Risk of asthma in heterozygous carriers for cystic fibrosis: A meta-analysis

Nielsen, Anne Orholm; Qayum, Sadaf; Bouchelouche, Pierre; Laursen, L. C.; Dahl, Ronald; Dahl, Morten

doi:10.1016/j.jcf.2016.06.001

Cited by 32 publications

(30 citation statements)

References 25 publications

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“…data from bronchial brush samples implicated that the lung pathology in CF is predominated by Th17 and Th1 gene signatures (43), the increased pulmonary presence of the ILC2-activating cytokine IL-33 and augmented levels of the type-2 effector cytokines IL-5, IL-9, and IL-13 in CF BAL and sputum samples as well as the upregulation of local Th2 responses upon chronic infections with Pseudomonas aeruginosa in CF patients strongly argued for a potential, albeit less elucidated, involvement of ILC2s in CF pathogenesis (13,14,42,(44)(45)(46). Accordingly, the risk of asthma, a prototypical ILC2-initiated allergic disease (47), was found to be significantly higher in CF patients compared to non-carriers of a CFTR mutation (48), implicating exaggerated ILC2 activities in CF. In line with this, Cftr −/− mice showed elongated ILC2 responses compared to C57Bl/6 wild type mice upon infection with Aspergillus fumigatus (14).…”

Section: Introductionmentioning

confidence: 99%

ILC2 Lung-Homing in Cystic Fibrosis Patients: Functional Involvement of CCR6 and Impact on Respiratory Failure

et al. 2020

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Cystic fibrosis patients suffer from a progressive, often fatal lung disease, which is based on a complex interplay between chronic infections, locally accumulating immune cells and pulmonary tissue remodeling. Although group-2 innate lymphoid cells (ILC2s) act as crucial initiators of lung inflammation, our understanding of their involvement in the pathogenesis of cystic fibrosis remains incomplete. Here we report a marked decrease of circulating CCR6 + ILC2s in the blood of cystic fibrosis patients, which significantly correlated with high disease severity and advanced pulmonary failure, strongly implicating increased ILC2 homing from the peripheral blood to the chronically inflamed lung tissue in cystic fibrosis patients. On a functional level, the CCR6 ligand CCL20 was identified as potent promoter of lung-directed ILC2 migration upon inflammatory conditions in vitro and in vivo using a new humanized mouse model with light-sheet fluorescence microscopic visualization of lung-accumulated human ILC2s. In the lung, blood-derived human ILC2s were able to augment local eosinophil and neutrophil accumulation and induced a marked upregulation of pulmonary type-VI collagen expression. Studies in primary human lung fibroblasts additionally revealed ILC2-derived IL-4 and IL-13 as important mediators of this type-VI collagen-inducing effect. Taken together, the here acquired results suggest that pathologically increased CCL20 levels in cystic fibrosis airways induce CCR6-mediated lung homing of circulating human ILC2s. Subsequent ILC2 activation then triggers local production of type-VI collagen and might thereby drive extracellular matrix remodeling potentially influencing pulmonary tissue destruction in cystic fibrosis patients. Thus, modulating the lung homing capacity of circulating ILC2s and their local effector functions opens new therapeutic avenues for cystic fibrosis treatment.

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Section: Introductionmentioning

confidence: 99%

ILC2 Lung-Homing in Cystic Fibrosis Patients: Functional Involvement of CCR6 and Impact on Respiratory Failure

et al. 2020

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“…Thus, CF carriers, having only 1 defective CFTR gene, are not considered to be at increased risk for CF-related conditions (9,10), and CF carriers are routinely informed that they are not at increased health risk (11)(12)(13). However, some studies have found a higher-than-expected proportion of CF carriers with a limited number of CF-related conditions, including congenital bilateral absence of vas deferens (14,15), sinusitis (16)(17)(18), pancreatitis (19)(20)(21), bronchiectasis (22)(23)(24), mycobacterial infections (25)(26)(27), and asthma (23,28). But these investigations generally focused on single conditions, were based on small numbers of patients, did not include controls, and did not compare risk between CF carriers and people with CF.…”

mentioning

confidence: 99%

Cystic fibrosis carriers are at increased risk for a wide range of cystic fibrosis-related conditions

Miller

Comellas

Hornick

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

138

146

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Autosomal recessive diseases, such as cystic fibrosis (CF), require inheritance of 2 mutated genes. However, some studies indicate that CF carriers are at increased risk for some conditions associated with CF. These investigations focused on single conditions and included small numbers of subjects. Our goal was to determine whether CF carriers are at increased risk for a range of CF-related conditions. Using the Truven Health MarketScan Commercial Claims database (2001–2017), we performed a population-based retrospective matched-cohort study. We identified 19,802 CF carriers and matched each carrier with 5 controls. The prevalence of 59 CF-related diagnostic conditions was evaluated in each cohort. Odds ratios for each condition were computed for CF carriers relative to controls. All 59 CF-related conditions were more prevalent among carriers compared with controls, with significantly increased risk (P < 0.05) for 57 conditions. Risk was increased for some conditions previously linked to CF carriers (e.g., pancreatitis, male infertility, bronchiectasis), as well as some conditions not previously reported (e.g., diabetes, constipation, cholelithiasis, short stature, failure to thrive). We compared our results with 23,557 subjects with CF, who were also matched with controls; as the relative odds of a given condition increased among subjects with CF, so did the corresponding relative odds for carriers (P < 0.001). Although individual-level risk remained low for most conditions, because there are more than 10 million carriers in the US, population-level morbidity attributable to the CF carrier state is likely substantial. Genetic testing may inform prevention, diagnosis, and treatment for a broad range of CF carrier-related conditions.

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“…In bronchoalveolar lavage fluid and sputum of patients with CF, the presence of IL-33 as well as IL-5, IL-9 and IL-13 was upregulated, suggesting that local type 2 responses may somehow contribute to CF pathogenesis (100)(101)(102). In line with this, the risk for manifestation of allergic asthma was reported to be higher in patients with CF (103). Morelli et al reported an association of a single nucleotide polymorphism in the IL-9 gene with high Aspergillus-specific IgE levels in females with CF (101).…”

Section: Role Of Ilc2s In Human Fibrotic Lung Diseasesmentioning

confidence: 62%

Functional Contribution and Targeted Migration of Group-2 Innate Lymphoid Cells in Inflammatory Lung Diseases: Being at the Right Place at the Right Time

2021

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During the last decade, group-2 innate lymphoid cells (ILC2s) have been discovered and successfully established as crucial mediators of lung allergy, airway inflammation and fibrosis, thus affecting the pathogenesis and clinical course of many respiratory diseases, like for instance asthma, cystic fibrosis and chronic rhinosinusitis. As an important regulatory component in this context, the local pulmonary milieu at inflammatory tissue sites does not only determine the activation status of lung-infiltrating ILC2s, but also influences their motility and migratory behavior. In general, many data collected in recent murine and human studies argued against the former concept of a very strict tissue residency of innate lymphoid cells (ILCs) and instead pointed to a context-dependent homing capacity of peripheral blood ILC precursors and the inflammation-dependent capacity of specific ILC subsets for interorgan trafficking. In this review article, we provide a comprehensive overview of the so far described molecular mechanisms underlying the pulmonary migration of ILC2s and thereby the numeric regulation of local ILC2 pools at inflamed or fibrotic pulmonary tissue sites and discuss their potential to serve as innovative therapeutic targets in the treatment of inflammatory lung diseases.

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Risk of asthma in heterozygous carriers for cystic fibrosis: A meta-analysis

Abstract: The results show that heterozygous carriers for CF have a higher risk of asthma than non-carriers.

Cited by 32 publications

References 25 publications

ILC2 Lung-Homing in Cystic Fibrosis Patients: Functional Involvement of CCR6 and Impact on Respiratory Failure

ILC2 Lung-Homing in Cystic Fibrosis Patients: Functional Involvement of CCR6 and Impact on Respiratory Failure

Cystic fibrosis carriers are at increased risk for a wide range of cystic fibrosis-related conditions

Functional Contribution and Targeted Migration of Group-2 Innate Lymphoid Cells in Inflammatory Lung Diseases: Being at the Right Place at the Right Time

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