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Environmental
Health Perspectives Supplements Volume 110, Number 4, August 2002
Environmental Contributions to the Allergic Asthma Epidemic
Farrah Kheradmand,1,3 Kirtee Rishi,1,3 and
David B. Corry2,3
1Departments of Medicine and 2Immunology, and
3The Biology of Inflammation Center, Baylor College of Medicine,
Houston, Texas, USA
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Full Article in PDF
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Abstract
Current data overwhelmingly document the existence of a worldwide asthma
epidemic, although individual studies remain controversial. The epidemic
is thought to involve primarily persons with allergic asthma, and many
diverse theories, based on an immunopathologic understanding of disease,
have recently emerged to explain this involvement. In the context of recent
insights into the immune basis of experimental asthma, we discuss in this
review the leading asthma epidemic theories, including a new theory based
on inhaled environmental proteases. Although no single theory may yet
be fully embraced, there exists substantial hope that a unifying mechanism
for the epidemic will be revealed through additional research. Key
words: adjuvant, air pollution, aspirin, asthma, costimulatory molecule,
dust mite, helminth, immunoglobulin E, protease, TH2 cell.
Environ Health Perspect 110(suppl 4):553-556 (2002).
http://ehpnet1.niehs.nih.gov/docs/2002/suppl-4/553-556kheradmand/abstract.html
This article is part of the monograph Environmental
Air Toxics: Role in Asthma Occurrence?
Address correspondence to D.B. Corry, Baylor College
of Medicine, Medicine/Pulmonary Section, One Baylor Plaza, Suite 520B,
Houston, TX 77030 USA. Telephone: (713) 798-8740. Fax: (713) 798-3619.
E-mail: dcorry@bcm.tmc.edu
This work was supported by U.S. National Institutes
of Health grants K08HL03344, K08HL03732, and R01HL64061, and the Caroline
Weiss Law Fund for Molecular Medicine.
Received 3 October 2001; accepted 17 January 2002.
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Introduction
Evidence has accumulated over the past 30 years indicating that the allergic
syndromes, especially asthma, have increased in prevalence and severity (1).
These trends have, for perhaps the first time, transformed what was formerly
a relatively inconspicuous ailment into an epidemic illness of significant public
health concern. In addition to chronic disability and negative impact on quality
of life, the economic burden of asthma is now substantial (2,3). Perhaps
most disturbing, these alarming asthma statistics are not confined to the United
States but are reflected throughout the industrialized world (4), creating
an unprecedented medical conundrum. Legitimate doubt as to the existence of
the asthma epidemic may be raised on the basis of supporting epidemiologic data.
Many studies documenting a rise in disease prevalence are based on patient questionnaires,
which are subject to considerable bias. Despite this and other methodologic
objections, an increase in asthma prevalence has been consistently documented
throughout the world--indeed, there appear to be no studies that refute this
trend (4). Further, asthma mortality data, which provide a far more objective
end point than prevalence statistics, are also increasing in the same countries
where prevalence is rising (5). Thus, despite reasonable objections to
the methodology of many supporting studies, current literature overwhelmingly
supports the existence of a true asthma epidemic.
In this review we consider the potential role the environment in mediating
the epidemic of asthma. We first consider the immune mechanisms that may underlie
the causes of asthma and subsequently the major theories that have recently
emerged to explain the epidemic.
The Immune Response and Asthma
Many of the asthma epidemic theories incorporate recent insights into the
immunopathologic basis of allergic inflammation. Inflammatory responses are
complex, involving numerous cells and secreted products that activate a diverse
range of host-protective responses. However, partially compensating for this
complexity is the redundancy of immune responses, in which the same inflammatory
mechanisms are activated in response to many different inflammatory insults.
This redundancy is such that much of immunity can be organized into two principal
responses called T-helper type 1 (TH1) and type 2 (TH2).
TH1 cells, which secrete interferon gamma and other cytokines, confer
protection against pathogens such as bacteria. In contrast, TH2 cells,
which secrete cytokines such as interleukin (IL) 4, IL-5, and IL-13, control
larger pathogens such as parasitic worms. Both T-cell types are mutually antagonistic
and are rarely found together at the same inflammatory site. T-helper cells
are usually protective, of course, but they are also associated with maladaptive
responses. TH2 cells especially are thought to contribute to allergic
diseases including asthma and allergic rhinitis (6,7) by secreting cytokines
such as IL-4 and IL-13 (8) or by promoting secretion of allergenic products
such as immunoglobulin E (IgE) (9).
Theories of the Asthma Epidemic
The major theories regarding the asthma epidemic propose that environmental
changes create a relative imbalance in TH1 and TH2 cells
and/or an overall increase in allergenic products. Yet, despite what appears
to be a unifying pathophysiologic framework, extremely diverse theories have
emerged. Under the following subheadings, we discuss the evidence that supports
and refutes these theories and indicate where future studies might be helpful
in clarifying unresolved issues.
Infection
Through complex means, a variety of infections are believed to influence the
expression of asthma. For example, a relative deficiency in TH1-inducing
infections or inflammations involving the upper and lower airway may lead to
excess TH2 activation in the airway (10,11). Presumably, low-grade
infections with TH1-dependent pathogens such as Mycobacterium
tuberculosis, the causative agent of human tuberculosis, and related organisms
antagonize TH2 cells and thereby suppress diseases such as asthma.
Experimental support for this theory exists, as shown by the ability of mycobacteria
such as M. tuberculosis to suppress allergic lung inflammation (12,13).
In addition, certain bacterial products such as DNA (unmethylated CpG motifs)
are sufficient to block or reverse experimental allergic lung disease (14).
However, the negative statistical association of tuberculin reactivity (a skin
test-based index of exposure to M. tuberculosis) with subsequent
atopic disease in Japanese schoolchildren (10) has not been confirmed
in other populations (15). Further, although mycobacterial diseases such
as tuberculosis have been declining in importance for a century or more (16),
it is not clear why this has resulted in increased allergic disease only in
the last 30 years. Thus, while mycobacteria and their products clearly antagonize
allergic lung inflammation, the evidence that exposure to these organisms has
changed sufficiently to account for the epidemic is inconclusive.
Other infections are proposed to contribute to allergic disease, including
chronic infections with the bacterium Chlamydia pneumoniae, respiratory
viruses, parasites such as Toxocara canis, and fungi, including Aspergillus
species. In all respects, these organisms differ markedly from each other
and probably contribute in very different ways to allergic disease. Parasites
and fungi likely cause disease directly, as extracts from these organisms are
powerful allergens (17,18). Despite their long associations with asthma,
the mechanisms by which C. pneumoniae and viruses may mediate allergic
disease are not clear. However, in an allergic setting, an inappropriate TH2
immune response may be generated against any respiratory tract pathogen, delaying
clearance of the infection and effectively converting the organism into a self-replicating
allergen (19). In accord with a recent study, eradication of the organism
under these circumstances may not necessarily resolve the underlying asthma
(20). Thus, some infections may exacerbate existing disease, but no studies
yet demonstrate that infections are intrinsic causes of asthma, and they cannot
currently be implicated in the asthma epidemic.
A related theory proposes an entirely different etiology for allergic disease--that
lack of TH2-dependent pathogens, especially intestinal helminths,
creates an imbalance of polyclonal compared with specific IgE. Lack of exposure
to parasites is proposed to lead to increased specific IgE, which, if not countered
by the effects of polyclonal antibody, becomes extremely efficient at triggering
allergic disease (21). Parasite infestations have clearly declined in
Western societies, but like tuberculosis, this trend was all but complete long
before the asthma epidemic began. Further, additional data suggest that asthma
rates may not differ significantly between urban, parasite-free groups and rural,
heavily parasitized populations, suggesting that factors other than parasites
themselves may be more important (22). Another serious obstacle with
this hypothesis is the clinical evidence that elimination of virtually all IgE,
using modified neutralizing antibodies, has little effect on clinically relevant
physiologic end points in asthma patients (23).
The Hygiene Hypothesis
This theory also implicates a variety of infections or microbial products
(or lack thereof) in mediating immune bias in favor of TH2 reactivity
and predisposition to asthma. An important additional tenet of this theory is
that such exaggerated TH2 conditioning occurs primarily in the perinatal
period, involving the aberrant tendency of the neonate to preferentially mount
TH2 immunity. With maturity, the immune system adopts a more balanced
activation profile characterized by both TH1 and TH2 responses
(24). For unclear reasons, genetically predisposed individuals retain
their TH2 predisposition, potentially resulting in childhood asthma
that carries over into adulthood (25). A critical assumption of this
theory is that maternally acquired allergens are carried across the placenta
and against which the fetus begins making TH2 responses (26).
Thus, the fetus is literally born allergic. Genetic factors are acknowledged
to play a role, but these are presumably secondary to primary alterations in
exposure to the various infectious agents or their products discussed earlier.
In addition, hyperactive intrauterine mechanisms that attempt to limit the embryotoxic
effects of TH1 cytokines are also thought to play a role (25).
In addition to the difficulties in understanding how infections may contribute
to the asthma epidemic, several independent observations challenge the assumption
that the neonatal immune response is TH2 biased and therefore predisposed
to asthma. The greater susceptibility of neonates to infections, rather than
indicative of such an abnormality, more likely reflects simply a normal one
that has yet to develop memory. Further, whereas some innate components of immunity
such as neutrophils may be truly immature or only partially functional in the
neonate (27), neonatal T cells actually produce both TH1 and
TH2 cytokines comparable to their adult counterparts (28).
Also, rather than inducing ineffective immune responses, as some reports have
implied, immunization of newborns or even fetal baboons with common antigens
produces normal, competent antibody responses (29). Thus, there are few
data to support the existence of an intrinsic, neonatal T-cell defect that might
underlie a predisposition to allergy. It is further difficult to understand
how antigens would accumulate in the maternal blood in sufficient quantity to
cross over to the fetus to induce sensitization. Neonatal T cells do react to
a variety of foodborne and other environmental antigens, but this appears to
be an extremely common and perhaps ubiquitous feature of pregnancy, and therefore
one that is unlikely to participate in the asthma epidemic (30,31). However,
other mechanisms by which the neonate might acquire an allergic predisposition
have been suggested. One provocative concept is that maternal-derived amniotic
cytokines bias the developing fetal immune system toward TH2 reactivity
(32).
The maternal-fetal relationship is clearly complex and one that may have
important consequences for allergic reactivity and asthma in early and late
life. Maternal intrauterine factors may ultimately be shown to be important
in determining allergic reactivity of the newborn, but it is unclear how such
mechanisms can account for the asthma epidemic. It seems more likely at this
time that an environmental factor simultaneously affecting the mother and the
newborn may largely account for concomitant maternal and neonatal allergic sensitization
and asthma, and perhaps the asthma epidemic as well.
Air Pollution
Certain air pollutants are associated with respiratory allergy and have been
shown experimentally to modify TH2 function and IgE secretion. Tobacco
smoke acts as an immunologic adjuvant, promoting antigen-specific IgE production
in sensitized mice (33). More general air pollutants may also influence
the severity of allergic disease. Diesel exhaust particles (DEP) augment nasal
cytokine production and increase production of allergen-specific IgE in humans
(34,35). In mice, DEP exacerbate antigen-induced experimental allergic
airway disease but are incapable of inducing disease independent of antigen
(36). Therefore, like certain infectious etiologies, diverse hydrocarbon-based
air pollutants may exacerbate existing allergic disease, but there is no evidence
yet that they give rise to new cases, and their role in the asthma epidemic
consequently remains to be established.
Aspirin Use
The use of aspirin in pediatric patients began to decline about 20 years ago
at approximately the time when the childhood asthma epidemic began. Aspirin,
unlike its substitute acetaminophen, blocks prostaglandin E2 (PGE2)
synthesis by inhibiting the enzyme cyclooxygenase-2. PGE2 in turn
promotes TH2 development and TH2-like effects. The switch
away from aspirin to acetaminophen in children, the result of aspirin's association
with the devastating neurologic illness Reye's syndrome, therefore, resulted
in a population with higher average PGE2 levels and potentially greater
susceptibility to allergic diseases such as asthma (37). Arguing against
this provocative theory is that the asthma epidemic also involves adults who
use aspirin. Further, other cyclooxygenase inhibitors, including nonsteroidal
anti-inflammatory drugs such as ibuprofen, are commonly used in children and
do not induce Reye's syndrome. Finally, no independent association of acetaminophen
use with the asthma epidemic in children has yet been determined.
Exercise and Obesity
This theory postulates that decreased physical activity and increased obesity,
increasingly common characteristics of American children, might partly be responsible
for the epidemic (38). These same changes are associated with epidemic
increases in other lifestyle-related illnesses such as type 2 diabetes mellitus,
suggesting a possible common etiology between childhood asthma and diabetes
(39). Although intriguing, no studies have yet provided insight into
how asthma might arise with decreased activity, obesity, or diabetes. However,
the evolving lifestyle of the Westernized child probably also includes greater
amounts of time spent indoors, perhaps resulting in increased exposure to an
indoor pollutant that induces asthma.
Environmental Proteases
There exists a consistent biochemical connection between the allergens associated
with asthma and other organisms that activate TH2 cells and allergic
mechanisms. The larvae of intestinal parasites secrete many products, but of
particular interest are proteases, which they require presumably to burrow through
host connective tissue that otherwise impedes their visceral migrations (40).
As secreted products common to virtually all intestinal helminths, proteases
are therefore logical triggers for immune, and especially TH2, activation
and parasite eradication. Other organisms associated with allergic reactivity
and asthma also possess protease activity. The pollen of many plant species
contains proteases required for fertilization. Because they cannot take food
internally, fungi, which are strongly associated with asthmalike diseases such
as allergic bronchopulmonary aspergillosis (41), must secrete proteases
to digest organic matter. Further, the house dust mite, the organism serologically
most commonly linked with asthma, is thought to shed a variety of asthmagenic
proteins, but the most important of these are also proteases (42). Finally,
the major cat allergen identified from the serum of asthma patients, Fel d I,
is, or is associated with, a protease (43).
The strong association of proteases and clinically relevant allergens suggests
a testable hypothesis regarding the role of these enzymes in asthma. This theory
predicts that proteases act as immunologic adjuvants or costimulatory molecules,
directing TH2 activation without necessarily serving as antigens
themselves. Such a nonimmunogenic, adjuvant role of proteases would be required
to explain the lack of serologically identifiable protease in other major human
allergens. Even if shown, a TH2 adjuvant role for proteases does
not by itself explain the asthma epidemic. Among other tasks, a change in overall
accumulation and exposure to environmental proteases would have to be documented
around the time at which the epidemic began. Surprisingly, such potential sources
were originally identified many years ago and include laundry detergent proteases
that proved to be risk factors for asthma in detergent factory workers (44,45).
It is also striking that the first documentation of these epidemics occurred
immediately before the global asthma epidemic, at a time when worldwide distribution
of enzyme-containing cleaning products was just beginning. What remains unclear,
however, is whether industrially derived proteases have accumulated worldwide
within the populations experiencing the asthma epidemic. Mechanistic insight
into how proteases activate TH2 cells is also lacking, although recent
studies have begun to address this issue. For example, proteases may facilitate
antigen presentation through the airway by disrupting airway tight junctions
(46) and may exacerbate existing disease by disrupting IgE receptors
(42).
Conclusions
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Table 1
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A summary of the major theories deployed recently to account for the asthma
epidemic, including the major arguments supporting and refuting them, is presented
in Table 1. What most clearly emerges from this summary is a lack of experimental
evidence that strongly supports any of the proposed hypotheses. Several environmental
perturbations have the potential to modify immune function, particularly regarding
TH2 activation, in ways that may exacerbate preexisting asthma. Thus,
the adjuvant-like effects of air pollution-based hydrocarbons and the relative
lack of PGE2 due to decreased aspirin use may similarly increase
production of IgE and TH2 cytokines, thereby aggravating preexisting
asthma. However, such agonist effects on disease are undocumented for any actual
population of asthmatics. The other mechanisms are less clearly associated with
immune function but are intriguing, primarily because of their statistical/epidemiologic
associations with asthma and/or the asthma epidemic. The several epidemiologic
links between environmental proteases and asthma are particularly interesting,
but available data only weakly link proteases to immune function. Maternal-fetal
interactions that may influence neonatal immune function also have intriguing
connections to allergic disease, but the hygiene hypothesis is significantly
undermined by conflicting data. Finally, environmental perturbations must be
shown to induce new cases of disease before they can account for the asthma
epidemic. Strikingly, none of the proposed mechanisms has yet been shown to
be etiologic in this most important regard.
Future studies on the causes of the asthma epidemic will require new experimental
and epidemiologic approaches and the expertise of diverse scientists. The results
of these investigations are difficult to predict. None of the current epidemic
theories can be dismissed on the basis of available data, but it is unlikely
that all will be found to have merit after further study. A likely outcome of
future research is that a more inclusive epidemic theory will emerge, one that
incorporates features of some of the current hypotheses as well as wholly new
concepts. A multifactorial etiology of the epidemic appears likely at this time,
but a single major environmental factor, perhaps one of those considered above,
may ultimately be shown to be most important. Future investigations will be
valued not merely as academic exercises but as a means for resolving the asthma
epidemic and improving respiratory health worldwide.
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Last Updated: August 5, 2002
