The epidemic of asthma and allergy

 

  1. Stephen T Holgate, DSc FRCP

  1. Respiratory Cell & Molecular Biology Division, School of Medicine,
    University of Southampton, Southampton General Hospital, Southampton SO16 6YD,
    UK
  1. E-mail:
    s.holgate{at}soton.ac.uk

In his treatise On Asthma: Its Pathology And Treatment first
published in 1860, Henry Hyde Salter
(Figure 1), a physician at the
Charing Cross Hospital, London, differentiated asthma from other causes of
breathlessness as `paroxysmal dyspnoea of a peculiar character with intervals
of healthy respiration between
attacks’.1 6 years
later, from an analysis of 150 unpublished cases, he described many of the
characteristic features of this disease including hyperresponsiveness to cold
air and exercise and attacks provoked by exposure to chemical and mechanical
irritants, to particular kinds of air as well as to certain foods and
wine.2,3
His observations were further enhanced by the use of the spirograph, the
earliest record of a water
spirometer.4 In
these publications Salter identified asthma as a spasmodic stricture occurring
throughout the conducting airways, and differentiated the condition from
bronchial catarrh, recent bronchitis and old bronchitis
(Figure 2). He drew special
attention to the musical rhonchus that characterized asthmatic
bronchoconstriction and indicated that the sibilant bronchi could not be
relieved by coughing. Also of great significance was his observation of cells
in the asthmatic sputum, which he identified by the presence of a nucleus,
nucleolus and cell wall. The identification of eosinophils in sputum had to
await the development of eosin by Paul Ehrlich some 15 years
later.5 Sir William
Osler, in his first edition of Principles and Practice of
Medicine,
6
likewise drew attention to the factors that could exacerbate asthma including
allergens, air pollutants, infections, exercise, weather, food and
emotions.

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Figure 1

Henry Hyde Salter (1823–1871)

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Figure 2

Plate from Salter’s Treatise (1860) illustrating the different causes of
airflow obstruction

Hyperresponsiveness of the conducting airways, a characteristic feature of
all forms of asthma, can be quantified in the laboratory by use of inhalation
bronchial provocation tests with such agents as methacholine and histamine. In
asthma the dose–response curve to these agonists is displaced to the
left in proportion to disease severity, and at high agonist concentrations
there is loss of the normal protective plateau
(Figure 3). As pointed out by
both Salter and Osler, hyperresponsiveness is in part the result of a
characteristic type of inflammation that affects the conducting airways and is
accompanied by marked structural changes to the airways which include an
increase in airway smooth muscle and deposition of matrix leading to an
overall thickening of the airway wall (remodelling). The pathological features
of asthma are vividly illustrated by Huber and Koessler in their classic paper
of 1922.7 These
combine to make the airways contract too much and too easily in response to
exogenous and endogenous stimuli, as well as contributing to the diurnal
variation in airway calibre that is characteristic of the disease.

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Figure 3

Typical dose–response curves in normal and asthmatic individuals
on aerosol bronchial provocation with increasing concentrations of
methacholine

Today, fibreoptic bronchoscopy allows ready access to airways, and lavage
and mucosal biopsy samples confirm the presence of a special type of
inflammation characterized by infiltration of the airway wall with activated T
lymphocytes, mast cells, basophils, eosinophils and macrophages. In addition,
morphometric studies on airways from patients who have died from or with
asthma have quantified the impressive increase in airway smooth muscle that
occurs in this disease, along with structural changes that include shedding of
epithelial cells and epithelial mucous metaplasia, deposition of collagen and
other matrix proteins in the lamina reticularis beneath a normal epithelial
basement membrane, increased deposition of proteoglycans and repair collagen
throughout the airway wall, and an increase in submucosal microvessels and
nerves—all changes tantamount to airway remodelling. The fact that these
structural changes occur in early childhood, at the inception of
asthma,8 indicates
that they are fundamental to pathogenesis and occur parallel to, rather than
as a consequence of, airway
inflammation.9

THE RISING TRENDS OF ASTHMA AND ALLERGY

The past three decades have witnessed a spectacular increase in the
prevalence of asthma and allergic disease worldwide, especially in those
countries with a Western
lifestyle.10 In the
International Study of Asthma and Allergy in Children, the highest prevalences
of asthma were in Australia, New Zealand and the UK, where in 2003 more than
20% of children aged 13–14 years reported asthma
symptoms.11 By
contrast, in Central Africa, Central and Eastern Europe and China the
prevalence of childhood asthma was less than 5%. The European Community
Respiratory Health
Survey12 has
revealed similar intercountry differences in prevalence of adult asthma and
bronchial hyperresponsiveness. While part of the explanation for these wide
differences in disease prevalence may be genetic, in that those countries with
the highest disease prevalence were host to large migrations of people from
the UK, a critical role for environmental factors in driving the expression of
asthma and other allergic diseases is almost
certain.10 This
argument is made all the more compelling by the observation that, in countries
where prevalence studies have been conducted by identical methods over a span
of 10–25 years, the disease prevalence has increased progressively in
children, adolescents and adults (Figure
4
).13

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Figure 4

The rising trends in asthma in different countries. The paired
prevalence rates in each country were obtained with the same instruments

Clues to the environmental factors that drive the rising trends may be had
from a closer look at disease mechanisms. With the recognition that
gene–environmental interactions are critical to the pathogenesis of
allergic disorders such as asthma, there has been a major focus on the
immunological and inflammatory mechanisms that underlie the origins of allergy
and its progression to allergic inflammation. It was Charles Harrison Blackley
(Figure 5) in Experimental
Researches on the Cause and Nature of Catarrhus Aestivus

(1873)14 who drew
our attention to the importance of pollen exposure as a causal factor in
hayfever and `hay asthma’. Having installed the world’s very first pollen
counter on the roof of his house in Manchester, Blackley was able to show
clearly that his own symptoms of rhinitis and asthma coincided exactly with
the peak increase in the count of pollen grains collected over each
twenty-four hours across June and July. In the closing paragraph of his
monograph14 he
states:

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Figure 5

Charles Harrison Blackley (1820–1900)

`I am, as I have intimated, quite aware that other agents may yet be found
to produce symptoms not unlike those of hayfever. Amidst the great number of
bodies there are with functions similar to those of pollen, it would not be
surprising if we should find some that have a similar kind of action; and it
is not improbable that among these, we may find the exciting causes of some
diseases which are far more formidable than hayfever.’

How right he was. Some 20 years later, Osler drew attention to the
importance of house dust as a trigger of both rhinitis and asthma. The
identification of the dust mites Dermatophagoides pteronyssinus and
D. farinae (or rather their faeces) as causal agents led to extensive
research on the environmental factors most conducive to dust mite reproduction
and survival as well as on the substances that lead to an allergic response.
We now know that such allergens, whether in mite faeces or other sources such
as pollen grains, fungal hyphae or animal material, may have intrinsic
biological properties, including proteolytic enzyme activity, that help them
penetrate epithelial barriers and gain access to the mucosal or epidermal
tissue where they evoke the allergic
response.15 In
countries with a high prevalence of allergic disease, up to 40% of the
population are sensitized to common environmental allergens such as grass and
tree pollen, dust mite excreta and animal materials, the highest prevalence of
sensitization being found in those countries with the greatest incidence of
allergic disease.

IMMUNOLOGICAL BASIS FOR ASTHMA AND ALLERGY

Sensitization to allergens usually starts at mucosal or dermal surfaces
when the allergen is taken up by antigen presenting cells (APCs; dendritic or
Langerhans cells). In genetically susceptible individuals, selective peptides
are generated by APCs and presented to naïve T lymphocytes in local
lymphoid tissue16
which then multiply and differentiate into a subtype of T cells designated
Th2-like.17 In
addition to being implicated in the pathogenesis of allergy and asthma,
Th2-like cells are fundamental to the development of an effective immune
response against
parasites.18 It
would seem that in the Western world this arm of the immune response has been
highjacked by environmental allergens, leading to specific sensitization and
allergic disease. A second set of T lymphocytes designated Th1-like with
capacity to secrete interferon γ (IFN-γ) negatively regulates the
ability of Th2-like cells to develop. In babies born to families with a strong
history of allergic disease, there exists a defect in the Th1 arm of the
immune response with a consequent increase in Th2
responsiveness.19
More recently, additional T lymphocyte subsets designated regulatory T cells
(T reg cells) and Th3-like cells have been found to modify the extent of both
Th1 and Th2 responses through their ability to secrete anti-inflammatory
cytokines, transforming growth factor β (TGF β) and interleukin 10,
thereby adding a further level of complexity to T cell mediated immune
regulation (Figure
6
).20

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Figure 6

The role of cytokines in directing the balance between T lymphocyte
subsets.
Th2-like T cells orchestrate the inflammatory response of asthma
and allergy. T reg and Th3 inhibit both Th1 and Th2 responses

Box 1 Influence of infection in protecting against allergy

  • Strong socioeconomic gradient

  • Less allergy in large families

  • Less allergy in lastborn siblings

  • Less allergy in rural than urban environments

  • Less allergy in developing countries

  • Less allergy in relation to gastrointestinal infections—e.g.
    hepatitis A, toxoplasmosis, Helicobacter pylori

  • Less allergy in children attending daycare centres

  • Less allergy in children attending Steiner schools

The expansion of Th2-like T cells occurs in the local lymphoid
tissue—i.e. the site of antigen presentation. The net result of this
process is the coordinate secretion of a range of small-molecular-weight
cytokines encoded in a cluster on chromosome 5q31-34 (including interleukins
3, 4, 5, 6, 9 and 13 and granulocyte–macrophage colony stimulating
factor) with the capacity to induce the lymphocytes to switch from making IgM
to making the allergic antibody IgE (interleukins 4 and 13), and encourage the
migration and maturation of tissue mast cells (interleukins 3, 4, 6, 9, 13).
Th2 cytokines also upregulate the expression of specific adhesion molecules
(vascular cell adhesion molecule 1 and intercellular adhesion molecule 1) on
microvascular endothelial cells which trap and activate passing leukocytes,
specifically eosinophils, basophils and
monocytes.21 The
mast cell is particularly important in initiating the allergic response,
because cross-linking of the IgE bound to the surface of these cells produces
an explosive release of granule-associated and newly formed chemical mediators
and cytokines which interact with constituent cells in smooth muscle, nerves,
blood vessels and mucus glands to produce the clinical manifestations of
allergy.

PREVENTION OF ALLERGY BY REDUCING EXPOSURE TO ALLERGENS

An obvious way to prevent allergic disease in high-risk individuals, or to
prevent or reverse symptoms, is to restrict contact with an offending
allergen. In some cases separation of a sensitized individual from an
offending allergen (e.g. a laboratory worker sensitized to rodent allergens)
can produce a dramatic effect, but in other circumstances the results are less
impressive. This is particularly the case for house dust mite avoidance. Some
workers argued strongly that encasement of bedding with dust mite impermeable
materials, together with measures to reduce dust mite exposure in the bedroom
and living area of the house, would have a major impact in reducing
sensitization and subsequent development of allergic disease, as well as
reducing symptoms in those already sensitized. However, primary prevention
studies in
infants22 and the
use of reasonable (but not exhaustive) dust mite avoidance strategies in
adults have proved
disappointing.23,24
In children with dust mite related asthma and eczema, mite reduction
strategies have been reported to be more
successful.25,26

THE HYGIENE HYPOTHESIS

Exposure to increased amounts of allergens, such as those derived from
house dust mite, may account for some of the increase in allergy seen in
countries with a Western lifestyle. In Australia, a rise in dust mite exposure
has been linked to the sealing of air conditioned houses and the use of soft
furnishings, but increased exposure to allergens cannot explain the large
inter-country differences in allergic disease and allergen sensitization, nor
the rising trends. In 1989 David
Strachan27 stated,
on the basis of epidemiological work, that `the apparent rise [in the
prevalence of allergic disease]… could be explained if allergic diseases
were prevented by infection in early childhood, transmitted by unhygienic
contact with older siblings, or acquired prenatally…’. Since that time
extensive epidemiological research has shown that exposure to microorganisms
or their products may account in part for the rising trends in allergic
disease. Some the findings are summarized in Box 1. A particularly striking
observation is that, compared with children in the general population,
children brought up on livestock farms (and thus in frequent contact with farm
animals) have a 50–75% reduction in the prevalence of allergic disease
such as hayfever in parallel with a reduction in sensitization to common
environmental
allergens.28 A key
question arising from these studies is how exposure to microorganisms is able
to protect children from allergic sensitization. Bacterial cell walls contain
complex endotoxins such as lipopolysaccharides (Gram-negative bacteria) and
muramic acid (Gram-positive bacteria); fungal spores and hyphae contain
chitin; bacteria contain unmethylated CpG DNA sequences; and viruses contain
double-stranded RNA. Each of these substances is able to stimulate specific
toll-like receptors (TLRs) on antigen presenting cells. Viral double-stranded
RNA activates TLR3, lipopolysaccharide activates TLR4 and CpG activates TLR9.
Activation of TLRs directs a protective immune response by upregulating the
expression of Th1, Th3 and Treg T lymphocytes, thereby inhibiting Th2 mediated
allergic
sensitization.20
The importance of these mechanisms is illustrated by the work of
Braun-Fährlander and colleagues showing that, in children brought up in a
rural environment, the endotoxin load in their mattresses is inversely related
to the occurrence of hayfever, hayfever symptoms and grass
sensitization.29 As
an extension of these ideas Donata Vercelli has advanced the concept of the
endotoxin `switch’—whereby in children born of allergic parents who
exhibit a defective Th1 response, exposure to the contents of microorganisms
through the activation of TLRs (part of the innate immune response) is able to
compensate by enhancing Th1-like responses with consequent reduction of Th2
responses.30

With recognition of the importance of TLRs as an integral component of the
innate immune response involved in protection against allergic disease,
attempts are being made to harness these mechanisms in the form of vaccine
development.31 When
conjugated to the oligonucleotide CpG, the major ragweed allergen Amb
a1
is 100-fold less allergenic than unlinked Amb a1 in those
sensitized to ragweed and has been shown to give total protection against
ragweed during the pollen season in the
USA.32 Studies such
as these, as well as the use of CpG alone or given as a mixture along with an
allergen or a peptide derived from the allergen, are being investigated in
human clinical trials following very promising results in
animals.33,34

IgE AS A THERAPEUTIC TARGET

IgE, originally described as `reagin’ by Prausnitz and Küstner in
1922,35 is the
principal trigger for an allergic tissue response on exposure to a specific
allergen. Since the molecular identification in 1968 of reagin as the fifth
immunoglobulin,36,37
IgE has been a major target for development of treatment. IgE directed to
specific allergens binds strongly to the high affinity IgE receptor
(FC∈R1-αβγ2) present on mast cells and
basophils. Cross-linkage of adjacent IgE molecules by prevailing allergen
results in dimerization of the receptors and cell activation with secretion of
various inflammatory mediators and
cytokines.38
Administration of a humanized monoclonal antibody against the C∈3 region
of IgE, the component that binds to the α-chain of FC∈R1, results
in sequestration of circulating
IgE39 with eventual
loss of IgE binding to cells within
tissues.40 The
anti-IgE itself will not activate IgE bound to its receptors or mast cells or
basophils since the epitope against which the antibody is directed is obscured
by binding to the FC∈R1 receptor
(Figure
7
).41
Anti-IgE (omalizumab) has yielded striking clinical improvement in adults and
children with steroid-requiring
asthma42,43
and has recently been approved for clinical use in the USA. Bronchial biopsies
from asthmatic patients receiving omalizumab for twelve weeks demonstrated a
pronounced reduction in airway inflammation (including eosinophils) in
parallel with a loss of IgE and its receptor from mast
cells.40 This
exciting therapeutic approach to asthma and allergy is now being followed by
generation of peptide vaccines with the capacity to induce a therapeutic
antibody response to cell IgE C∈3 domain by coupling non-self protein or
peptide to self structures. These second-generation vaccines have proven to be
highly effective in non-human primate models of allergic disease and are about
to enter clinical
trials.44

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Figure 7

The inhibitory effect of the anti-human IgE monoclonal antibody
omalizumab on the allergic cascade

TISSUE SUSCEPTIBILITY FACTORS IN ASTHMA

While IgE-dependent sensitization and subsequent allergic inflammation in
the lower airways is undoubtedly important in asthma pathogenesis, the picture
changes with disease progression: as the disease becomes more severe and
chronic (and therefore refractory to corticosteroids) the structural elements
of the airway wall, including airway smooth muscle, contribute more to the
clinical expression of the disease than does the inflammation. In structural
studies a close correlation has been seen between the thickness of the lamina
reticularis (beneath the airway epithelium) and the thickness of the airway
wall and amount of smooth
muscle.45 In infant
rhesus monkeys, exposure to house dust mite allergens results in thickening of
the lamina reticularis and a parallel increase in airway smooth muscle bundle
orientation and thickness in the larger
airways.46 These
structural changes are accompanied, in the `asthmatic’ monkeys, by a large
increase in airway hyperresponsiveness as well as an increase in
mucus-secreting goblet cells in the airway epithelium. If allergen-exposure is
discontinued after the first six months of life, there is no reversal of the
lamina reticularis thickening or of the accompanying increase in airway smooth
muscle, even after 2
years.47 This
points to the importance of susceptibility genes not only in the development
of the allergic response but also in determining the tissue response to
allergic processes.

ADAM33—THE FIRST NOVEL ASTHMA GENE

In collaboration between the Genome Therapeutic Corporation,
Schering-Plough Research Institute, USA and the University of Southampton, we
have undertaken a positional cloning effort to identify novel susceptibility
genes involved in the development and progression of asthma
(Figure
8
).48
It has long been known that, although asthma and allergies run in families,
bronchial hyperresponsiveness and allergy are separate genetic traits that are
inherited independently. Genetic modelling has shown that asthma is a complex
disease involving several genes with moderate effect and important
interactions with the environment. In 480 families with two or more affected
asthmatic children, a genome-wide screen involving microsatellite markers led
to the identification of a major area of linkage between asthma and bronchial
hyperresponsiveness on chromosome 20p13. Through physical mapping of the
region and identification of the genes underlying the peak of linkage by use
of bacterial artificial chromosomes, 40 genes were within the 90% confidence
interval. Subsequent case–control and family-based transmission
disequilibrium test (TDT) association mapping led to the identification of a
disintegrin and metalloprotease (ADAM) gene as responsible for the linkage
signal. ADAM33 is a complex molecule whose expression is restricted
largely to mesenchymal cells including fibroblasts and smooth
muscle.48,49
It is made up of five domains—activation, proteolytic, adhesion, fusion,
and signalling. Single nucleotide polymorphisms that are most strongly
associated with asthma in our original study have been shown, in asthmatic
adults, to predict rapid decline in lung function over a 20-year
interval50 and, in
children with allergic and asthmatic parents, impaired lung function at ages 3
and 5 years.51 The
precise mechanism whereby polymorphic variation in ADAM33 is
associated with asthma is not known, although removal of the gene’s function
by means of antisense oliognucleotides appears to prevent the differentiation
of airway fibroblasts into a contractile phenotype (myofibroblasts) when
incubated in vitro with the profibrogenic growth factor TGF-β.
In addition to ADAM33, two asthma genes have been described by the
Oxford group— PHF-11
52 and
DPP-1253—both
involved in amplifying IgE and Th2 mediated inflammation.

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Figure 8

Positional cloning strategy used to identify the novel asthma gene ADAM
33

CONCLUSIONS

From the extraordinarily perceptive clinical and physiological observations
made by Salter, Blackley, Osler, Ehrlich, Prausnitz, Küstner the
Ishizakas and Johannsson, the foundations for the scientific basis of allergic
disease and asthma have been laid. The application of modern molecular
medicine to well phenotyped patients will undoubtedly lead to the
identification of new molecules fundamental to the pathogenesis of complex
diseases such as asthma. However, the real challenge for the future is to
understand how the changing environment associated with the Western culture is
leading to altered expression of these genes and a prevalence of serious
allergic disease that in the UK is reaching epidemic
proportions.52 The
increasing recognition that both inflammatory and structural changes are
needed in teh airways, for asthma to become fully manifest in its chronic
form, is opening the debate as to which environmental factors are critical to
the inception and progression of the disease in genetically susceptible
individuals. It is through understanding of the interplay between these
factors that we can hope for better means of prevention and treatment, and
even cure.

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