The impact of mannose‐binding lectin polymorphisms on lung function in primary ciliary dyskinesia

Videbæk, Katja; Buchvald, Frederik; Holgersen, Mathias G.; Henriksen, Alison; Eriksson, Frank; Garred, Peter; Nielsen, Kim G.

doi:10.1002/ppul.24346

Cited by 11 publications

(12 citation statements)

References 29 publications

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“…Despite MBL deficiency not being the cause of cystic fibrosis, several studies have shown the impact of MBL expression and polymorphisms on the course of CF disease (13). Similar findings were found in patients with non-CF bronchiectasis and in patients with primary ciliary diyskenesia (31)(32)(33). Our data shows that serum levels of MBL were highly related to MBL haplotypes with MBL serum concentrations being unaffected by patients age, gender, and PA status.…”

Section: Discussionsupporting

confidence: 84%

Genetic Association With Pseudomonas aeruginosa Acquisition in Cystic Fibrosis: Influence of Surfactant Protein D and Mannose-Binding Lectin

et al. 2021

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Background:Pseudomonas aeruginosa (PA) infection in cystic fibrosis (CF) is associated with poor prognosis. Surfactant protein-D (SFTPD) and mannose-binding lectin (MBL) play a critical role in innate immunity and response to bacterial infections. We investigated serum levels and genetic variants of SFTPD and MBL in CF patients.Method: Thirty-five Caucasian patients homozygous for ΔF508del were genotyped for functional relevant polymorphisms within MBL2 (promoter−221 Y/X, codons 52, 54, and 57) and SFTPD genes (Met11Thr, Ala160Thr, and Ser270Thr). Serum levels of collectins, clinical characteristics, and PA status were correlated with genetic data.Results: Patients age, gender, and PA status did not affect MBL and SFTPD serum concentrations. MBL concentrations were correlated with MBL haplotypes. Patients with chronic Pseudomonas aeroginosa infection (PAC) and MBL insufficiency had a shorter interval between first PA infection and onset of PAC (0.01 vs. 4.6 years, p < 0.04) as well as a lower median age at transition to PAC (9.8 vs. 16.4 years, p < 0.03) compared to MBL sufficient patients with PAC. SFTPD serum level and FEV1% (Spearman r = −0.41, p < 0.03) showed a negative correlation irrespective of PA infection status. The hazard ratio to PA acquisition was increased in carriers of the SFTPD haplotype 11Thr-160Ala-270Ser compared to carriers of the common 11Met-160Thr-270Ser haplotype [HR 3.0 (95%CI: 1.1–8.6), p < 0.04].Conclusion: MBL insufficiency leads to a shorter interval between first PA infection and onset of chronic infection. Susceptibility to PA acquisition is associated with SFTPD genetic variants with 11Thr-160Ala-270Ser as risk haplotype for early PA infection. This may be due to presence of threonine associated with oligomeric structure of SFTPD and binding ability to bacteria.

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Section: Discussionsupporting

confidence: 84%

Genetic Association With Pseudomonas aeruginosa Acquisition in Cystic Fibrosis: Influence of Surfactant Protein D and Mannose-Binding Lectin

et al. 2021

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“…Asp+, Aspergillus positive; AspÀ, Aspergillus negative; BALF, bronchoalveolar lavage fluid; CF, cystic fibrosis; HC, healthy volunteers; hMSC, human bone marrowderived mesenchymal stromal cell; ns, not statistically significant. (47). Notably, insufficient amount of mannose-binding lectin has been associated with adverse progression of CF lung disease (18).…”

Section: A B Cmentioning

confidence: 99%

Differential effects of the cystic fibrosis lung inflammatory environment on mesenchymal stromal cells

Abreu

Hampton

Hoffman

et al. 2020

American Journal of Physiology-Lung Cellular and Molecular Phys

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Growing evidence demonstrates that human mesenchymal stromal cells (MSCs) modify their in vivo anti-inflammatory actions depending on the specific inflammatory environment encountered. Understanding this better is crucial to refine MSC-based cell therapies for lung and other diseases. Using acute exacerbations of cystic fibrosis (CF) lung disease as a model, the effects of ex vivo MSC exposure to clinical bronchoalveolar lavage fluid (BALF) samples, as a surrogate for the in vivo clinical lung environment, on MSC viability, gene expression, secreted cytokines, and mitochondrial function was compared to effects of BALF collected from healthy volunteers. CF BALF samples which cultured positive for Aspergillus sp. (Asp) induced rapid MSC death, usually within several hours of exposure. Further analyses suggested the fungal toxin gliotoxin as a potential mediator contributing to CF BALF-induced MSC death. RNA sequencing analyses of MSCs exposed to either Asp+ or Asp- CF BALF samples identified a number of differentially expressed transcripts, including those involved in interferon-signaling, anti-microbial gene expression, and cell death. Toxicity did not correlate with bacterial lung infections. These results suggest that the potential use of MSC-based cell therapies for CF or other lung diseases may not be warranted in the presence of Aspergillus.

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“…Nevertheless, in a report by Pifferi et al, 18 no association was found between MBL2 genotypes and clinical findings other than severity of bronchiectasis in PCD, and they concluded that MBL played a relatively minor role as a disease modifier in PCD. However, in another retrospective longitudinal study by Videbaek K et al 19 which included a larger number of patients with PCD, it was shown that MBL‐deficient patients based on MBL2 genotypes with the A/O genotype ignoring MBL serum measurement were diagnosed earlier and their FEV1 declined significantly faster per year than PCD patients with MBL sufficiency carrying A/A genotype, and they suggested that MBL genotype might be a disease modifier in PCD.…”

Section: Discussionmentioning

confidence: 99%

Impact of mannose‐binding lectin 2 gene polymorphisms on disease severity in noncystic fibrosis bronchiectasis in children

Doğru

Polat

Tan

et al. 2020

Pediatric Pulmonology

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Background Mannose‐binding lectin (MBL) is a complement protein involved in the innate immune system, and is associated with some chronic respiratory diseases including noncystic fibrosis (non‐CF) bronchiectasis in adults. The aim of this study was to investigate the frequency of MBL2 gene polymorphisms in children with non‐CF bronchiectasis, and the effect of MBL deficiency on disease severity. Methods Fifty children with non‐CF bronchiectasis (bronchiectasis group) and 50 healthy controls (control group) were included. The demographic findings, number of acute pulmonary exacerbations in the previous year, airway cultures, pulmonary function tests, and radiologic scores of the bronchiectasis group were recorded. DNA extraction was performed in both groups and MBL2 gene polymorphisms in codons 52, 54, 57 in exon 1 and H/L, Y/X in the promoter region were studied using real‐time polymerase chain reaction. Haplotypes were made by genotypes, and MBL serum expression was classified according to the genotypes in the literature. Results The bronchiectasis group consisted of 23 (46%) patients with primary ciliary dyskinesia, 5 (10%) with primary immunodeficiency diseases, and 22 (44%) with idiopathic bronchiectasis. There were no statistically significant differences between the bronchiectasis and control groups in terms of allele and genotype frequencies of polymorphisms in codons 52, 54, 57 in exon 1 and promoter H/L. However, the YX heterozygote genotype was more frequent in the control group (82%) compared with the bronchiectasis group (50%) (P = .002). The frequency of patients with intermediate serum MBL expression genotype was higher in the bronchiectasis group (20%) than in the control group (0%) (P = .001). In the bronchiectasis group, there were no significant differences in growth, annual pulmonary exacerbation rates in the last year, pulmonary function tests, radiologic scores, and microbiologic findings between low, intermediate, and high‐expressing genotypes. Conclusions In children with non‐CF bronchiectasis, MBL genotype was different from healthy controls. MBL deficiency associated only with MBL genotype was not related to disease severity in this group of patients.

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The impact of mannose‐binding lectin polymorphisms on lung function in primary ciliary dyskinesia

Cited by 11 publications

References 29 publications

Genetic Association With Pseudomonas aeruginosa Acquisition in Cystic Fibrosis: Influence of Surfactant Protein D and Mannose-Binding Lectin

Genetic Association With Pseudomonas aeruginosa Acquisition in Cystic Fibrosis: Influence of Surfactant Protein D and Mannose-Binding Lectin

Differential effects of the cystic fibrosis lung inflammatory environment on mesenchymal stromal cells

Impact of mannose‐binding lectin 2 gene polymorphisms on disease severity in noncystic fibrosis bronchiectasis in children

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