ReviewMicrobes and mucosal immune responses in asthma
Introduction
The increasing incidence of allergy, atopy, and asthma in industrialised countries means that these are lifestyle diseases and a global health-care problem.1, 2 Indeed, the asthma and allergy epidemic is occurring in urban communities throughout the industrially developed nations, with a particular increase in children.3 Notably, this increase in asthma and allergy is also accompanied by an increase in autoimmune diseases, and for the period 1950–2000 has been related to a decrease in infectious diseases.4
Fortunately, most patients with asthma can be treated effectively by inhaled corticosteroids or the combination of these drugs and long-acting β-adrenoceptor agonists, as recommended by the Global Initiative on Asthma (GINA) guidelines.5 Although this treatment is anti-inflammatory and provides symptomatic benefit, it might be needed on a lifelong basis, and many asthmatics are poorly compliant with their recommended treatment. Although allergen immunotherapy is improving continually, it only provides benefit for some patients with allergic asthma, and new strategies for allergic inflammation are being developed.6
Both genes and the environment affect the host immune response to microbes. In large genome-wide association studies in asthma, investigators have identified several genetic loci that affect susceptibility to various asthma types.7 Some genes affect epithelial barrier function and thus modify interactions between microbes and the mucosal immune system. For example, filaggrin (FLG) has barrier functions in the skin and airways and is associated with allergic skin and airway disease. Other genes associated with asthma have roles in mucosal immune responses, including ORM-1 (yeast) like protein 3 (ORMDL3), which can affect sphingolipid metabolism during inflammation.8 Genes for proteases involved in tissue remodelling, including human A disintegrin and metalloprotease-33 (ADAM33), have been associated with asthma susceptibility. Additionally, environmental effects cause epigenetic changes9 through processes such as DNA methylation, histone acetylation, and micro RNA activities, all of which change the host immune response to microbes. Atopy (elevated IgE) is now generally thought to arise from gene–environment effects, starting during prenatal and early postnatal development.10, 11
Hence, a compelling need exists to understand the ways in which asthma is initiated and exacerbated, and to develop new treatments on the basis of these new insights.12 In the past 15 years, a series of studies with monoclonal antibodies directed against eosinophils and other allergic cells have shown the need to target these treatments to particular patients.13 Although asthma is still viewed as an inflammatory disease of the airways, we believe that a renewed focus is needed on the way that aberrant responses to microbes contribute to airway mucosal inflammation in asthma.14
Section snippets
Microbes and man
The respiratory tract is bombarded constantly by bacteria, viruses, dust, and aeroallergens15 (figure 1). Throughout evolution, human beings have faced the threat of epidemics, plague, and pestilence, and the more frequent inhalation of organic and inorganic dusts. To meet all these challenges, the mucosal immune system needs to remain in a state of readiness to mount diverse responses to the complex and changing threats posed by pathogens. This preparedness for pathogens relies on specific
The mucosal barrier and sentinel function
The surface of the airways is lined by a ciliated epithelium, although dendritic cells have processes that interdigitate between the epithelial cells to ensure intimate contact with the airway lumen.83 Hence, the initial interactions between microbes and the host immune response involve epithelial cells and dendritic cells, although airway macrophages and intraepithelial lymphocytes and other leucocytes are also involved.
The epithelium in asthma is fragile and might be denuded, with disruption
The circle of lymphoid cells
The initial interactions of microbes with epithelial cells, dendritic cells, and macrophages at the mucosal surface create potential to activate a wide range of different lymphoid types. We use the descriptor of a circle to express the way in which a group of different lymphoid cells can initiate several pathways, which radiate outwards and are coordinated simultaneously during a dynamic immune response (figure 2). The huge variety of chemokines and cytokines produced by the epithelium and
The Th2 pathway
Only about half of patients with asthma have eosinophilic manifestations,94, 95 although the cellular and molecular details of the mucosal Th2 pathway are unravelling (figure 3). Molecular phenotyping of asthma can be done in a non-invasive way by measurement of the fraction of expiratory nitric oxide and sputum eosinophils.94 Additionally, the Th2 pathway can be revealed in some asthmatics by gene expression analysis of bronchial cells and tissue.96
Epithelial cells and dendritic cells are now
Pattern recognition receptors
So far, we have discussed the complexity of genes, microbes, and the mucosal immune response. However, a unifying process is the way in which bacteria, viruses, and allergens activate the immune response through microbial pathogen-associated molecular patterns.103 Pathogen-associated molecular patterns are contained within bacteria, viruses, and other pathogens; damage-associated molecular patterns expressed by host cells also contribute to asthma. Pathogen-associated molecular patterns
The Seven Ages of Asthma
Although some paediatricians hesitate to label young children as asthmatic, asthma can be diagnosed at any age and various phenotypes can be defined according to clinical and molecular approaches.107 Throughout life, a continuing dynamic association is played out between immune systems, the environment, and microbes. This interplay translates to the so-called Seven Ages of Asthma (figure 5). Stages up to infancy are generally not aligned to treatments, although global guidelines are available
Fetal development
The feto-placental unit produces a range of cytokines, and transmits various maternal immunoglobulins (including IgG), dietary factors, and cells.11 However, because the maternal immune system contributes to the characteristics of the child's immune system, some effects could be from before conception. The prenatal period of growth of the airways and development of the immune system is now recognised as a crucial window when maternal exposure to environmental and nutritional factors programmes
Studies with monoclonal antibodies
In the past 15 years, a series of informative clinical studies have been done with highly specific monoclonal antibodies targeting individual components of type 2 mucosal immune responses in asthma.13 However, the clinical actions of monoclonal antibodies against elements of type 2 immune responses in asthma are mainly with regard to exacerbations, despite the use of biomarkers to guide this treatment,123 which suggests that other mechanisms are also important in the pathophysiology of asthma.
Challenge models
Several inhaled challenges that have been done on patients have been fundamental to our understanding of the pathophysiology of allergy and asthma. An airway challenge has the particular advantage of giving a defined stimulus to an accessible tissue, to cause a controlled tissue reaction. Inhalation of specific allergens may be performed in patients with mild allergic asthma,131 which is the classical model to detect effects on the early and late asthmatic reactions.132 However, live viral
Conclusions
Throughout life, the human immune system interacts dynamically with microbes, allergens, dietary constituents, and metabolites. Asthma can be viewed as an abnormal airway mucosal inflammatory reaction to environmental and microbial stimuli that arises because of innate or acquired variations in the host response. Both good and bad bacteria, viruses, and allergens occur in relation to initiation and exacerbation of asthma for particular patients at key times in their lives. In view of the
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