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Development of Atopy and Asthma: Candidate Environmental Influences and

Important Periods of Exposure


David B. Peden
Department of Pediatrics and The Center for Environmental Medicine and Lung Biology, The School of Medicine, The University of North
Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

Atopy is a major risk factor for the development of asthma. Immune processes that lead to the environments that induce expression of
development of antigen-specific IgE are essential to the development of atopy. This review proatopy genes. Prime examples of such envi-
examines the immune processes that are candidate targets for modulation by environmental ronments are those rich in airborne (house
agents; environmental and lifestyle factors that have been suggested as modulators of the dust mite and pollen) and orally encountered
development of atopy; and the impact of known environmental agents on atopic processes in the antigens (11). Likewise, with decreased expo-
airway. The most important periods of immune development with regard to expression of atopy are sure to such environmental factors, there is
likely during gestation and early childhood. A better understanding of which environmental agents often a decrease in the severity of atopic dis-
are important, as well as the period of life during which these agents may exert an important effect, ease in affected individuals (3,12). The effects
is essential to devising rational environmental avoidance strategies for at-risk populations. Key of air pollutants, lifestyle factors, and urban-
words: asthma, atopy, immunoglobulin E (IlgE), immunoglobulin G (IgG), T-helper cell type 1 (Thl), ization on the development of atopy and
T-helper cell type 2 (Th2). - Environ Health Perspect 1 08(suppl 3):475-482 (2000).
http.//ehpnetl.niehs.nih.gov/docs/2000/suppl-3/475-482peden/abstract.html asthma are more controversial.
A logical target for examination of the
effect of environment and lifestyle on develop-
ment of asthma is the effect of environmental
Asthma is one of the most common diseases Asthma and Atopy influences on the immune response to anti-
in both adults and children in the United Asthma is a complex multifactorial disease gens, with emphasis on development of atopy.
States. A major risk factor for the develop- that is characterized by reversible airway
ment of asthma is atopy. Atopy generally obstruction, airway hyperresponsiveness, and Antigen Presentation
refers to the development of immune eosinophilic airway inflammation (1). Atopy Development of immune responses to
responses to foreign antigens that are charac- is the most significant risk factor for asthma specific antigens is a complex process, and it
terized by the production of antigen-specific development, with approximately 85% of has been reviewed elsewhere (13,14). Initially,
IgE. Development of atopic responses has children who develop asthma and 40-50% of antigens are taken up by a number of cells
been linked to several genes and gene prod- adults with new-onset asthma having an aller- that can act as antigen-presenting cells,
ucts. Thus, atopic diseases represent a com- gic response to aeroallergens (1-4). Several which, as their name implies, process antigens
plex gene-environment interaction in which studies reveal a link between IgE and asthma and then present them to either CD8+ or
environmental antigens interact with the (2,4-8). Even in nonatopic asthma, the pres- CD4+ T lymphocytes. These lymphocytes
immune system, producing atopic (IgE) ence of eosinophilic airway inflammation sug- then direct specific immune responses against
responses. Furthermore, other genes are likely gests that similar atopic-like immune processed specific antigens. CD8+ lympho-
important for full expression of asthma in processes are important in the development cytes direct responses against derived antigens
individuals. In addition to interaction of this disease (1,9). produced within host cells, whereas CD4+
between antigens and the host immune sys- However, atopy alone does not account lymphocytes direct responses against antigens
tem, other environmental and lifestyle factors for asthma: many persons are atopic but not encountered outside of the host cell (13,14).
may impact immune responsiveness such that asthmatic. Given the multiple processes Antigen presentation to CD8+ cytotoxic
IgE-type immune responses are favored over involved in asthma pathogenesis, it seems cells requires major histocompatibility com-
nonallergic responses. likely that several genes play a role in asthma plex (MHC) class I molecule expression on
The processes that mediate immune development. One example is airway hyper- the surface of the cell that is presenting the
responses to antigens are reviewed in this responsiveness, an important defining feature antigen. All body cells express MHC class I
paper, along with examples of how such of asthma. A polymorphism of the gene that molecules and the antigens typically pre-
processes are altered by genetic defects and codes for the 32 receptor is associated with sented to CD8+ lymphocytes are neoantigens
environmental and lifestyle influences that airway hyperresponsiveness and may mediate produced within the host cell itself. These
may support the development of atopic this phenomenon in asthma (10). The loca- antigens usually include tumor antigens or
responses. Of special interest are environ- tion of this gene is of interest-it is located viral proteins generated during the viral life
mental and lifestyle factors that may act near a cluster of genes on chromosome 5q, cycle in which viral DNA or RNA uses the
before conception, during gestation, or dur- which plays a key role in mediating atopic protein-generating capability of the host cell.
ing early childhood such that an atopic or inflammation. Although it has been thought
asthmatic phenotype is found within a given that atopic inflammation causes airway
individual. Identification of environmental hyperresponsiveness, the clustering of these This article is based on a presentation at the Workshop
factors present during these critical windows genes provides an alternate explanation for to Identify Critical Windows of Exposure for Children's
of exposure may allow for intervention from the link between atopy and airway hyper- Health held 14-16 September 1999 in Richmond, Virginia.
both a personal and a public health perspec- reponsiveness in asthma. Address correspondence to D.B. Peden, The
Center for Environmental Medicine and Lung Biology,
tive. Avoidance of these agents during Environmental influences are also an 104 Mason Farm Road, CB#7310, UNC School of
important periods in immune development important determinant in the development Medicine, The University of North Carolina at Chapel
could result in decreased expression of of an atopic or asthmatic phenotype. Hill, Chapel Hill, NC 27599-7310 USA. Telephone: (919)
966-0768. Fax: (919) 966-9863. E-mail: peden@
atopic/asthmatic phenotypes in genetically Persons prone for development of atopy may med.unc.edu
susceptible individuals. only develop such responses if living in Received 10 January 2000; accepted 29 March 2000.

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D.B. PEDEN

Antigenic proteins are processed in the host of products of purine metabolism. If they are with initial exposure to a particular antigen.
cell cytoplasm by proteosomes, which results lacking in enzymes that allow metabolism of After producing IgM, B lymphocytes eventu-
in the production of derivative antigenic pep- purines to nontoxic products, lymphocyte ally mature into plasma cells that secrete IgA,
tides. These peptides are then transported to cytotoxicity occurs, resulting in other variants IgG, or IgE. The process of switching from
the endoplasmic reticulum in the Golgi appa- of SCID. These syndromes exemplify how IgM to production of one of the final
ratus. MHC proteins and 12 macroglobulin alterations in APC/T-cell interaction or T-cell immunoglobulin classes also requires activa-
are produced in the Golgi apparatus and the physiology alter immune responses. Although tion of CD40 (13,14).
antigenic peptide is complexed with these these cited alterations are due to genetic IgA is produced in the mucosa and is
molecules and transported to the host cell defects, environmental agents that target secreted by mucosal cells onto the lumen of
membrane. This complex interacts with the these processes could also impact the ultimate the airway and gastrointestinal tracts. IgA is
CD8+ lymphocyte via the T-cell receptor, the nature of the immune response to inhaled also secreted into breast milk, where it is pas-
CD8 molecule, and the CD3 receptor that antigens. sively consumed by infants. IgA exists as a
are clustered on the surface on the CD8 cell. dimer and binds to antigens, keeping them
These activated CD8+ cells then attack the Atopic T Helper (Th)-2 from adhering to mucosal surfaces and gain-
host cell bearing the antigenic peptides, Versus Nonatopic Thi ing entry into the body proper. IgG exists in
destroying that cell and, when effective, the Immune Responses the bloodstream as monomers; four subclasses
source of the antigenic peptides (13,14). There is no formal or standardized definition of IgG have been identified. IgGI and IgG3
Immune responses directed against for atopy. Persons are thought to be atopic if are thought to bind protein antigens and
proteins produced outside of host cells are they have one of a number of typical allergic IgG2 and IgG4 recognize polysaccharides.
directed by CD4+ T lymphocytes. These anti- clinical syndromes, induding atopic dermati- Receptors for IgG (FcYRI, -II, and -III) are
gens, which usually derive from bacteria, tis, food allergy, allergic rhinitis, and at least found on a number of effector cells, including
extracellular viral partides, uni- or multicellu- certain forms of asthma, such as that which polymorphonuclear neutrophils (PMNs).
lar parasites, or molecules produced by plants typically exists in early childhood. Atopic IgG binds to bacteria and can also activate
or animals, are processed by specialized or responses are often seen in response to a num- complement (via domains on the CH3 region
professional antigen-presenting cells (APCs). ber of allergens (such as animal, plant, or fun- of the molecule). IgG can confer protection
A number of cells can act as APCs, including gal antigens), which may be encountered by against foreign antigens by facilitating phago-
dendritic cells in the skin, alveolar macro- oral or inhalant routes or venoms from sting- cytosis of antigens by PMNs via FcyRs or by
phages, B lymphocytes, and venular endothe- ing insects. One difficulty in defining atopy is activation of complement, which directly
lial cells. The unique antigen presentation that many persons may develop several allergic causes foreign cell lysis or allows for interac-
function of these cells is mediated by expres- diseases or they may only manifest with one tion of the foreign antigen with phagocytes
sion of MHC class II molecules (13,14). disease. Likewise, persons who are otherwise via complement receptors. Interestingly,
APCs take up antigen via phagocytosis and thought to be nonatopic may mount an atopic IgG4 is associated with IgE and the true
digest these extracellularly derived molecules in response to an isolated antigen, such as a function of IgG4 is not dearly understood.
a lysosome or endosome. Independently, venom from a stinging insect, or a protective IgE is primarily produced in local tissues
MHC II molecules are generated in the Golgi eosinophilic response to multicellular para- (such as the gut or airway) and, after being
apparatus. Vesides containing MHC II mole- sites. Nonetheless, a key feature in any func- secreted by IgE-producing plasma cells, binds
cules then fuse with the endosomes containing tional definition of atopy is the development to cells that bear either high-affinity (FcERI)
digested foreign antigens and the antigen is of IgE antibodies directed against specific anti- or low-affinity (FcERII or CD23) receptors.
bound to the MHC II molecule. This complex gens, which is often associated with eosinophil FcERI receptors are expressed by mast cells
is then transported to the surface of the APC and mast cell activity (13,14). and basophils and cross-linking of IgE on
and interacts with clustered receptors on the Conversely, CD4+-mediated responses these cells leads to the release of histamine
surface of the CD4+ T lymphocyte. that result in IgG production and neutrophilic and production of a number of cytokines.
These cell molecules include the CD4+ inflammation are thought to be nonatopic. CD23-bearing cells include eosinophils and
receptor, the T-cell receptor, and the CD3 Nonatopic responses are typically elicited by platelets. In general, IgA impedes antigen
molecule. After the MHC II-antigen com- bacteria and viruses that are encountered as binding to mucosal surfaces, IgG facilitates
plex interacts with the surface molecules of the result of the infection of tissues. Atopic neutralization or phagocytosis of foreign anti-
the CD4+ T cell, the T cell is activated. The and nonatopic immune responses occur in gens, and IgE induces histamine release and
resulting immune response ultimately results persons who have an atopic disease. However, other phenomena associated with atopy or
in production of immunoglobulins directed it is interesting to note that many immune response to parasites (13,14).
against specific antigens (or antibodies) as deficiency diseases with blunted nonallergic
well as secretion of a number of cytokines responses are associated with phenotypic fea- Cytokine Mediation of Thi
that promote growth and differentiation of tures of atopy, such as eczema and increased and Th2 Responses by
effector cells in bone marrow and other tis- IgE production (13,14). CD4+ Lymphocytes
sues which complete the immune response CD4+ lymphocytes direct B cells to There is a difference in cytokine secretion
directed against the specific antigen (13,14). produce immunoglobulin directed against profiles of CD4+ T cells recovered from
A number of inherited immune defects specific antigens. B cells require antigen-bind- atopic and nonatopic subjects (16,17). These
demonstrate how essential these processes are ing and T-cell help to proceed with the initial cytokines mediate specific responses in
in directing immune responses (15). Defects formation of IgM. Activation of CD40 by immune cells and other tissues that result in
in expression of CD3 and the T-cell receptor CD40 ligand [a member of the tumor necro- the Thl and Th2 characteristics outlined in
by lymphocytes are a cause of one variant of sis factor (TNF)-a family] is necessary for "Atopic T Helper (Th)-2 Versus Nonatopic
severe combined immune deficiency (SCID). this response. This activation is expressed on Thl Immune Responses" (11). A summary
Defects in tyrosine kinase activity, such as a T lymphocytes. IgM is the initial immuno- of these cytokine actions follows [reviewed
lack of ZAP-70, also result in SCID. globulin response to any antigen by B cells, by Blumenthal (3) and Borish and
Lymphocytes are also susceptible to build-up and increases in circulating IgM correlate Rosenwasser (16)].

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Cytokines associated with Thl responses the action of IL-4. IL-13 is homologous with (DZ) twins with regard to asthma. MZ twins
include interleukin (IL)-2, interferon-y, and IL-4 and, like IL-4, induces B cell switching exhibited a 19.8% concordance for asthma
IL-12. IL-2 is secreted by Thl cells and stim- from IgM to IgE. versus 4.8% in DZ twins in one study. A sec-
ulates clonal expansion of antigen-specific Many other cytokines promote both Thl ond study involving 2,902 twin pairs
T cells, CD8 cell maturation, and is a switch and Th2 responses, including IL-1, IL-3, revealed 30 versus 12% concordance in MZ
factor for B lymphocytes, inducing them to IL-8, granulocyte macrophage colony-form- versus DZ twins [reviewed by Blumenthal
mature from IgM-secreting cells to IgGI- ing unit (GM-CSF), and TNF-a. IL-1 is (3) and Edfors-Dubs (19)]. With atopy
secreting cells. IL-2 is thought of as a Thl important in general T-cell activation. IL-3 is rather than asthma as an end point, 50-60%
cytokine, and is essential for all immune an essential growth factor for hematopoeitic concordance has been reported in twin pairs.
function defects in the IL-2 receptor in lym- cells, and is essential for mast cell and These studies indicate that there is a genetic
phocytes. IL-2 receptor defects also account eosinophil proliferation. IL-8 is primarily component for asthma and/or atopy.
for one of the most common forms of SCID. known as a chemotactic and priming agent However, it is clear that not all atopic per-
Interferon-y induces expression of Fc7Rs, for PMNs, but also has actions on basophils sons have the same diseases. Even monozy-
MHC class I, and MHC class II molecules on and eosinophils. GM-CSF is an important gotic twins, who have identical genomes, do
the surface of macrophages (facilitating their growth factor for neutrophils, eosinophils, not have 100% concordance with regard to
actions as antigen-presenting cells), promotes and macrophages. TNF-a has a broad spec- the development of asthma or atopic dis-
B cells to switch from secretion of IgM to trum of action, including upregulation of eases. The failure to observe 100% concor-
IgG2, inhibits B cell switch to IgE secretion, MHC class I and II molecules and activation dance (or even levels approaching 100%)
and induces other T cells to express a Thl of virtually every cell in the immune system. strongly suggests that environmental as well
rather than Th2 cytokine phenotype. IL-12 is Of interest are general observations exam- as genetic factors influence atopic or asthma
primarily secreted by macrophages (an ining the Thl versus Th2 response in phenotype expression.
antigen-presenting cell) and acts on T lym- humans (15). All healthy humans, whether The technique of mapping genes that code
phocytes to induce secretion of a Thl rather thought to be atopic or not, have a robust for mediators important in asthma and atopy
than Th2 cytokine profile. Thl response. Defects in Thl responsiveness (or at least phenotypes or disease characteris-
Cytokines associated with Th2 responses are associated with significant morbidities tics important in asthma or atopy) has been
include IL-4, IL-5, IL-10, and IL-13 (Table 1). linked to decreased immune function used to explore the genetic basis of asthma
IL-4 acts on B lymphocytes to induce the (increased infection and increased incidence and atopy (the candidate gene approach).
switch from IgM secretion to IgE and IgG4 of tumors). Conversely, the majority of Such studies carried out in a number of labo-
secretion and also contributes to the expres- humans do not manifest significant signs of ratories suggest that chromosome 5q31-33
sion of VCAM-1 on endothelial cells in post- Th2 immune activation (atopic diseases) and may be important in asthma and atopy, with
capillary venules. VCAM-1 is a ligand for an apparent lack of Th2 responses is not rou- genes for IL-3, IL-4, IL-5, IL-13, and GM-
VLA-4, a molecule expressed on eosinophil tinely linked to poor health. Many congenital CSF clustered on the 5q locus (3,20-22). This
membranes. Interaction of these molecules is immunodeficiency states, including several technique also indicates that the P subunit of
essential for migration of eosinophils from the varieties of SCID, hyper IgE syndrome, and the high affinity IgE receptor is located on
bloodstream to end-organ tissues. IL-5 pro- Wiskott-Aldrich syndrome, are typified by chromosome 11 q. All-in-all, candidate gene
motes eosinophil maturation and survival. diminished Thl and exaggerated Th2 studies have suggested linkages of potentially
IL-10 acts on macrophages to inhibit expres- responses. Likewise, exaggeration of atopic important genes with regions 5q (12 AR and
sion of MHC class II molecules and inhibits characteristics has been reported in some those listed above), 6p (HLA-DR), 1 lq, 12q
Thl responses by blunting production of acquired immunodeficiency virus patients. (interferon-Y), 13q, and 14q (TCR).
interferon-y. This cytokine also promotes T There appears to be a relationship between Positional cloning techniques (3) allow
cells to exhibit a Th2 phenotype by enhancing decreased Thl function and increased Th2 for examination of the genome for loci associ-
function. Uncovering the basis for Thl and ations with phenotypic features of asthmatic
Th2 balance may uncover potential targets and atopic subjects without a priori knowl-
Table 1. Summary of some key cytokines in atopy. for study of the effect of environmental expo- edge of the inflammatory or immune func-
Cytokine Description sures on the development of atopic diseases. tion of any subsequently identified DNA
sequences. Such studies suggest linkages of
GM-CSF An important growth factor for neutrophils, Genes Associated with Atopy asthma or atopy with regions 2q, 5p, 1 Ip,
eosinophils, and macrophages and Asthma
IL-1 An important T-lymphocyte activator 17p, 19q, and 21q (18-22).
IL-3 A hematopoeitic cell growth factor impor- Approximately 10% of the U.S. population
tant in mast cell and eosinophil growth has an atopic disorder (with reports of as high Development of Atopy
[l-4 Mediates immunoglobulin class switching as 30% having at least one positive skin test and Asthma
of B lymphocytes from IgM to IgE; response). An estimated 5-7% of the U.S.
contributes to the expression of VCAM-1, population has asthma. A common feature of Prenatal and Preconcepiional Influences
which allows for eosinophil adhesion (Parental Influences and Exposures)
to endothelial cells atopic disease is that it develops in susceptible
IL-5 An important growth factor for eosinophils individuals who experience exposure to sig- Aside from having a genetic predisposition
[l-8 A potent neutrophil chemoattractant, also nificant environmental or lifestyle-related for atopy, no specific preconceptional influ-
primes eosinophil responses stimuli. Susceptibility for development of ences that are strongly linked to development
IL-1D Acts as an anti-inflammatory cytokine; atopic disease appears to have familial associa- of atopy have been identified in humans. Th2
blunts expression of MHC class 11 tions and genetic components. responses can clearly occur in fetal life, as
molecules on antigen-presenting cells; demonstrated by antigen-specific IgE and the
blunts secretion of interferon-yby Evidence for a genetic component for
T lymphocytes asthma is found in studies of disease pheno- of allergen-responsive lymphocyte
presence
IL-13 Mediates immunoglobulin class switching types on twin pairs (3,18,19). There is sig- and mononuclear cells in cord blood
of B lymphocytes from IgM to IgE; shares nificantly greater concordance among (5,7,11,232). Furthermore, infants can
some homology with IL-4 monozygotic (MZ) twins than dizygotic have positive skin tests to food allergens,

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D.B. PEDEN

presumably due to maternal ingestion of food atopy until Thi stresses (and response to that food allergen avoidance in at-risk infants
allergens. However, attempts at decreasing those stresses) occur (24,25,31,3!). is protective against the development of
maternal exposure to food allergens have not atopy ( 11).
been shown to decrease fetal levels of IgE or Postnatal Influences and the In addition to allergen exposure, maternal
the likelihood of the child having atopic dis- Development of Atopy and tobacco smoking has also been linked to
ease (11). Nonetheless, several studies have Atopy in Children increased rates of wheezing and asthma in
shown that maternal factors outweigh pater- Early exposure to allergens in susceptible exposed children, increased bronchial reac-
nal factors in the development of atopy or individuals has been postulated as an impor- tivity, and increased total and antigen-
asthma in children (11,28). These observa- tant factor in development of an atopic phe- specific IgE (11,39-41). Exposure to
tions support the hypothesis that maternal notype (eczema, rhinitis, or asthma) during environmental tobacco smoke (ETS) may
influences, whether genetic, transplacental, or childhood. Correlations between early expo- enhance atopy by a number of mechanisms.
environmental, may play a role in the devel- sure to seasonal airborne allergens and devel- These include increased airway mucosal per-
opment of atopy or asthma. opment of atopic responses to those allergens meability or direct effect on immune func-
Recent studies have focused on immune have been reported. Specifically, seasonal tion. The link between ETS and asthma
function of neonates as it relates to atopy allergens prevalent during the first month of appears clear with regard to exacerbation of
development. Several studies showed that life seem to predict eventual development of preexisting disease. Although there is still
mononuclear cells recovered from cord blood atopic airway disease related to that allergen debate on the effect of ETS in the develop-
have robust proliferative responses to stimu- in later childhood. Similar arguments have ment of asthma or atopy, the preponderance
lation with allergens [including house dust been made regarding house dust mite expo- of the evidence supports the hypothesis that
mite antigen, rye grass pollen extract, Fel d I sure, with children living in environments ETS enhances atopy development in suscep-
(cat allergen), ovalbumin, and ,-lactoglobu- with increased levels of mite allergen in col- tible individuals.
lin]. Similarly, stimulated cord blood lected house dust during the first year of life
mononuclear cells secreted Th2 cytokines, being more likely to develop asthma. Studies Environmental Influences in
including IL-4, IL-5, IL-9, IL-10 and IL-13. that examined efforts to reduce the incidence the Development of Atopy
It is noteworthy that the Th2-type cord of atopic airway disease by decreasing allergen and Asthma
blood mononuclear cell (CBMC) responses exposure during the first year of life are in the I have outlined "normal" factors that may
occur both in infants who were thought to very early stages. One such study reported influence the development of asthma and
be at low risk for development of atopy that the combination of decreased airway and atopy in fetal life and in early and later child-
(based on family history) as well as those oral allergen exposure seems to decrease inci- hood. These factors primarily dealt with aller-
thought to be at higher risk for atopy dence of atopic diseases at 2 and 4 years of gen exposure, maternal dietary exposure, and
(11,24,29-35). Interferon-y also appears to age (5,11,31). patterns of immune expression in fetal and
be important in the development of atopy at Perhaps better understood is the relation- early life. I now expand on the initial review
a young age (30,31,36-38). Interferon-y is ship between food allergen exposure and the and examine a number of potential lifestyle
associated with Thl responses, antagonizes development of atopic responses [reviewed by and environmental influences that have been
the action of IL-4, and blunts production of the Early Treatment of the Atopic Child proposed as modulating factors in the devel-
IL-4 (16). Studies in many laboratories study group (5), Bjorksten et al. (11), and opment of atopy. These include living in
demonstrate that CBMCs or peripheral Platts-Mills et al. (37)]. Positive allergy skin urban versus rural settings, dietary factors,
blood mononuclear cells from neonates have tests have been reported within the first 3 exercise patterns, having experienced infec-
diminished ability to produce interferon--y months of life in nearly 30% of children born tions, or the use of antibiotics (which might
compared to cells from normal adults after to atopic parents. The disease state most com- influence deviation of the immune system
stimulation with mitogens. This blunting monly associated with food allergy in infants away from Th2 responses and toward Thl
generally resolves by 5 years of age. However, is eczema, and 80-90% of infants with responses).
there appears to be a trend in which inter- eczema will develop a positive skin test to air- Additionally, there are some data examin-
feron-~y responses in cells obtained from chil- borne allergens. It has been argued that both ing the role of specific environmental influ-
dren who develop atopic disease are even maternal and neonatal exposure to food aller- ences (including ETS, diesel exhaust,
more blunted than those from nonatopic gens contributes to the development of spe- endotoxin exposure, and criteria air pollu-
children. Some have argued that production cific allergen responses. A milk and egg tants) having an effect on developing certain
of adult levels of interferon-y by mono- allergy is perhaps the most common of the patterns of immune expression. I review what
nuclear cells occurs later in atopic children food allergy states in infants (5,11). is known or commonly hypothesized about
than in nonatopic children. Thus, blunting Infants who are exclusively breast-fed the role of these influences on the develop-
of Thl responses may be important in main- appear to have decreased risk for the develop- ment of atopy and asthma and highlight the
taining Th2 responses. ment of food allergy than infants who are not known influence of specific pollutants on
These results, and others, have led to the breast-fed or who are have other food expo- immune responses.
argument that a Th2 phenotype is relatively sures. It has also been suggested that food
universal in all neonates and that subsequent allergens that may be secreted into breast milk Lifestyle Influences on the
postnatal development of atopy may be due may pose a risk for sensitization in those Development of Atopy
to the failure of Thl responses to adequately exposed infants. Although decreased foreign A number of epidemiological studies have
develop. This notion is supported by animal food exposure is one mechanism by which pointed to the potential role of lifestyle as a
observations that dendritic cell function is breast-feeding of infants may be protective, factor that modulates the expression of atopy
dampened in neonatal rodents. This prevents the presence of maternal IgA in breast milk in susceptible individuals [reviewed by Platts-
robust Thl responses from occurring during may also be important. Although data can be Mills et al. (327]. One of the most intriguing
fetal life. It has been speculated that dampen- cited on either side of the breast-feeding argu- examples of the effect of lifestyle is the exami-
ing Thl responses is important for fetal sur- ment regarding its role in protection against nation of the prevalence of asthma and atopy
vival and that all infants are predisposed for food allergies, the weight of evidence indicates in children from eastern and western Germany

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ENVIRONMENTAL FACTORS IN DEVELOPMENT OF ATOPY

at times after the political reunification of that Infections and Antibiotics: Effect on correlates with the subsequent development
state. Shortly after reunification in 1990, Thi versus Th2 Cytokine Expression of atopy. Similarly, in societies in which anti-
studies of the prevalence of atopy and asthma biotic use is decreased and natural infections
in children from East and West Germany There is evidence to suggest that fetal immune are more frequent, atopy occurs less frequently.
revealed that children from the east, albeit function is primarily of the Th2 type (23-25, However, despite these data, it seems unlikely
more likely to be diagnosed with bronchitis, 30,31,33,34,37,43). It has been further sug- that children at very high risk for asthma
were less likely to have atopy, had fewer posi- gested that environmental stresses which sup- (inner-city African Americans) have increased
tive skin tests, and were less likely to have press Thl responses of the infant may allow exposure to antibiotics compared to more
asthma than their western counterparts (42). for the persistence of Th2 immune function, affluent populations at lesser risk (31,32).
Although it was unclear which lifestyle fac- thus increasing the potential for development In addition to antigen-specific immune
tors were influencing atopy development, of atopic diseases such as asthma (31,37,44). responses, it has been suggested that accessory
there were some candidate influences. Among the most frequently reported immuno- molecules expressed by bacteria (classic Thl
Children in the east were more likely to be logical features manifesting in children with stimuli) may contribute to immune matura-
placed in day care than those in the west. atopic diseases is decreased ability of circulat- tion such that Thl responses are emphasized
Also, potential differences in diet, especially ing mononuclear cells to produce interferon-y (31,48). Lipopolysaccharide (LPS) is a mole-
fat intake, were suggested as possible influ- after in vitro stimulation with either mitogens cule expressed on all gram-negative bacteria
ences. In the early 1990s, particulate pollu- or specific allergens (24,30,36,31,45). that interacts with antigen-presenting cells
tion was higher in the east, whereas private Interferon-y plays a key role in expression of a and other immune effector cells via the
automobile use and ozone exposure were Thl phenotype and antagonizes the action of CD14 receptor. Treatment of APCs with
more common in the west. Allergen exposure IL-4, which allows for the development of IgE. LPS results in secretion of IL-12, which in
was not thought to be substantially different Against this backdrop, the role of interven- turn blunts Th2 responses and stimulates
in the east than in the west. tional modifiers of Thl responsiveness (vac- interferon-y secretion. It has been argued that
It is now a few years later, and rates of cines, infections, and antibiotics) on atopy will mucosal colonization with bacteria, including
atopy in eastern Germany have increased and be reviewed. LPS-bearing organisms, allows for nonspecific
are approaching those found in western Perhaps one of the most interesting and deviation toward the Thl phenotype.
Germany. This has been associated with the controversial observations on the role of Thl Recently, it was found that the gene for
development of a more westernized lifestyle stimuli on Th2 expression is found when CD14 colocalizes with genes for IL-3, IL-4,
in the east, including decreased use of coal in examining the effect of the antituberculosis vac- and GM-CSF on the chromosome region
industry, increased automobile use, and cine Bacillus Calmette-Guerin (BCG) on the 5q3 1.1. Furthermore, a specific polymor-
increased availability of high-fat foods. development of atopy. Japanese schoolchildren, phism has been identified (a C-to-T transi-
Decreased exercise and changes in architec- who routinely undergo BCG vaccination, had a tion at base pair -159) in which those
tural style have also been associated with the significant inverse relationship between delayed children homozygous for the T allele have
development of atopy and asthma. A compar- hypersensitivity to Mycobacterium tuberculosis significantly higher levels of soluble CD14
ison of heating styles in rural versus urban and incidence of asthma and elevation of IgE than do heterozygotes or those who are
western Germany shows decreased asthma (46). As with many studies of environmental homozygous for the C allele (48). In turn,
and atopy in the rural setting, in which influences on atopic disease, there are con- serum levels of CD14 (which could mediate
wood- and coal-burning furnaces are used to founding data. Studies in Britain fail to show a LPS interaction with APCs) have a significant
heat homes. It was thought that bedroom and relationship between response to BCG vaccina- positive correlation with interferon-y and a
indoor temperatures were less in these homes tion and atopy (46). Furthermore, whether the negative correlation with IL-4 (48). This
than in urban homes, which might contribute observations by Shirakawa et al. (45) result observation supports the hypothesis that an
to decreased expression of atopy. Dampness from the effect of the vaccine itself or the innate imbalance between Thl and Th2 influences
and water damage have also been associated ability of that child to respond to that vaccine is the development of atopic disease.
with increased expression of allergic disease. open to debate (46). However, experiments in
Similar observations have been made mice, which demonstrate that immunization Spedfic Pollutants and Their Effects
between other previously Eastern Bloc and with BCG blunts development of allergen-spe- on Th2 Inflammation
western countries, as well as comparisons of cific IgE and eosinophilic responses to allergen A number of ambient air pollutants are
asthma in rural versus urban Africa, Europe, after allergen challenge, support the idea that thought to contribute to the exacerbation of
and the Pacific (New Zealand and Australia). BCG vaccine is a potent Thl stimulus (47). asthma. Indeed, criteria pollutants such as
This effect of more recent westernization of Taken together, these observations support the NO2 and O3 have been associated with
lifestyle in these locations mirrors the devel- notion that BCG stimulates increased Thl asthma exacerbation in epidemiological
opment of asthma in previously westernized function and is associated with decreased Th2 studies and, in challenge and animal studies,
countries. Likewise, the problem of asthma in immune responsiveness. can enhance immediate and late-phase
inner-city minority populations suggests a It has also been argued that decreased responses to inhaled allergens in already sensi-
role for urbanization in the expression of incidence of infection and frequent use of tized individuals (49-51). However, with
atopy (37). antibiotics may also be contributing to the perhaps some animal data to the contrary,
All in all, it seems quite likely that urban- development of atopy. The hypothesis is that these pollutants do not appear to play a sig-
ization is a key feature in the development of by decreasing exposure to Thl stimuli (either nificant role in the actual development of the
asthma and atopy. This likely represents by active infection or by alteration of bacterial Th2 phenotype. In contrast, diesel exhaust
alterations in the environment, which allow colonization, which may stimulate Thl particles (DEPs) shift the immune phenotype
for the expression of important genes that immune responses), the Th2 immune respon- toward a Th2 pattern (51).
result in an atopic phenotype. Delineation of siveness expressed by the fetus has a better DEPs. Numerous animal (murine) and in
the specific features of urban lifestyle that chance of being maintained, thus allowing for vitro studies have demonstrated that DEPs
allow the atopic phenotype to be expressed expression of the immune phenotype. The enhance allergen-induced immune responses,
is incomplete. use of antibiotics in the early years of life including increasing IgE production and

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D.B. PEDEN

enhancing cytokines involved in eosinophilic ETS. There is extensive literature indicat- pathogenesis or the induction of atopy. There
or allergic inflammation, especially IL-4, IL-5, ing that ETS is a significant exacerbating fac- are several complete reviews outlining the
and GM-CSF, as well as airway hyperrespon- tor for a number of respiratory tract diseases, effects of ozone and other criteria air pol-
siveness (51-56). DEPs induce B-lymphocyte including asthma, which has been extensively lutants in asthma and atopy (48-51).
immunoglobulin isotype switching to IgE reviewed (39-41). Asthma-specific end points
(57,58). Polyaromatic hydrocarbon residues increased by ETS include the risk of hospital- Summary and Gaps in
on DEPs may be responsible for this effect on ization, medication use, airway hyperrespon- Knowledge
allergic inflammation (56). siveness and, rarely, atopy or increased IgE The development of atopy is a complex
Diaz-Sanchez et al. (57) used nasal (39-41). ETS or maternal smoking during immune process. I have outlined some of the
challenge studies in humans and reported pregnancy appears to be an especially impor- processes involved in immune responsiveness,
that challenge of volunteers (four atopic and tant risk factor for the development of asthma including antigen presentation, action of
seven nonatopic) to DEP increased nasal IgE in the first year of life. However, despite either CD8+ or CD4+ lymphocytes, and
production 4 days after DEP challenge with- strong epidemiological evidence that ETS expression of a Thl or Th2 phenotype for
out any effect on IgG, IgA, or IgM. They also poses a significant risk for asthma exacerba- CD4+-mediated responses. I also reviewed a
noted shifts in the ratio of the five isoforms of tion, candidate mechanisms of action remain number of defects that exist in the immune
IgE with the challenge. This effect was very undefined (40). system that serve as experiments of nature,
dose specific; only a 0.3-mg dose of DEP Recently, tobacco smoke extracts were which demonstrates the multitude of poten-
caused this result. shown to alter monocyte function in mice tial targets for environmental modification of
Diaz-Sanchez et al. (57) also found that (59). Among those functions suppressed are immune responsiveness.
DEP challenge of the nasal mucosa causes those that are commonly mediated by inter- These findings suggest that fetal immune
increased cytokine production by cells feron-y, including phagocytosis of opsonized responsiveness mediated by CD4+ lympho-
recovered in lavage fluid. Subjects under- antigens, MHC class II molecule expression, cytes is skewed toward Th2 expression. In
went lavage pre- and postchallenge with 0.3 oxidative burst, and NO synthesis. Activities turn, subsequent development of atopic dis-
mg DEP. Cells recovered in the prechal- not suppressed, including TNF-a production, ease during postnatal life may actually be per-
lenge lavage had detectable mRNA levels for are not induced by interferon-y. Similarly, sistence of the fetal atopic state. It has been
interferon-y, IL-2, and IL-13, whereas those PAHs, the same species of molecules that additionally suggested that the relative failure
recovered postchallenge were associated likely mediate the Th2-promoting actions of of Th 1 influences to deviate the immune
with detectable levels of IL-2, IL-4, IL-5, DEPs, are also found in ETS. response away from a Th2 expression is
IL-6, IL-10, IL-1 3, and interferon-y in Endotoxin. An inability to respond to important in the development of clinically
recovered cells. IL-4 protein was also mea- LPS (mediated by CD14 receptor polymor- significant atopy. Some of this may be due to
sured in postchallenge lavage [reviewed by phisms) may enhance initial expression of a certain genetic influences that support Th2
Peden (50)]. Although it is unclear which Th2-immune phenotype (47). However, in responses (genes supporting the production
type of cells were present in lavage fluid persons already sensitized, it seems likely that of IL-4) as well as genetic predisposition
before or after challenge, it was not thought LPS augments the expression of Th2 inflam- against full development of Thl responses
to be due to increased lymphocyte number. mation. There is evidence that levels of LPS (i.e., genes which might blunt production of
When coupled with challenge with a spe- in house dust are more predictive of asthma interferon-y). However flawed this hypothesis
cific allergen (ragweed), DEP yielded an severity in mite-sensitive asthmatics than mite may prove to be, it does provide a construct
enhanced ragweed-specific IgE and IgG allergen levels in the same samples (60). on which we might begin to examine the role
response to ragweed allergen compared to Furthermore, asthmatics have increased non- of environmental influences on the expression
ragweed alone. This effect included specific airway responsiveness after exposure of atopic disease in postnatal life.
increased expression of IL-4, IL-5, IL-6, IL- to LPS [reviewed by Peden (50)]. Atopic sub- Superimposed on any genetic predisposi-
10, and IL-13, decreased expression of jects yield eosinophilic responses to LPS and tion that may exist is the role of environmen-
interferon-y and IL-2, and no effect on total LPS pretreatment enhances response to tal influences that might induce either Thl
IgE and IgG. inhaled allergens (50,61). Likewise, allergen responses (certain immunizations such as
Compared to other pollutants such as challenge yields increased levels of CD 14 in BCG, bacterial infections and stimuli, and
ozone, DEP appears to be unique in its effect bronchoalveolar lavage fluid and enhances colonization with bacteria) or Th2 responses
on IgE production. The in vivo effect of PMN and eosinophil responses to LPS in the (early exposure to allergens, especially food
DEP on IgE isotype switch can be replicated nasal airways (50,62). However, for the most allergens and indoor aeroallergens). Other
in vitro with extracts from DEP containing part, the ability of LPS to induce asthma and influences may be important as well, includ-
the polyaromatic hydrocarbon (PAH) frac- atopic responses has only been observed in ing toxicological stimuli that may shift the
tion from these particles, as well as the spe- subjects already found to have atopy. immune response toward a Th2 response
cific PAH compounds phenanthrene and Ozone and other criteria pollutants. As (such as PAH moities from diesel exhaust and
2,3,7,8-tetracholorodibenzo-p-dioxin (56). with LPS, ozone clearly has adverse effects on tobacco smoke).
Thus, PAHs, by their action on B cells, persons already diagnosed as atopic or asth- Another important question is if the tim-
appear to play a central role in the effect of matic (48-51). This pollutant is linked to ing of exposure to potential environmental
diesel exhaust on allergic inflammation. increased medication use, increased hospital- stresses is important in subsequent postnatal
Additionally, DEPs can also promote CD80 ization, and increased emergency room visits. expression of an atopic/asthmatic phenotype
(an important molecule for MHC class II Likewise, in both animal and human models, (Table 2). Other than carrying genes that
antigen presentation) expression in this gas can enhance both immediate and predispose an individual to developing
macrophages as well as in enhanced LPS- late-phase inflammation associated with aller- atopic responses, preconceptional exposure
induced IL-10 responses. These effects on gen exposure and can directly induce of parents to environmental factors is
macrophages could alter their ability to pre- eosinophil responses in atopic subjects. unlikely to be an important window of
sent antigen in such a way as to promote However, there is no clear indication that this exposure for the development of atopy in
Th2 responses to those antigens. pollutant, SO2, or NO2 play a role in asthma subsequent offspring.

480 Environmental Health Perspectives * Vol 108, Supplement 3 * June 2000


ENVIRONMENTAL FACTORS IN DEVELOPMENT OF ATOPY

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