Identification of novel immune phenotypes for allergic and nonallergic childhood asthma

Raedler, Diana; Ballenberger, Nikolaus; Klucker, Elisabeth; Böck, A.; Otto, Ragna; Costa, Olivia Prazeres da; Holst, Otto; Illig, Thomas; Buch, Thorsten; Mutius, Erika von; Schaub, Bianca

doi:10.1016/j.jaci.2014.07.046

Cited by 136 publications

(181 citation statements)

References 36 publications

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“…Figure 2 in a review by Colonna (29) on TREM-related immunology illustrates schematically its influence on downstream inflammatory response. Murine models also support a role for TREM-1 in the modulation of fungus-induced allergic asthma (33), and increased expression of TREM1 was observed in transcriptomic profiles of children with nonallergic asthma (25).…”

Section: Discussionmentioning

confidence: 78%

“…From the C2 CGP collection, three gene sets related to immature T-lymphocytespecific transcripts were enriched during optimal asthma control (LEE_DIFFERENTIATING_T_LYMPHOCYTE, LEE_NAIVE_T_LYMPHOCYTE, and LEE_EARLY_T_LYMPHOCYTE_DN), a gene set of transcripts differentially expressed in neutrophils attracted to skin lesions (THEILGAARD_NEUTROPHIL_ AT_SKIN_WOUND_DN) was enriched during suboptimal control, and a gene set of transcripts specific to immature neutrophils (MARTINELLI_IMMATURE_ NEUTROPHIL_UP) was enriched during suboptimal control. Transcriptional profiles of asthma related to eosinophils and neutrophils have been observed in induced sputum samples (24) and in blood (25). We then examined the replicated GSEA results for the involvement of other types of inflammatory and disease pathways in asthma control (see Table E4).…”

Section: Bridge Wbmentioning

confidence: 99%

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Gene Expression Profiling in Blood Provides Reproducible Molecular Insights into Asthma Control

Croteau‐Chonka¹,

Qiu²,

Martínez

et al. 2017

Am J Respir Crit Care Med

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Rationale: Maintaining optimal symptom control remains the primary objective of asthma treatment. Better understanding of the biologic underpinnings of asthma control may lead to the development of improved clinical and pharmaceutical approaches.Objectives: To identify molecular pathways and interrelated genes whose differential expression was associated with asthma control.Methods: We performed gene set enrichment analyses of asthma control in 1,170 adults with asthma, each with gene expression data derived from either whole blood (WB) or unstimulated CD4 1 T lymphocytes (CD4), and a self-reported asthma control score representing either the preceding 6 months (chronic) or 7 days (acute). Our study comprised a discovery WB cohort (n = 245, chronic) and three independent, nonoverlapping replication cohorts: a second WB set (n = 448, acute) and two CD4 sets (n = 300, chronic; n = 77, acute). Measurements and Main Results:In the WB discovery cohort, we found significant overrepresentation of genes associated with asthma control in 1,106 gene sets from the Molecular Signatures Database (false discovery rate, ,5%). Of these, 583 (53%) replicated in at least one replication cohort (false discovery rate, ,25%). Suboptimal control was associated with signatures of eosinophilic and granulocytic inflammatory signals, whereas optimal control signatures were enriched for immature lymphocytic patterns. These signatures included two related biologic processes related to activation by TREM-1 (triggering receptor expressed on myeloid cells 1) and lipopolysaccharide. Conclusions:Together, these results demonstrate the existence of specific, reproducible transcriptomic components in blood that vary with degree of asthma control and implicate a novel biologic target (TREM-1).

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Section: Discussionmentioning

confidence: 78%

Section: Bridge Wbmentioning

confidence: 99%

Gene Expression Profiling in Blood Provides Reproducible Molecular Insights into Asthma Control

Croteau‐Chonka¹,

Qiu²,

Martínez

et al. 2017

Am J Respir Crit Care Med

View full text Add to dashboard Cite

show abstract

“…Our data also provide clues about potentially novel mechanisms of childhood asthma inception by emphasizing the functional connection between SMAD3, a regulator of both the asthmaprotective T regulatory and the asthma-promoting Th17 cell differentiation programs [1,26], and IL-1β, a key asthma mediator in both children [21] and adults [22,23]. Indeed, in neonates who became asthmatic by age 9, SMAD3 promoter hypermethylation, an epigenetic configuration consistent with low SMAD3 expression, was strongly associated with high IL-1β production.…”

Section: The Epigenetic Trajectory To Asthma Begins At Birth (If Not mentioning

confidence: 78%

“…A meta-analysis revealed that for each 10% increase in methylation at a representative CpG site in the SMAD3 DMR there is nearly a two-fold increased risk of childhood asthma [meta-analysis Odds Ratio (OR) =1.95 (95%CI: 1.23, 3.10), P=0.005]. Moreover, SMAD3 methylation in IIS neonates with maternal asthma was strongly and positively associated with neonatal production of IL-1β, an innate inflammatory mediator that is increasingly recognized as a key asthma mediator in both children [21] and adults, especially in neutrophilic asthma [22,23].…”

Section: The Epigenetic Trajectory To Asthma Begins At Birth (If Not mentioning

confidence: 99%

The Neonatal Methylome as a Gatekeeper in the Trajectory to Childhood Asthma

DeVries

Vercelli

2017

Epigenomics

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Asthma is a heterogeneous group of conditions that typically begin in early life and result in recurrent, reversible bronchial obstruction. The role played by epigenetic mechanisms in the pathogenesis of childhood asthma is understood only in part. Here we discuss asthma epigenetics within a developmental perspective based on our recent demonstration that the epigenetic trajectory to childhood asthma begins at birth. We next discuss how this trajectory may be affected by prenatal environmental exposures. Finally, we examine in vitro studies that model the impact of asthma-associated exposures on the epigenome. All of these studies specifically surveyed human DNA methylation and involved a genome-wide component. In combination, their results broaden our understanding of asthma pathogenesis and the role the methylome plays in this process.

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“…Current paradigm of the asthma development involves intricate interactions between host genetics (8) and environmental stressors (9). Before and first few years of life is likely to be particularly critical period during which epigenetic (9,10), metabolomic (11), and transcriptomic (12)(13)(14) signaling mechanisms influence the robustness of the host's underlying immune susceptibility (15).…”

Section: Introductionmentioning

confidence: 99%

Linking childhood allergic asthma phenotypes with endotype through integrated systems biology: current evidence and research needs

Choi

Song

Zhang

2017

Reviews on Environmental Health

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Abstract Asthma and other complex diseases results from a complex web of interactions involving inflammation, immunity, cell cycle, apoptosis, and metabolic perturbations across multiple organ systems. The extent to which various degrees of the age at onset, symptom severity, and the natural progression of the disease reflect multiple disease subtypes, influenced by unique process of development remains unknown. One of the most critical challenges to our understanding stems from incomplete understanding of the mechanisms. Within this review, we focus on the phenotypes of childhood allergic asthma as the basis to better understand the endotype for quantitative define subtypes of asthma. We highlight some of the known mechanistic pathways associated with the key hallmark events before the asthma onset. In particular, we examine how the recent advent of multiaxial -omics technologies and systems biology could help to clarify our current understanding of the pathway. We review how a large volume of molecular, genomic data generated by multiaxial technologies could be digested to identify cogent pathophysiologic molecular networks. We highlight some recent successes in application of these technologies within the context of other disease conditions for therapeutic interventions. We conclude by summarizing the research needs for the predictive value of preclinical biomarkers.

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Identification of novel immune phenotypes for allergic and nonallergic childhood asthma

Cited by 136 publications

References 36 publications

Gene Expression Profiling in Blood Provides Reproducible Molecular Insights into Asthma Control

Gene Expression Profiling in Blood Provides Reproducible Molecular Insights into Asthma Control

The Neonatal Methylome as a Gatekeeper in the Trajectory to Childhood Asthma

Linking childhood allergic asthma phenotypes with endotype through integrated systems biology: current evidence and research needs

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