Mechanisms of DiseaseAn immunoepidemiological approach to asthma: identification of in-vitro T cell response patterns associated with different wheezing phenotypes in children
Introduction
Current concepts of the mechanisms underlying atopy have evolved from studies in mice which defined the Th1/Th2 paradigm.1 Support for the general applicability of this model to asthma in human beings comes from findings of activated T-helper (Th)2 cells in airway biopsies from atopic asthmatics,2 and allergen-specific Th2 memory cells in their blood.3 However, it is becoming increasingly clear that human allergen-specific Th memory involves a broader range of immune response phenotypes than that in mice. Notable examples include production of interleukin 10, which is a Th2 marker in mice1 but is secreted by human Th1 and Th2 clones4 and the production in non-atopics of Th2 dependent IgG4 in the absence of IgE.5
Attempts to establish a direct causal relation between Th2 polarised immunity to allergens and airway disease in human beings have also been complicated by the inconsistent epidemiological association between Th2 dependent skin prick reactivity to inhalants and symptomatology. By contrast with inbred mice in which sensitisation and subsequent exposure to inhalants is a highly efficient mechanism for induction of bronchial hyper-responsiveness (BHR), only a few sensitised people develop wheeze,6 suggesting that additional cofactors are needed for disease expression.
Genetic variations in mechanisms involved in regulation of tissue responses to inflammation7 and bronchoconstrictors8 might be important in this context. However, an additional possibility merits consideration; notably that variations in clinical phenotypes in atopics might be the result of covert differences in underlying immune response profiles. The population segment in whom these responses are least understood are children, spanning the age ranges of highest asthma prevalence. The dearth of information on relations between asthma symptoms and specific immune effector mechanisms in children greatly restricts the capacity for rational drug trial design (and drug target identification) relevant to paediatric asthma. To elucidate these relations, we have undertaken a broad-ranging study of allergen-specific T cell immunity in 172 children from a cohort being studied prospectively for development of asthma and atopy. We sought to define: (1) in-vitro cytokine response patterns associated with skin prick test reactivity; (2) allergen-specific cytokine response profiles that distinguish symptomatic from asymptomatic atopics; (3) relations between immune parameters and wheezing symptoms within the overall population; and (4) immunological determinants of wheezing phenotypes in non-atopics.
Section snippets
Patients
Study subjects were participants in the assessment of a longitudinal birth cohort study. Antenatal recruitment of this cohort has been described previously.9 Of the 194 birth cohort participants, data from the 147 probands (age range 8·6–13·5 years) who consented to blood collection could be included in the present paper along with data from 25 consenting siblings (mean age 11 years [range 7·4–17·4]). The study was approved by our institutional ethics committee. Written consent was obtained
Results
95 (55·2%) of the 172 children were atopic as defined by skin-prick test. The dominant allergen in the population was house dust mite (73 [42·4%] positive), followed by rye (55 [32·0%]). 26(15·1%) had asthma at the time of analysis, and of these, 22 (85%) were atopic, 30 (17·4%) had wheeze and 25 (83%) of these were atopic, and BHR was present in 62 (35·9%) of whom 45 (73%) were atopic.
Before undertaking the main study, we assessed the potential effects of bacterial lipopolysaccharide (LPS)
Discussion
The results of this study show that atopy to inhalant allergens is associated with a mixed Th1/Th2 immune response profile in children. Moreover, the contribution of individual Th1-associated and Th2-associated effector mechanisms to this mixed response profile is highly heterogeneous, and variations in response patterns seem to be associated with variations in clinical phenotypes. The importance of inflammation in the pathogenesis of asthma, and the central role of Th2 cells in driving this
Glossary
- Interleukin 5
- Principal growth factor for eosinophils; produced mainly by CD4+ Th2 cells.
- Interleukin 10
- Major anti-inflammatory cytokine; produced by both Th1 and Th2 cells and by cells of innate immune system.
- Interleukin 13
- Synergies with interleukin 4 in promoting IgE production; also promotes mucus production in airways.
- Tumour necrosis factor (TNF) α
- Potent pro-inflammatory cytokine produced mainly by cells of innate immune system and by Th1 cells.
- Interferon γ
- Potent pro-inflammatory cytokine
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