Elsevier

The Lancet

Volume 365, Issue 9454, 8–14 January 2005, Pages 142-149
The Lancet

Mechanisms of Disease
An immunoepidemiological approach to asthma: identification of in-vitro T cell response patterns associated with different wheezing phenotypes in children

https://doi.org/10.1016/S0140-6736(05)17704-6Get rights and content

Summary

Background

Increasing evidence suggests that patterns of T cell immunity to inhalant allergens in genetically diverse human populations are more heterogeneous than previously assumed, and that covert differences in expression patterns might underlie variations in airway disease phenotypes. We tested this proposition in a community sample of children

Methods

We analysed data from 172 individuals who had been recruited antenatally to a longitudinal birth cohort study. Of the 194 birth cohort participants, data from the 147 probands (age range 8·6–13·5 years) who consented to blood collection were included along with data from 25 consenting siblings (mean age 11 years [range 7·4–17·4]). We ascertained clinical phenotypes related to asthma and allergy. We measured T cell responses to allergens and mitogens, together with blood eosinophils and IgE/IgG antibodies, and assessed associations between these indices and clinical phenotypes.

Findings

Atopy was associated with allergen-specific T-helper (Th)2 responses dominated by interleukin 4, interleukin 5, interleukin 9, interleukin 13, whereas interleukin 10, tumour necrosis factor α, and interferon γ responses were common to both atopics and non atopics. The wheal size from skin prick with allergen was positively associated with in-vitro interleukin 5 and interferon γ responses, and negatively associated with interleukin 10. Asthma, especially in atopics, was strongly associated with eosinophilia/interleukin 5, and bronchial hyper-responsiveness (BHR) was associated with eosinophilia plus polyclonal interferon γ production. BHR in non-atopics was associated with elevated allergen-specific and polyclonal interleukin 10 production.

Interpretation

Parallel immunological and clinical profiling of children identified distinctive immune response patterns related to asthma and wheeze compared with BHR, in atopics non-atopics. Immunological hyper-responsiveness, including within the Th1 cytokine compartment, is identified as a hallmark of BHR.

Relevance to practice

These findings highlight the heterogeneity of immune response patterns in asthmatic children, including those with seemingly homogeneous Th2-driven atopic asthma. Further elucidation of the covert relationships between wheezing phenotypes and underlying immunophenotypes in this age group will potentially lead to more effective treatments for what is an unexpectedly heterogeneous collection of disease subtypes.

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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