shown to be as-
sociated with asthma, lung cancer, and DNA damage.
Not only maternal smoking affects fetal lung development
and function but also postnatal Environmental Tobacco
Smoke (ETS) increases the child’s risk of pulmonary mal-
function [59], fig. 1. ETS includes both side stream tobacco
smoke and exhaled mainstream smoke. High concentration
of more than 3,800 toxic substances such as carbon monox-
ide, carbon dioxide, acrolein, ammonia, sulfur dioxide, cro-
tonaldehyde, formaldehyde, hydrogen cyanide, and PAH
negatively affect the mucociliary function, damage lung
cells and tissues, and especially the Clara cells, thus inhibit-
ing lung cell proliferation/regeneration [75]. In addition, it
has been demonstrated that a single cigarette puff generates
the stunning potent oxidant mixture of 1015 toxic free rad-
icals [76], resulting in activation of transcriptional factors
[77] that regulate the Th2 immune responses.
Studies have shown that children exposed to mothers
smoking more than 10 cigarettes per day have a 63% in-
creased likelihood of developing asthma [42]. ETS has
been identified as an asthma risk factor for both children
and adults. Tobacco allergenic glycoproteins survive com-
bustion and remain immunologically active influencing the
immune system of children and adults [78]. Moreover, it
appears that there is a gene-environment synergistic inter-
action between genetic susceptibility and ETS. Genes in
chromosomal regions 1p, 5q, and 7p were shown to inter-
act with ETS contributing to asthma risk, while genes in
regions 1q and 9q are probably related to asthma predis-
position via a pathway independent of ETS infant expos-
ure [74]. Hence, childhood asthma appears to be the conse-
quence of the interplay between genes and ETS. Exposure
to ETS results in elevated IgE, Th2 immune responses,
histamine release from mast cells, and influx of eosino-
phils into the lungs that account for asthma and other sys-
temic inflammatory diseases. Tobacco smoke is by far the
most important environmental risk factor for asthma and
allergic diseases. Despite the well-established detriment-
al health effects of ETS in children it is surprising that
there are no guidelines to regulate ETS exposure of chil-
dren within households.
The modern industrialised environmental impact
Approximately 12 polymorphic genes that have been found
to regulate childhood asthma, control airway function and
remodelling, mediate inflammatory responses, regulate
IgE, and control cytokine and chemokine production [79].
Despite the fact that none of these genes have changed over
the past two decades, a dramatic increased incidence of
asthma is observed.
The modern industrialised lifestyle appears to be a signi-
ficant contributor to asthma exacerbation rather than the
genetic factors, fig. 1. In modern societies the improved
hygiene in combination with vaccination and early use of
antibiotics [80], which alter the gastrointestinal flora, result
in a reduced incident of infection that would normally stim-
ulate the infant’s immune system and hence these events
collectively exacerbate asthma incidents [81]. Furthermore,
a number of studies indicate that specific respiratory vir-
uses may be implicated in childhood wheezing and asthma
[82], while gastrointestinal exposure to bacteria has a bene-
ficial effect on the maturation of immune system and pro-
tection against asthma [79].
Several studies have demonstrated that while children are
born immunologically naïve and bear several genetic pre-
dispositions towards asthma [i.e., these include polymorph-
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Swiss Medical Weekly · PDF of the online version · www.smw.ch Page 6 of 14
isms in Tim1 [83], ADAM33, ANAN33 [84], NOD1 and
NOD2 [85], and others in choromosomes 5, 6, 11, 12,
14. Most likely, it is the early postnatal environmental
factors that determine either the development of asthma
or the immune protection against it. The latter includes
environmental stimuli such as prevalence of colonisation
of gastrointestinal tract with Gram-positive bacteria (i.e.,
commensal lactobacillus and bifidobacteria), exposure to
insults from daycare or older siblings, contact with farm
animals and dog/cat allergens that mediate the early de-
velopment of the infant immune system possibly by Toll-
like receptors (TLR-2, TLR-4, TLR-9), which induce Th1
responses [79], fig. 1. On the other hand, lack of envir-
onmental stressors, such as no other siblings, a germ-free
environment, lack of prolonged breastfeeding, low lactoba-
cillus, vaccination, and early use of antibiotics drive devel-
opment of Th2 immune response and over production of
cytokines (i.e., IL-4, IL-5, IL-9 and IL-13) that are associ-
ated with asthma, fig. 1.
There is a weak but still significant link between childhood
obesity and asthma, fig. 1. In the USA 32% of children
are either obese or overweight and this is attributed to
the Western industrialised diet pattern that includes mainly
obesogenic high density energy foods such as processed
sugars, animal trans fatty acids, and low whole unpro-
cessed plant foods. The most prevalent hypothesis is that
high body weight in children is a state of chronic low grade
inflammation, exacerbating AHR and contributing to the
development of asthma. Indeed in children a high body
mass index is frequently associated with insulin resistance,
hyperglyceridaemia, hypercholesterolaemia, and induction
of production of leukotrienes and other pro-inflammatory
factors known to be involved in respiratory tract infection
and airway inflammation. Moreover, studies have shown
that it is the non-allergic asthma that correlates the
strongest with obesity because it involves high concen-
tration of neutrophils, perturbation of adipokines levels
(adiponectin is an anti-inflammatory and leptin is a pro-
inflammatory adipokine) and IL-8 inflammatory pathways
[86].
Psychosocial factors
Aside from the genetic, epigenetic, and environmental
factors also psychosocial factors such as emotional stress
of both mother and infant, maternal anxiety or depression,
high levels of domestic and community violence, and in-
effective maternal responsive caregiving in early infancy
are strongly associated with childhood asthma and allergies
[87], fig. 1. There is accumulating evidence unveiling that
stressful events affect the buffering reactivity of
hypothalamic-pituitary-adrenal infantile axis (HPA axis)
causing low levels of endogenous glycocorticoids, which in
turn lead to allergic inflammation in airway responses that
may contribute to the onset of childhood asthma [88].
Race
Studies have shown that asthma is more prevalent in Afric-
an American children than other ethnic populations, where-
as among the culturally diverse Hispanic populations, the
Puerto Rican ancestry has the highest rate of mortality and
morbidity while Mexican Americans have the lowest rates.
However, Chinese Americans have the lowest rates of all
(American Lung Association State of Lung Disease in Di-
verse Communities 2010).
Pathology of childhood asthma
Over the past decade it has been realised that the severity
and the chronicity of persistent asthma cannot be explained
only by airway inflammation. Airway remodelling is an-
other contributing factor [89]. Bronchial biopsies revealed
inflammatory infiltrates dominated by eosinophils, mast
cells, lymphocytes, and bronchial goblet cell hyperplasia.
In severe disease predominantly raised levels of neutro-
phils were associated with increased levels of IL-4, IL-5,
IL-8, IL-13, matrix metalloproteinase 9 (MMP-9), tissue
inhibitor of matrix metalloproteinase 1 (TIMP-1), serum
soluble intracellular adhesion molecule 1 (ICAM-1), and
transforming growth factor β (TGF-β) [90]. These cy-
tokines seem to correlate with lung tissue remodelling as
these lead to vascular changes, thickening of lamina re-
ticularis, increased collagen deposition within the lamina
propia, smooth muscle hypertrophy and generation of my-
ofibroblasts [89]. For example, TGF-β stimulates collagen
deposition in the airway wall and the subepithelial con-
nective tissue. Collagen deposition is controlled by MMP-9
which has collagen-degrading properties and TIMP-1
which is an of inhibitor metalloproteases. The balance of
these two cytokines is thought to be disrupted in asthma,
and this has dire consequences on airway remodelling.
Briefly, inflammatory infiltrates result in altered airway
structures, changes in functional lung muscle, and thick-
ening of all compartments of airway walls. The functional
consequences of these events are airway narrowing (ob-
struction) and progression of asthma [18]. On the other
hand TGF-β in addition to its pro-asthmatic contribution
due to collagen deposition in lung airways has been known
to have anti-inflammatory properties by inhibiting differ-
entiation of immune cells (T cells, B cells, Th1, and Th2)
and inhibiting production of INF-γ and IL-2 [91]. It is well
established that TGF-β is a critical differentiating factor
that exerts potent immunosuppressive effects on Treg cells
[92]. Also during inflammation and infection TGF-β helps
to convert naïve T cells into Tregs and Th17 to combat in-
fection, while at the same time the same cytokine (TGF-
β) protects and maintains Tregs against apoptosis during
inflammation. TGF-β is believed to promote immune tol-
erance, maintain lung homeostasis and regulate its host
defence against insults [93]. The above show that the con-
tribution of TGF-β in childhood asthma is very complex
and still a matter of debate.
Beside cytokines and TGF-β, also growth factors contrib-
ute to the complex pathogenesis of childhood asthma. Re-
cently the family of growth factors called neurotrophins
has been shown to have an important role in the lung. In
specific the brain-delivered neurotrophin factor (BDNF) is
emerging as an important contributor in the early airway
and lung development. Disruption of BDNF expression has
been reported in premature neonates and during lung infec-
tion and inflammation. This may serve as an example of
the brain-lung axis in the pathogenesis of various complex
lung diseases [94].
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Asthma, lung innate immunity and
surfactant proteins A and D
The dogma of childhood asthma association with Th2 in-
flammation has recently been under question because i)
Th2 response patterns that mediate AHR and lung tissue
remodelling are not clearly linked to inflammation, and ii)
the Th2–based therapies for childhood asthma have limited
effectiveness [95].
Innate immunity is now emerging as an important factor
that may explain childhood asthma. While innate immunity
molecules protect the host from pathogens via recognition
of pathogen associated patterns, it is now known that innate
immunity also modulates a number of other processes such
as allergic responses. At this point we would like to high-
light the distinct role of AMs, the sentinel cells of lung in-
nate immunity, that are involved in pathogen defence, re-
cognition and removal of damaged tissue, neutralisation
and generation of ROS [96]. These functions are directly
linked to infection and OxS, both of which have been
shown to trigger childhood asthma. In AMs from asthmat-
ics, 38% of the differentially expressed genes were attrib-
uted to functions related to immune signaling response and
stress, correlating thus the important role of AMs in child-
hood asthma pathogenesis [97]. In the course of breathing
AMs are being exposed to allergens, microorganisms, and
various other environmental insults. AMs interact with in-
nate immunity molecules to bring about this first line of
defence. These molecules include the surfactant protein A
(SP-A) and SP-D [98,99]. Many studies have shown that
SP-A in addition to its role in surfactant-related (i.e., sur-
factant structure, function, and other) plays an important
role in innate immune functions, including the enhance-
ment of pathogen phagocytosis and cytokine production by
AMs [66,100], as well as the regulation of the AMs pheno-
type [69,70,101]. SP-A also has been shown to bind many
allergens including dust mite, pollen, fungi, indicating that
SP-A plays an important role in their clearance, and pos-
sibly in childhood asthma. SP-D is another important in-
nate molecule that binds AMs and modulates the adaptive
immune lymphocyte responses, playing a significant role
in the immunologic environment of the lung and in allergic
asthma [98].
The important roles of SP-A and SP-D in immunity have
been further exemplified by their ability to mediate adapt-
ive immune responses through interaction with dendritic
cells (DCs) [98]. DCs the most potent antigen presenting
cells, have the ability to activate naïve T-cells, and can ini-
tiate immune responses. DCs are distributed in lung paren-
chyma, airway epithelium, and alveolar space in order to
capture inhaled antigens and present these antigens to T-
cells. DCs mature in response to bacterial endotoxin, tissue
damage, and pro-inflammatory cytokines. SP-D has been
shown to enhance bacterial antigen uptake by DCs and to
interact with DCs in order to present these antigens to T-
cells. Specifically, SP-D binds immature DCs and enhances
production of CD86, which is a T-cell activation ligand,
and in this way augments antigen presentation [102]. On
the other hand, SP-A has been shown to modulate lung in-
flammation by inhibiting DCs proliferation and preventing
T cell activation. In specific, SP-A down-regulates the mat-
uration of DCs by inhibiting the expression of co-stimulat-
ory molecules CD86 and MHC-II, thus leading to inhibi-
tion of the activation of T-cells [103]. The above show that
most probably SP-A and SP-D are the “yin” and “yang” of
the lung’s DCs-mediated adaptive immunity.
SP-A is an important molecule in asthma and lung innate
immunity. It has been shown to i) inhibit T-cell prolifera-
tion, ii) modulate phagocytosis of allergens and pathogens,
iii) regulate cell surface proteins and metalloproteinases,
and iv) modulate ROS production. SP-A and SP-D protect
the host by recognising pathogen-associated molecular pat-
terns and act as the bridging molecules in the clearance
of apoptotic cells [104]. It is also known that SP-A and
SP-D in asthmatic mouse models downregulate eosino-
phil inflammation, reduce production of IgE, and polar-
ise T helper cell cytokines from Th2 towards Th1 phen-
otype. Moreover, these lung collectins (SP-A and SP-D)
are implicated in Aspergillus fumigatus (Afu)-induced al-
lergic asthma [105]. Specifically, these surfactant proteins
have been shown to i) bind glycosylated antigens and aller-
gens of Afu and to enhance their phagocytosis, ii) inhibit
specific IgE binding to these allergens, iii) block histam-
ine release from sensitised basophils, and when SP-A is ad-
ministered exogenously to protect against Afu-induced pul-
monary sensitivity.
Another plausible scenario for the involvement of SP-A in
childhood asthma is that SP-A can alter the immune cells’
cytokine release. In vivo experimental models have demon-
strated that in Afu-sensitised mice there was a transient
decrease of SP-A levels while IL-4 and IL-5 mRNA and
protein levels increased leading to an atopic Afu-induced
T-cell proliferation [105,106]. Moreover, SP-A has been
shown not only to exert a protective effect in Afu-induced
mouse asthma but also polymorphisms in the human SP-
A2 gene have been associated with vulnerability to Afu-in-
duced lung disease in humans [107].
SP-A genetic variants and childhood asthma: Human SP-
A is encoded by two functional genes SP-A1 and SP-A2,
and each gene has been identified with several polymorph-
ic variants shown to associate with several lung diseases in-
cluding asthma. The SP-A1 and SP-A2 variants have been
identified with functional and regulatory differences [66,
100,108,109]. The function and the expression of some
of these variants have been shown to change in response
to OxS, indicating that these variants could contribute to
lung disease via quantitative and/or qualitative derange-
ment [63,64,68,110,111]. We have demonstrated that the
ratio of SP-A1/SP-A differs among individuals as a func-
tion of age and health status (including asthma) [112,113],
and that SP-A from asthmatics does not abrogate inflam-
mation as effectively as the SP-A from non-asthmatic sub-
jects [113]. This dysfunction may be the result of an altered
SP-A1/SP-A ratio. In fact this is a likely scenario because
AMs from SP-A1 and SP-A2 humanised transgenic (hTG)
mice (i.e. mice that lacked mouse SP-A but each carried a
different human SP-A1 or SP-A2 variant) showed signific-
ant differences in the proteome profile derived from mice
carrying the SP-A1 variant versus those carrying the SP-
A2 variant [114]. Previous work from our laboratory has
shown that a single exogenous treatment with SP-A of SP-
A knockout mice is sufficient to nearly restore the AMs
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proteomic phenotype and make it similar to that of wild
type [115]. In other words, when SP-A knockout mice (that
lacked SP-A) were treated with SP-A, the AMs proteom-
ic expression profile of the treated mice was closer to the
wild type AM profile than the knockout AM profile indic-
ating that SP-A has a major impact on the expression pro-
file of the AMs. The fact that SP-A1 and SP-A2 differen-
tially affect AMs indicates that an imbalance in the ratio (as
it has been shown in asthmatics) may alter the phenotype
of AMs and perhaps their function. This may in turn neg-
atively affect the downstream processes and contribute to
asthma and/or its exacerbation. The above data collectively
provide evidence for a role of innate immunity and SP-A
and SP-D in asthma. Moreover, the fairly large number of
SP-A1 and SP-A2 variants, may have (via subtle quantit-
ative and/or qualitative derangement) a further differential
impact on asthma susceptibility among individuals. Future
studies may help to understand SP-A variant-mediated sus-
ceptibilities and thus contribute to considerations in per-
sonalised medical therapies.
Breastfeeding and protection of
childhood asthma risk
It is well established that infant breastfeeding is strongly
associated with reduction of respiratory illnesses in later
childhood and adolescence, although this association for
childhood asthma is slightly different. It appears that there
is a direct relation between the duration of breastfeeding
and asthma protection when there is maternal history of
asthma. On the other hand, no correlation has been found
between lack of breastfeeding and infants who were atopic
themselves or with no maternal asthma history [116].
Maternal milk apart from its nutritional components con-
tains various molecules and cells shown to have a protect-
ive role in the newborn infant and also play an important
role in the early acquired immune programming. For ex-
ample one such molecule is IgA. This is produced by the
secretory cells of the breast and protects the nursing infant
from the microbial antigens that the mother has been ex-
posed to [117].
Recently (2012) a report stated that breastfed infants are
exposed to maternal microbiota. The authors suggested that
exposure to mibrobiota determines the development of the
infantile gut flora and possibly plays a protective role
[118]. However, it is uncertain whether these bacteria ori-
ginate from the maternal breast milk itself or the oral bac-
teria of the breast fed baby that enter breast milk and
change its composition.
Therapeutic interventions
Childhood asthma is being treated by various medications
either providing long term asthma control or quick-relief
solutions. Long-term asthma medications include corticos-
teroids, long-acting beta agonists, leukotriene modifiers/in-
hibitors, theophylline, anticongestants and antihistamines.
Quick-relief (rescue) medications include bronchodilators,
sort-acting beta antagonists and oral or intravenous cor-
ticosteroids. It is important to highlight that the available
medications merely target the symptoms and do not cure
asthma.
Another option is subcutaneously administered immuno-
therapy (SCIT), which has shown significant improvement
for control of allergic childhood asthma symptoms and
medication needs. Although immunotherapy has proven to
be efficacious for allergic asthma, it holds a major draw-
back, namely, the possibility of a major systemic allergic
reaction in response to the treatment itself.
Omalizumab is a recombinant DNA-derived humanised
IgG1k monoclonal antibody that selectively binds free IgE
and is currently being used for Anti-IgE therapy in children
over the age of 6 years. This therapy has been shown to re-
duce the free circulating IgE, the high affinity IgE recept-
ors, and the mast cell and basophil activation [119].
Another treatment which is neither widely available nor ap-
propriate for every asthmatic child is the bronchial thermo-
plasty (BT). BT was approved by the FDA in 2010 and is
used primarily to treat severe persistent asthma that can-
not be controlled with conventional therapies. BT reduces
smooth muscle mass, via thermal energy, and thus attenu-
ates the ability of smooth muscle cells to constrict. This can
reduce the number of asthma attacks.
Since asthma appears to be a chronic inflammatory Th1/
Th2–disease, a potential therapeutic intervention is to im-
itate the naturally occurring infections and/or to reduce
regular early childhood vaccination regimens. As sugges-
ted by the authors of a multi-centre allergy study in 2002,
one could stimulate Th1 immune system responses by exo-
genous administration of lactobacilli or endotoxin Gram-
negative extracts early in infancy [79]. Although this was
tested in a murine model in 2010 [120], so far it has not
been tested on human subjects.
Conclusions
Childhood asthma is a complex multifactorial chronic
bronchial inflammatory morbidity characterised by mast
cell and mucosal eosinophil infiltration controlled by cy-
tokines of Th2 lymphocytes. It appears that childhood
asthma is the result of interplay between genetics, envir-
onmental insults, and epigenetic factors that favour the
Th2 biased cell response and select against Th1 cell re-
sponse. These events in turn trigger and exacerbate child-
hood asthma. Innate immunity is emerging as an important
player in asthma, and the innate host defence molecules
SP-A and SP-D appear to play a role as well. A diagram-
matic summary of the susceptibility factors that may in-
crease the risk of asthma or protect from asthma is shown
in figure 1.
Comments
The available treatments seem to suppress rather than cure
childhood asthma. The interplay of genetics with envir-
onmental insults through epigenetics may identify novel
mechanisms of childhood asthma and unveil new potential
points for therapeutic interventions. A concerted effort
must be put forward to comprehend the underlying mech-
anisms as to why some children under certain circum-
stances develop asthma while others do not. We must un-
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derstand the interplay between genetic variants of host de-
fense molecules (such as SP-A and SP-D) and the envir-
onment and how these may differentially affect disease
susceptibility and/or disease severity. This in turn may help
explain the inter-individual vulnerability to asthma incid-
ence and provide opportunities for therapeutic intervention
and/or prevention of childhood asthma.
Funding / potential competing interests: This work was
supported by the NIH HL34788 grant.
Correspondence: Professor Joanna Floros, PhD, Evan Pugh
Professor of Pediatrics and Obstetrics and Gynecology,
Director, Penn State CHILD Research, 500 University Drive,
P.O. Box 850, US-Hershey, PA 17033–0850, US,
Jfloros[at]hmc.psu.edu
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Figures (large format)
Figure 1
Diagrammatic summary of childhood asthma causes, risks and protective factors. The figure depicts the causes and the risk factors of
childhood asthma that include genetics, epigenetics and environmental insults. These favour the Th2 biased cell response and select against
Th1 cell response leading to inflammation and exacerbation of asthma (red arrows). The figure shows the factors leading to the Th1 cell
response that produces anti-inflammatory cytokines and these in turn protect against asthma (blue arrows). The role of innate immunity in
asthma, as exemplified by AMs, DCs, SP-A and SP-D is also noted with a broken line. The human cartoons were taken from Google. (Infant
cartoon: http://123freevectors.com/black-baby/#.UVtFcFdyPfo, Asthmatic child: http://krames.sjmctx.com/HealthSheets/3,S,88710, Healthy child:
http://www.wernerbaumgartner.info/)
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Figure 2
Contributions of different immune system cells and molecules in pathogenesis of childhood asthma. The solid lines describe the T helper cells
that have been associated with asthma in humans whereas the broken lines represent asthma studies that have been conducted in animal
models and their role in human is yet to be determined. Th2 responses lead to production of IL-4, IL-5, IL-9, IL-13 which are associated with
increased levels of IgE and eosinophils leading to asthma. Th1 responses include anti-inflammatory cytokine INF-γ, and early infant immune
system development (possibly by TLR-2, TLR-4, TLR-9). Th1 responses render protection against asthma. Tregs inhibit the production of Th2
cells and Th2 cytokines, and are regulators of immune system self-tolerance, prevent autoimmunity and suppress allergies. Th17 cells produce
pro-inflammatory cytokines IL-17A, IL-17F, IL-21, IL-22, IL-26 and are associated with an increased number of neutrophils and amount of
inflammation. Th22 cells, which produce pro-inflammatory IL-22, are believed to play an important role in asthma pathogenesis. Th9 cells produce
IL-9, which stimulates expression of FcεRI-α and mast cell proteases. Th9 cells are also believed to play an important role in asthma disease.
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