Respiratory Cell & Molecular Biology Division, School of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK
E-mail: s.holgate{at}soton.ac.uk
| INTRODUCTION |
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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 doseresponse 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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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 nervesall 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 |
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Clues to the environmental factors that drive the rising trends may be had from a closer look at disease mechanisms. With the recognition that geneenvironmental 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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`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 |
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(IFN-
) 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 ß (TGF ß) and interleukin 10,
thereby adding a further level of complexity to T cell mediated immune
regulation (Figure
6).20
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| Box 1 Influence of infection in protecting against allergy
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The expansion of Th2-like T cells occurs in the local lymphoid tissuei.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 granulocytemacrophage 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 |
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| THE HYGIENE HYPOTHESIS |
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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 |
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R1-
ß
2) 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
-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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| TISSUE SUSCEPTIBILITY FACTORS IN ASTHMA |
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| ADAM33THE FIRST NOVEL ASTHMA GENE |
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| CONCLUSIONS |
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| REFERENCES |
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