It has been recognised for decades that asthma is an inflammatory disease of the airways. In adult asthma, there is now good evidence that many of the disease-related traits (eg, eosinophilic airway inflammation, mast cell hyper-degranulation, atopy, raised IgE levels) may be largely attributable to inappropriate activation and cytokine production by CD4+ T cells. The few specific pathology studies that have been performed on tissues from infants and very young children with asthma have suggested that the same disease mechanisms that operate in adult asthma are likely to contribute to asthma in early childhood, at least in some form. As defects in lung function associated with asthma appear to occur within the first two years of life, there is currently great hope that a detailed understanding of immune processes in early asthma may lead to specific preventive or curative interventions. However, at present, there is very little direct evidence of the actual immunological mechanisms that operate in very young children with asthma. Most of our current knowledge is based on animal models.
The so-called "TH2 hypothesis" of asthma stems from studies in the late 1980s by Mosmann et al.1,2 Their observations of long-term, intensely stimulated mouse CD4+ lymphocytes in vitro revealed that they could be polarised into two distinct populations: type 1 helper T cells ("TH1 cells") and type 2 helper T cells ("TH2 cells"). TH1 cells produce interferon gamma (IFN-γ), tumour necrosis factor beta (TNF-β), and interleukins IL-2, IL-12 and IL-18. These cytokines help to clear intracellular pathogens and viruses and are linked to cell-mediated immunity. TH2 cells, which produce IL-4, IL-5, IL-9 and IL-13, are important in fine-tuning B cell antibody production and defending against extracellular pathogens (especially helminths). Because TH2 cytokines induce eosinophilia, IgE production, mucus secretion and mast cell growth in animals in vivo and in human cells in vitro, they have been specifically linked to asthma.
The "TH2 model" of asthma has been widely accepted, and in humans there is clear evidence for TH2-like cytokine patterns in T cells obtained by bronchoalveolar lavage.3,4 Further evidence comes from recent studies of IL-12, which is a natural endogenous inhibitor of TH2-type responses. Morahan et al have identified a close association between impairment of IL-12 expression (due to promoter polymorphism) and a markedly increased risk of developing severe asthma.5 However, detailed analysis of individual cytokine profiles in single T cells has proven that distinct TH2 cells do not exist in humans — in both childhood asthma and adult asthma there is increasing evidence for a mixed TH1/TH2 cytokine pattern, in which IFN-γ and IL-5 are concurrently high.6
Animal models predict that, if primary TH2 immune deviation (ie, bias towards the TH2 response) could be prevented, early asthma might be preventable or curable. The molecular basis of primary immune sensitisation and immune deviation has therefore been intensively researched. It was rapidly appreciated that TH1 and TH2 immune deviations are mutually inhibitory. Cell biology studies have proven that the broad cytokine profile of CD4+ T cells polarises under the influence of cytokines. This polarisation results in T cells producing a smaller number of cytokines in distinctive patterns that can be difficult to reverse if the driving stimulus is intense or prolonged. TH2 immune deviation is driven by IL-4, produced by the CD4 cells themselves and by other cells, such as mast cells and perhaps some natural killer cell subpopulations. IL-4 is particularly effective when cytokines associated with the TH1 response (IFN-γ, IL-12 and IL-18) are neutralised by gene manipulation or monoclonal antibodies.2,7 In the early stages of immune deviation, the cytokine profile remains plastic and can be easily redirected by simply changing the cytokine conditions. Thus, TH2 responses can be suppressed by combinations of IFN-γ, IL-12 and IL-18, and intrinsic TH1 cytokines reduce the intensity of the TH2 response in animal models in vivo.8,9 However, as the intensity or duration of stimulation progresses, this plasticity is lost as cell-surface-receptor components and internal signalling molecules specific to TH1 cytokine responses are selectively down-regulated. Similarly, TH1 responses become refractory to redirection by IL-4. This effect is demonstrated in vivo by the observation that anti-IL-4 antibodies completely prevent asthma in animals if given before allergic sensitisation has occurred, but have no effect at all on established asthma.10
In infants and children, TH2 immune deviation and allergic sensitisation develop and consolidate slowly over years, although, paradoxically, these responses are weaker than in children who do not develop asthma or allergy in later life.3,11 There has been great interest recently in the observation that the in-utero environment is strongly TH2-biased (perhaps to prevent a cell-mediated immune response against the fetus?) and that the immune response in infants has a TH2 bias that only slowly reverts to the adult default TH1-biased pattern over the first three to five years of life.
Some researchers, using highly sensitive detection methods, have suggested that sensitisation to aeroallergens (eg, house-dust mite, cat allergen) occurs in utero and that antigen-specific TH2-biased responses occur in T cells recovered from cord blood at birth. Even if this is true, it would seem likely that further postpartum development of the TH2 compartment is necessary to develop the TH2-biased armed effector T cells that coordinate tissue inflammation and damage.
As aeroallergens are ubiquitous, it remains unclear why some individuals develop asthma while others do not. This issue is further clouded by epidemiological studies showing an inconclusive (or, paradoxically, protective) relationship between domestic exposure to cat and house-dust mite allergens and the development of asthma.12 It is clear from animal studies that the default immune response to aero-allergens is to develop "tolerance" (non-responsiveness), which may be mediated by lung macrophages. As aeroallergens are swallowed as well as breathed in, and as mucosal immune responses tend to be shared at anatomically distinct mucosal surfaces because of lymphocyte trafficking, there is currently great interest in whether normal tolerance occurs via the lungs or via the gut (in a manner analogous to food-allergy tolerance) — or both. Respiratory infection also impairs tolerance.13 Subtle breakdown in tolerance, perhaps associated with differing patterns of gut flora or infection, might explain the rising global trend in asthma prevalence.
The "hygiene hypothesis" proposes that infections acquired early in life may protect children against asthma. Gram-negative bacteria (through lipopolysaccharide [LPS]-induced IFN induction), mycobacteria and most viruses strongly induce TH1 responses. These pathogens, or their purified components, have been shown to prevent or lessen TH2-type responses in animals.14 The hygiene hypothesis is strengthened by certain epidemiological evidence and by the recent discovery that polymorphisms in CD14, an LPS coreceptor, are associated with increased asthma risk in children.15 These genetic variants of CD14 may reduce the intensity of LPS responses, thereby reducing development of TH1-type immunity.
It is clear that asthma is a complex disease involving multiple genetic determinants. The picture is complicated by the fact that, in established asthma, disease exacerbations may be associated with TH1-type cytokine expression. Furthermore, TH1-biased lymphocytes grown in vitro have been shown to worsen asthma, rather than suppress disease, when transferred to animals. Research on tolerance and its failure has also focused on the contribution of infections to the development of asthma, as inflammation induced by infection reduces tolerance to aeroallergens.16
The observation that more intense antigen stimulation of T cells in vivo tends to lead to tolerance rather than more severe disease raises the issue of whether the TH2 hypothesis can account for varying degrees of asthma severity. Interleukin-13 (associated with the TH2 response) is present in persistent disease, but its expression can occur independently of T cells once disease is established.17 Similarly, IL-4 (closely related to IL-13) can impair responses to steroids by inducing an inactive form of the steroid receptor.18 However, it seems more likely that separately inherited gene polymorphisms control disease severity independently of TH2-biased cell populations, although TH2 immune deviation may be necessary for primary disease induction. In adult asthma there is some doubt as to whether TH2-biased T cell populations are needed to sustain long-established disease. Potent immunosuppressive agents, such as cyclosporin A, are poorly effective against established asthma, and even antibody-mediated depletion of CD4 lymphocytes seems to produce little clinical benefit.
The therapeutic time window in which to manipulate the immunobiology of early asthma may be small indeed. Nevertheless, there is very strong evidence from animal models that, should they be proven safe, immune modulators may be very useful in treating early disease (see page 6619).