Sarcoidosis is a polygenic immune disorder with predominant manifestation in the lung. Genome-wide linkage analysis previously indicated that the extended major histocompatibility locus on chromosome ...6p was linked to susceptibility to sarcoidosis. Here, we carried out a systematic three-stage SNP scan of 16.4 Mb on chromosome 6p21 in as many as 947 independent cases of familial and sporadic sarcoidosis and found that a 15-kb segment of the gene butyrophilin-like 2 (BTNL2) was associated with the disease. The primary disease-associated variant (rs2076530; P(TDT) = 3 x 10(-6), P(case-control) = 1.1 x 10(-8); replication P(TDT) = 0.0018, P(case-control) = 1.8 x 10(-6)) represents a risk factor that is independent of variation in HLA-DRB1. BTNL2 is a member of the immunoglobulin superfamily and has been implicated as a costimulatory molecule involved in T-cell activation on the basis of its homology to B7-1. The G --> A transition constituting rs2076530 leads to the use of a cryptic splice site located 4 bp upstream of the affected wild-type donor site. Transcripts of the risk-associated allele have a premature stop in the spliced mRNA. The resulting protein lacks the C-terminal IgC domain and transmembrane helix, thereby disrupting the membrane localization of the protein, as shown in experiments using green fluorescent protein and V5 fusion proteins.
Lung transplantation is often the only treatment for end-stage lung disease. Following lung transplantation, infections and transplant rejections are major obstacles to short- and long-term success. ...Therefore, close monitoring for these complications is required after lung transplantation. The role of prescheduled surveillance bronchoscopies after lung transplantation is controversial. Thus, we aimed to retrospectively analyze the therapeutic implications of surveillance bronchoscopies in 110 consecutive lung transplant recipients.
Results of 400 prescheduled surveillance bronchoscopies of 110 consecutive lung transplant recipients were analyzed. Positive results (pathologic histology, microbiology, or virology) were further investigated for their effect on clinical decision making. Additionally, cellular composition of bronchoalveolar lavage (BAL) was analyzed.
Two hundred five surveillance bronchoscopies showed pathologic findings. In 81 cases clinical treatment was changed based on the results. That is, 20% of all prescheduled bronchoscopies directly influenced clinical decision making. Furthermore, analyses of BAL indicate that increased alveolar eosinophils are associated with an increased risk of transplant rejection.
Prescheduled surveillance bronchoscopies identify clinically unsuspected but therapeutically relevant pathologic findings in approximately 20% of cases. BAL cell composition may confer additional information, especially in cases when biopsy is not possible.
•Prescheduled surveillance bronchoscopies after lung transplantation may influence therapeutic decision making in up to 20% of cases.•Unexpected microbiological findings and unexpected acute cellular rejection are the most important findings for changing therapy.•Bronchoalveolar lavage and alveolar differential cell count may help to identify patients at risk for acute rejection; for example, in cases when parenchymal biopsies are not possible.
Sarcoidosis is granulomatous disease of unknown origin affecting organ function and quality of life. The King's Sarcoidosis Questionnaire (KSQ) serves as a tool to assess quality of life in ...sarcoidosis patients with general health and organ specific domains. A German translation has been validated in a German cohort. In this study we assessed, whether clinical parameters influence KSQ scores.
Clinical data (e.g. lung function, organ impairment, serological parameters) for the German validation cohort were extracted from clinical charts and investigated by correlation and linear regression analyses.
KSQ subdomain scores were generally lower in patients with respective organ manifestation or on current therapy. LUNG subdomain was significantly predicted by lung functional parameters, however for general health status, only FeV1 exerted significant influence. GHS was not influenced by serological parameters, but was significantly negatively correlated with body mass index (BMI). KSQ provides additional information beyond lung function, clinical or serological parameters in sarcoidosis patients. Notably, high BMI is significantly negatively associated with patients' well-being as measured by KSQ-GHS.
This observation may direct further studies investigating the effect of obesity on sarcoidosis-related quality of life and strategies to intervene with steroid-sparing therapies and measures of life style modifications. Trial registration This study was registered in the German Clinical Trials Register (reference number DRKS00010072). Registered January 2016.
King's Sarcoidosis Questionnaire (KSQ) is a novel, validated, health-related quality of life questionnaire on sarcoidosis with 5 scales and 29 items. For future multinational observational and ...interventional studies on sarcoidosis, a validated German version of the KSQ is needed. The objective of our study is to translate the original KSQ and develop a German version possessing good psychometric properties and with as few modifications as possible.
We translated the KSQ into German, tested it in structured interviews in sarcoidosis patients, and asked consecutive patients in an outpatient clinic to complete it. We relied on the KSQ's original version to achieve its psychometric properties in the German version. Structural validity, internal consistency, construct validity, and fit to Rasch model were assessed. Our procedure's logic meant that in the first step we optimized the item selection in the German version to maximize its psychometric quality. In step two, we assessed the unmodified version's properties in comparison to the modified version's.
One hundred ninety-four patients with sarcoidosis were included and completed the questionnaires. Due to ambiguous factor loadings, four items of the scale "General Health Status" had to be eliminated. Another item was excluded to ensure the Rasch model fit. This modified, 24-item version of the KSQ shows acceptable Rasch model fit and good model fit in confirmatory factor analyses (TLI = 0.90, CFI = 0.91, RMSEA = 0.08). Cronbach's Alpha ranges from 0.82 to 0.91. Several hypotheses concerning construct validity (e.g., correlations with SF-36) are confirmed or partly confirmed. The measurement properties of the original unmodified version are similar in their construct validity and internal consistency; however, we were unable to confirm structural validity and fit to the Rasch model in the original version.
We translated and validated the German KSQ and report good psychometric properties. The reduced 24-item version has the advantage that all scales are unidimensional and fulfil the requirements of the Rasch model, ensuring its benefits. The original 29-item version, on the other hand, allows us to compare German data to international data however, at the price, of less structural validity and the lack of fit to the Rasch model.
This study was registered in the German Clinical Trials Register (reference number DRKS00010072 ). Registered January 2016.
The CC chemokine ligand 18 (CCL18) is produced by alveolar macrophages in patients with fibrosing lung disease and its concentration is increased in various fibrotic lung diseases. Furthermore CCL18 ...is elevated in several malignancies as it is produced by tumor associated macrophages. In this study we aimed to analyze the role of CCL18 as a prognostic biomarker for the development of early radiation induced lung toxicity (RILT), i.e. radiation pneumonitis after thoracic irradiation and its significance in the course of the disease. Sixty seven patients were enrolled prospectively in the study. Patients were treated with irradiation for several thoracic malignancies (lung cancer, esophageal cancer, thymoma), either with conventionally fractionated or hypo-fractionated radiotherapy. The CCL18 serum levels were quantified with ELISA (enzyme-linked immunosorbent assay) at predefined time points: before, during and at the end of treatment as well as in the first and second follow-up. Treatment parameters and functional tests were also correlated with the development of RILT.Fifty three patients were evaluable for this study. Twenty one patients (39%) developed radiologic signs of RILT Grade >1 but only three of them (5.6%) developed clinical symptoms (Grade 2). We could not find any association between the different CCL18 concentrations and a higher incidence of RILT. Statistical significant factors were the planning target volume (odds ratio OR: 1.003, p = 0.010), the volume of the lung receiving > 20 Gy (OR: 1.132 p = 0.004) and age (OR: 0.917, p = 0.008). There was no association between serial CCL18 concentrations with tumor response and overall survival.In our study the dosimetric parameters remained the most potent predictors of RILT. Further studies are needed in order to estimate the role of CCL18 in the development of early RILT.
The scavenger receptor MARCO is expressed in several subsets of naive tissue-resident macrophages and has been shown to participate in the recognition of various bacterial pathogens. However, the ...role of MARCO in antiviral defense is largely unexplored. Here, we investigated whether MARCO might be involved in the innate sensing of infection with adenovirus and recombinant adenoviral vectors by macrophages, which elicit vigorous immune responses
Using cells derived from mice, we show that adenovirus infection is significantly more efficient in MARCO-positive alveolar macrophages (AMs) and in AM-like primary macrophage lines (Max Planck Institute cells) than in MARCO-negative bone marrow-derived macrophages. Using antibodies blocking ligand binding to MARCO, as well as gene-deficient and MARCO-transfected cells, we show that MARCO mediates the rapid adenovirus transduction of macrophages. By enhancing adenovirus infection, MARCO contributes to efficient innate virus recognition through the cytoplasmic DNA sensor cGAS. This leads to strong proinflammatory responses, including the production of interleukin-6 (IL-6), alpha/beta interferon, and mature IL-1α. These findings contribute to the understanding of viral pathogenesis in macrophages and may open new possibilities for the development of tools to influence the outcome of infection with adenovirus or adenovirus vectors.
Macrophages play crucial roles in inflammation and defense against infection. Several macrophage subtypes have been identified with differing abilities to respond to infection with both natural adenoviruses and recombinant adenoviral vectors. Adenoviruses are important respiratory pathogens that elicit vigorous innate responses
and
The cell surface receptors mediating macrophage type-specific adenovirus sensing are largely unknown. The scavenger receptor MARCO is expressed on some subsets of naive tissue-resident macrophages, including lung alveolar macrophages. Its role in antiviral macrophage responses is largely unexplored. Here, we studied whether the differential expression of MARCO might contribute to the various susceptibilities of macrophage subtypes to adenovirus. We demonstrate that MARCO significantly enhances adenovirus infection and innate responses in macrophages. These results help to understand adenoviral pathogenesis and may open new possibilities to influence the outcome of infection with adenoviruses or adenovirus vectors.
EvA (Emphysema versus Airway disease) is a multicentre project to study mechanisms and identify biomarkers of emphysema and airway disease in chronic obstructive pulmonary disease (COPD). The ...objective of this study was to delineate objectively imaging-based emphysema-dominant and airway disease-dominant phenotypes using quantitative computed tomography (QCT) indices, standardised with a novel phantom-based approach.441 subjects with COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 1-3) were assessed in terms of clinical and physiological measurements, laboratory testing and standardised QCT indices of emphysema and airway wall geometry.QCT indices were influenced by scanner non-conformity, but standardisation significantly reduced variability (p<0.001) and led to more robust phenotypes. Four imaging-derived phenotypes were identified, reflecting "emphysema-dominant", "airway disease-dominant", "mixed" disease and "mild" disease. The emphysema-dominant group had significantly higher lung volumes, lower gas transfer coefficient, lower oxygen (PO2 ) and carbon dioxide (PCO2 ) tensions, higher haemoglobin and higher blood leukocyte numbers than the airway disease-dominant group.The utility of QCT for phenotyping in the setting of an international multicentre study is improved by standardisation. QCT indices of emphysema and airway disease can delineate within a population of patients with COPD, phenotypic groups that have typical clinical features known to be associated with emphysema-dominant and airway-dominant disease.
Sarcoidosis is a granulomatous disease that mainly manifests within the lungs and may thereby impair lung function. Beyond and independently from organ impairment, sarcoidosis may affect quality of ...life which can be quantified by questionnaires. The Leicester Cough Questionnaire (LCQ) has been developed to assess cough-related quality of life. We analysed data from a prospectively collected cohort of sarcoidosis patients for validation of the German LCQ version. Our analyses demonstrated that LCQ values add additional information beyond routinely monitored parameters (e.g. lung function). Only FeV1 and BMI slightly influence LCQ scores, where all other parameters tested did not correlate with LCQ scores. In summary, LCQ is a valuable tool providing information on the patient’ quality of life beyond routine follow-up parameters. FeV1 and BMI may represent treatable traits to reduce cough-related disease burden.
-LCQ and VAS are two tools to assess cough related quality of life.-LCQ and VAS in sarcoidosis are influenced by FeV1 and BMI-Serological parameters are not associated with LCQ score
Changes in microbial community composition in the lung of patients suffering from moderate to severe COPD have been well documented. However, knowledge about specific microbiome structures in the ...human lung associated with CT defined abnormalities is limited.
Bacterial community composition derived from brush samples from lungs of 16 patients suffering from different CT defined subtypes of COPD and 9 healthy subjects was analyzed using a cultivation independent barcoding approach applying 454-pyrosequencing of 16S rRNA gene fragment amplicons.
We could show that bacterial community composition in patients with changes in CT (either airway or emphysema type changes, designated as severe subtypes) was different from community composition in lungs of patients without visible changes in CT as well as from healthy subjects (designated as mild COPD subtype and control group) (PC1, Padj = 0.002). Higher abundance of Prevotella in samples from patients with mild COPD subtype and from controls and of Streptococcus in the severe subtype cases mainly contributed to the separation of bacterial communities of subjects. No significant effects of treatment with inhaled glucocorticoids on bacterial community composition were detected within COPD cases with and without abnormalities in CT in PCoA. Co-occurrence analysis suggests the presence of networks of co-occurring bacteria. Four communities of positively correlated bacteria were revealed. The microbial communities can clearly be distinguished by their associations with the CT defined disease phenotype.
Our findings indicate that CT detectable structural changes in the lung of COPD patients, which we termed severe subtypes, are associated with alterations in bacterial communities, which may induce further changes in the interaction between microbes and host cells. This might result in a changed interplay with the host immune system.
Genome-wide and candidate gene studies for pulmonary sarcoidosis have highlighted several candidate variants among different populations. However, the genetic basis of functional rare variants in ...sarcoidosis still needs to be explored. To identify functional rare variants in sarcoidosis, we sequenced exomes of 22 sarcoidosis cases from six families. Variants were prioritized using linkage and high-penetrance approaches, and filtered to identify novel and rare variants. Functional networking and pathway analysis of identified variants was performed using gene ontology based gene–phenotype, gene–gene, and protein–protein interactions. The linkage (
n
= 1007–7640) and high-penetrance (
n
= 11,432) prioritized variants were filtered to select variants with (a) reported allele frequency < 5% in databases (1.2–3.4%) or (b) novel (0.7–2.3%). Further selection based on functional properties and validation revealed a panel of 40 functional rare variants (33 from linkage region, 6 highly penetrant and 1 shared by both approaches). Functional network analysis implicated these gene variants in immune responses, such as regulation of pro-inflammatory cytokines including production of IFN-γ and anti-inflammatory cytokine IL-10, leukocyte proliferation, bacterial defence, and vesicle-mediated transport. The KEGG pathway analysis indicated inflammatory bowel disease as most relevant. This study highlights the subsets of functional rare gene variants involved in pulmonary sarcoidosis, such as, regulations of calcium ions, G-protein-coupled receptor, and immune system including retinoic acid binding. The implicated mechanisms in etiopathogenesis of familial sarcoidosis thus include Wnt signalling, inflammation mediated by chemokine and cytokine signalling and cadherin signalling pathways.
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