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

Heaton, Tricia; Rowe, Julie; Turner, Steven; Aalberse, R. C.; Klerk, Nicholas de; Suriyaarachchi, Devinda; Serralha, Michael; Holt, Barbara J.; Hollams, Elysia M.; Yerkovich, Stephanie T.; Holt, Kathryn E.; Sly, Peter D.; Goldblatt, Jack; Souëf, Peter Le; Holt, Patrick G.

doi:10.1016/s0140-6736(05)17704-6

Cited by 215 publications

(192 citation statements)

References 43 publications

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“…However, this model does contain SEB-induced IL-5 which can drive eosinophilia, in addition to eosinophil protein X, a product of activated eosinophils. Heightened eosinophil-related responses were previously identified as the strongest risk factor for wheeze and BHR in atopic school children [32].…”

Section: Discussionmentioning

confidence: 92%

Th2-associated immunity to bacteria in teenagers and susceptibility to asthma

Hollams

Hales²,

Bachert³

et al. 2010

Eur Respir J

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Bacterial colonisation of the airways is associated with increased risk of childhood asthma. Immunoglobulin (Ig)E against bacterial antigens has been reported in some asthmatics, suggesting a role for bacterial-specific type-2 immunity in disease pathogenesis. We aimed to investigate relationships between bacterial-specific IgE amongst teenagers and asthma susceptibility.We measured titres of IgE against Haemophilus influenzae, Streptococcus pneumoniae and Staphylococcus aureus in 1,380 teenagers, and related these to asthma symptomatology and immunophenotypes.IgE titres against S. aureus-derived enterotoxins were highest amongst atopics and were associated with asthma risk. Surprisingly, IgE titres against H. influenzae and S. pneumoniae surface antigens were higher, not stratified by atopy and independently associated with decreased asthma risk.The positive association between type-2 immunity to S. aureus and asthma phenotypes probably reflects IgE-mediated effector cell activation via enterotoxin super antigens which are secreted in soluble form. The contrasting benign nature of type-2 immunity to H. influenzae and S. pneumoniae antigens may reflect their lower availability in soluble forms that can crosslink IgE receptors. We theorise that instead they may be processed by antigen presenting cells and presented to type-2 memory cells leading to mucosal secretion of interleukin (IL)-4/IL-13, a mechanism widely recognised in other tissues to attenuate T-helper-1 associated bacterialinduced inflammation.

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Section: Discussionmentioning

confidence: 92%

Th2-associated immunity to bacteria in teenagers and susceptibility to asthma

Hollams

Hales²,

Bachert³

et al. 2010

Eur Respir J

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“…In the remodelled airway, mediators, cytokines and matrix molecules provide an optimal microenvironment for sustaining the chronic inflammatory response [18] and for providing a mechanism whereby more severe disease adopts an additional Th1 pattern involving neutrophils and pleiotropic cytokines, such as tumour necrosis factor (TNF)-a and interferon (IFN)-c, which are able to induce more cell stress and tissue damage [19]. There is also recent evidence that Th1-type cytokines contribute to childhood asthma [20,21]. PATHOGENESIS OF ASTHMA S.T.…”

Section: Epithelial Mesenchymal Communicationmentioning

confidence: 99%

Local genetic and environmental factors in asthma disease pathogenesis: chronicity and persistence mechanisms

Holgate¹,

Davies²,

Powell³

et al. 2007

Eur Respir J

120

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While asthma is an inflammatory disorder of the airways usually associated with atopy, an important additional component is involvement of the epithelium and underlying mesenchyme acting as a trophic unit (EMTU).In addition to allergens, a wide range of environmental factors interact with the EMTU, such as virus infections, environmental tobacco smoke and pollutants, to initiate tissue damage and aberrant repair responses that are translated into remodelling of the airways. While candidate gene association studies have revealed polymorphic variants that influence asthmatic inflammation, positional cloning of previously unknown genes is identifying a high proportion of novel genes in the EMTU.Dipeptidyl peptidase (DPP) 10 and disintegrin and metalloproteinase (ADAM)33 are newly identified genes strongly associated with asthma that are preferentially expressed in the airway epithelium and underlying mesenchyme, respectively.Also of increasing importance is the recognition that genes associated with asthma and atopy have important interactions with the environment through epigenetic mechanisms that influence their expression. This type of research will not only identify biomarkers of different types of asthma across the full range of phenotypic expression, but will also identify novel therapeutic targets that could influence the natural history of the heterogenes lung disease.

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“…Briefly, PBMC were cultured for 48 h in AIM‐V medium containing 2‐mercaptoethanol (50 μ m ) alone (medium control), with phytoheamagglutinin (PHA, 1 μg/ml, positive control), or with HDM ( Dermatophagoides pteronyssinus ) extract (10 μg/ml) which was prepared in‐house, with a single batch used for the whole study (endotoxin level was not quantified). This stimulation time (48 h) was validated in our previous studies 5, 20, 23, 24, 25. IL‐5, IL‐10, IL‐13 and interferon (IFN)‐γ protein in supernatants were assayed using time‐resolved fluorescence as previously described 20.…”

Section: Methodsmentioning

confidence: 99%

“…Coefficients of variation for both cohorts are shown in Table S3. We used identical protocols for in vitro studies in both cohorts; the methods are described in detail in our previous studies 5, 20, 23, 24. Briefly, PBMC were cultured for 48 h in AIM‐V medium containing 2‐mercaptoethanol (50 μ m ) alone (medium control), with phytoheamagglutinin (PHA, 1 μg/ml, positive control), or with HDM ( Dermatophagoides pteronyssinus ) extract (10 μg/ml) which was prepared in‐house, with a single batch used for the whole study (endotoxin level was not quantified).…”

Section: Methodsmentioning

confidence: 99%

“…Among other contributing mechanisms, the expression of asthma may be in part determined by the T‐cell immunity to inhalant allergens 4. In our previous studies characterizing immune responses of peripheral blood mononuclear cells (PBMCs), we have reported that responses to HDM allergens among asthmatic children are heterogeneous, even within the seemingly homogeneous group of children with atopic asthma 5.…”

Section: Introductionmentioning

confidence: 99%

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Relationship between cytokine expression patterns and clinical outcomes: two population‐based birth cohorts

Prosperi

Simpson

et al. 2015

Clin Experimental Allergy

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SummaryBackgroundModels that incorporate patterns of multiple cytokine responses to allergens, rather than individual cytokine production, may better predict sensitization and asthma.ObjectiveTo characterize the patterns of peripheral blood mononuclear cells’ (PBMCs) cytokine responses to house dust mite (HDM) allergens among children from two population‐based birth cohorts using machine learning techniques.Methods PBMCs collected at 8 years of age from the UK Manchester Asthma and Allergy Study (n = 268) and at 14 years of age from the Australian Raine Study (n = 1374) were cultured with HDM extract (10 μg/ml). Cytokine expression (IL‐13, IL‐5, IFN‐γ, and IL10) was measured in the supernatant. Cytokine patterns were identified using a Gaussian mixture model clustering, and classification stability was assessed by bootstrapping.ResultsA six‐class model indicated complex latent structure of cytokine expression. Based on the characteristics of each class, we designated them as follows: ‘Nonresponders’ (n = 905, 55%); ‘IL‐10 responders’ (n = 49, 3%); ‘IFN‐γ and IL‐13 medium responders’ (n = 56, 3.4%); ‘IL‐13 medium responders’ (n = 351, 21.4%); ‘IL‐5 and IL‐13 medium responders’ (n = 77, 4.7%); and ‘IL‐13 and IL‐5 high responders’ (n = 204, 12.4%). ‘IL‐13 and IL‐5 high responders’ were at much higher risk of HDM sensitization and asthma compared to all other classes, with 88% of children assigned to this class being sensitized and 28.5% having asthma.ConclusionUsing model‐based clustering, we identified several distinct patterns of cytokine response to HDM and observed interplay between cytokine expression level, cytokine patterns (especially IL‐13 and IL‐5), and clinical outcomes. ‘IL‐13 and IL‐5 high responders’ class was strongly associated with HDM sensitization. However, among HDM‐sensitized children, one‐third showed no PBMC response to HDM, and the majority of HDM‐sensitized children did not have asthma or wheeze. Our findings suggest that positive HDM ‘allergy tests’ and asthma are associated with a broad range of immunophenotypes, which may have important implications for the use of cytokine‐targeted treatment approaches.

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

Cited by 215 publications

References 43 publications

Th2-associated immunity to bacteria in teenagers and susceptibility to asthma

Th2-associated immunity to bacteria in teenagers and susceptibility to asthma

Local genetic and environmental factors in asthma disease pathogenesis: chronicity and persistence mechanisms

Relationship between cytokine expression patterns and clinical outcomes: two population‐based birth cohorts

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