Background
Cohort studies indicated that in certain individuals the basophils do not respond toward allergens due to a desensitization of their Fc epsilon receptor pathway. Cause and functional role ...as well as the implications on allergic reactions, however, are not clear yet.
Methods
A cross‐sectional study was carried out in the tropical urban environment of Singapore, where the allergic response is dominated by a single allergen (house dust mite; HDM). Blood samples were collected from 476 individuals and analyzed comprehensively to correlate the functional state of their basophils with the clinical state as well as the composition of the cellular and soluble plasma components.
Results
Inactivation of basophils (‘basophil anergy’) was observed in about 10% of the cohort. It was associated with a downregulation of basophil Syk and an apparent reduction in the incidence of allergic rhinitis. Correlations on the cohort level suggest that it represents a transitional state to be passed through during the interconversion of responder and nonresponder state.
Conclusions
Basophil anergy thus seems to function as activation barrier to prevent unwanted reactions against minor allergens. It may therefore be relevant for diagnostic purposes or therapeutic interventions of allergic diseases.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Neutrophils are an abundant immune cell type involved in both antimicrobial defence and autoimmunity. The regulation of their gene expression, however, is still largely unknown. Here we report an ...eQTL study on isolated neutrophils from 114 healthy individuals of Chinese ethnicity, identifying 21,210 eQTLs on 832 unique genes. Unsupervised clustering analysis of these eQTLs confirms their role in inflammatory responses and immunological diseases but also indicates strong involvement in dermatological pathologies. One of the strongest eQTL identified (rs2058660) is also the tagSNP of a linkage block reported to affect leprosy and Crohn's disease in opposite directions. In a functional study, we can link the C allele with low expression of the β-chain of IL18-receptor (IL18RAP). In neutrophils, this results in a reduced responsiveness to IL-18, detected both on the RNA and protein level. Thus, the polymorphic regulation of human neutrophils can impact beneficial as well as pathological inflammatory responses.
Expression quantitative trait loci (eQTL) databases represent a valuable resource to link disease-associated SNPs to specific candidate genes whose gene expression is significantly modulated by the ...SNP under investigation. We previously identified signal inhibitory receptor on leukocytes-1 (SIRL-1) as a powerful regulator of human innate immune cell function. While it is constitutively high expressed on neutrophils, on monocytes the SIRL-1 surface expression varies strongly between individuals. The underlying mechanism of regulation, its genetic control as well as potential clinical implications had not been explored yet.
Whole blood eQTL data of a Chinese cohort was used to identify SNPs regulating the expression of VSTM1, the gene encoding SIRL-1. The genotype effect was validated by flow cytometry (cell surface expression), correlated with electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP) and bisulfite sequencing (C-methylation) and its functional impact studied the inhibition of reactive oxygen species (ROS).
We found a significant association of a single CpG-SNP, rs612529T/C, located in the promoter of VSTM1. Through flow cytometry analysis we confirmed that primarily in the monocytes the protein level of SIRL-1 is strongly associated with genotype of this SNP. In monocytes, the T allele of this SNP facilitates binding of the transcription factors YY1 and PU.1, of which the latter has been recently shown to act as docking site for modifiers of DNA methylation. In line with this notion rs612529T associates with a complete demethylation of the VSTM1 promoter correlating with the allele-specific upregulation of SIRL-1 expression. In monocytes, this upregulation strongly impacts the IgA-induced production of ROS by these cells. Through targeted association analysis we found a significant Meta P value of 1.14 × 10
for rs612529 for association to atopic dermatitis (AD).
Low expression of SIRL-1 on monocytes is associated with an increased risk for the manifestation of an inflammatory skin disease. It thus underlines the role of both the cell subset and this inhibitory immune receptor in maintaining immune homeostasis in the skin. Notably, the genetic regulation is achieved by a single CpG-SNP, which controls the overall methylation state of the promoter gene segment.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Atrial fibrillation (AF) is caused by different mechanisms but current treatment strategies do not target these mechanisms. Stratified therapy based on mechanistic drivers and biomarkers of AF have ...the potential to improve AF prevention and management outcomes. We will integrate mechanistic insights with known pathophysiological drivers of AF in models predicting recurrent AF and prevalent AF to test hypotheses related to AF mechanisms and response to rhythm control therapy.
We will harmonise and combine baseline and outcome data from 12 studies collected by six centres from the United Kingdom, Germany, France, Spain, and the Netherlands which assess prevalent AF or recurrent AF. A Delphi process and statistical selection will be used to identify candidate clinical predictors. Prediction models will be developed in patients with AF for AF recurrence and AF-related outcomes, and in patients with or without AF at baseline for prevalent AF. Models will be used to test mechanistic hypotheses and investigate the predictive value of plasma biomarkers.
This retrospective, harmonised, individual patient data analysis will use information from 12 datasets collected in five European countries. It is envisioned that the outcome of this analysis would provide a greater understanding of the factors associated with recurrent and prevalent AF, potentially allowing development of stratified approaches to prevention and therapy management.
Aim. To characterise infiltrating T cells in kidneys and circulating lymphocyte subsets of adult patients with primary/idiopathic minimal change disease. Methods. In a cohort of 9 adult patients with ...primary/idiopathic minimal change recruited consecutively at disease onset, we characterized (1) infiltrating immune cells in the kidneys using immunohistochemistry and (2) circulating lymphocyte subsets using flow cytometry. As an exploratory analysis, association of the numbers and percentages of both kidney-infiltrating immune cells and the circulating lymphocyte subsets with kidney outcomes including deterioration of kidney function and proteinuria, as well as time to complete clinical remission up to 48 months of follow-up, was investigated. Results. In the recruited patients with primary/idiopathic minimal change disease, we observed (a) a dominance of infiltrating T helper 17 cells and cytotoxic cells, comprising cytotoxic T cells and natural killer cells, over Foxp3+ Treg cells in the renal interstitium; (b) an increase in the circulating total CD8+ T cells in peripheral blood; and (c) an association of some of these parameters with kidney function and proteinuria. Conclusions. In primary/idiopathic minimal change disease, a relative numerical dominance of effector over regulatory T cells can be observed in kidney tissue and peripheral blood. However, larger confirmatory studies are necessary.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Summary
Members of the multihaem cytochrome c family such as pentahaem cytochrome c nitrite reductase (NrfA) or octahaem hydroxylamine oxidoreductase (Hao) are involved in various microbial ...respiratory electron transport chains. Some members of the Hao subfamily, here called εHao proteins, have been predicted from the genomes of nitrate/nitrite‐ammonifying bacteria that usually lack NrfA. Here, εHao proteins from the host‐associated Epsilonproteobacteria Campylobacter fetus and Campylobacter curvus and the deep‐sea hydrothermal vent bacteria Caminibacter mediatlanticus and Nautilia profundicola were purified as εHao‐maltose binding protein fusions produced in Wolinella succinogenes. All four proteins were able to catalyze reduction of nitrite (yielding ammonium) and hydroxylamine whereas hydroxylamine oxidation was negligible. The introduction of a tyrosine residue at a position known to cause covalent trimerization of Hao proteins did neither stimulate hydroxylamine oxidation nor generate the Hao‐typical absorbance maximum at 460 nm. In most cases, the εHao‐encoding gene haoA was situated downstream of haoC, which predicts a tetrahaem cytochrome c of the NapC/NrfH family. This suggested the formation of a membrane‐bound HaoCA assembly reminiscent of the menaquinol‐oxidizing NrfHA complex. The results indicate that εHao proteins form a subfamily of ammonifying cytochrome c nitrite reductases that represents a ‘missing link’ in the evolution of NrfA and Hao enzymes.
This work reports the characterization of an octahaem multihaem cytochrome c (here named εHao since it is structurally related to hydroxylamine oxidoreductases) that occurs in various environmentally important organisms, most of which are Epsilonproteobacteria. Four prototypic εHao enzymes were purified and shown to be competent ammonium‐forming nitrite and hydroxylamine reductases, thus functionally resembling pentahaem cytochrome c nitrite reductase (NrfA). Consequently, εHao proteins represent a missing link within the ever‐growing multihaem cytochrome c family.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
In this multicenter, randomized trial comparing early rhythm control with usual care in patients with early atrial fibrillation and cardiovascular conditions, early rhythm control reduced the rate of ...death from cardiovascular causes and cardiovascular complications and did not affect the number of nights in the hospital.
Background Current incidence and outcome of patients with acute hypoxaemic respiratory failure requiring mechanical ventilation in the intensive care unit (ICU) are unknown, especially for patients ...not meeting criteria for acute respiratory distress syndrome (ARDS). Methods An international, multicentre, prospective cohort study of patients presenting with hypoxaemia early in the course of mechanical ventilation, conducted during four consecutive weeks in the winter of 2014 in 459 ICUs from 50 countries (LUNG SAFE). Patients were enrolled with arterial oxygen tension/inspiratory oxygen fraction ratio ≤300 mmHg, new pulmonary infiltrates and need for mechanical ventilation with a positive end-expiratory pressure of ≥5 cmH 2 O. ICU prevalence, causes of hypoxaemia, hospital survival and factors associated with hospital mortality were measured. Patients with unilateral versus bilateral opacities were compared. Findings 12 906 critically ill patients received mechanical ventilation and 34.9% with hypoxaemia and new infiltrates were enrolled, separated into ARDS (69.0%), unilateral infiltrate (22.7%) and congestive heart failure (CHF; 8.2%). The global hospital mortality was 38.6%. CHF patients had a mortality comparable to ARDS (44.1% versus 40.4%). Patients with unilateral-infiltrate had lower unadjusted mortality, but similar adjusted mortality compared to those with ARDS. The number of quadrants on chest imaging was associated with an increased risk of death. There was no difference in mortality comparing patients with unilateral-infiltrate and ARDS with only two quadrants involved. Interpretation More than one-third of patients receiving mechanical ventilation have hypoxaemia and new infiltrates with a hospital mortality of 38.6%. Survival is dependent on the degree of pulmonary involvement whether or not ARDS criteria are reached.
The existence of T-cell subsets naturally committed to perform immunoregulation has led to enthusiastic efforts to investigate their role in the immunopathogenesis of transplantation. Being able to ...modulate alloresponses, regulatory T cells could be used as an immunodiagnostic tool in clinical kidney transplantation. Thus, the measurement of Foxp3 transcripts, the presence of regulatory T cells in kidney biopsies, and the phenotypic characterisation of the T-cell infiltrate could aid in the diagnosis of rejection and the immune monitoring and prediction of outcomes in kidney transplantation. Interestingly, the adoptive transfer of regulatory T cells in animal models has been proven to downmodulate powerful alloresponses, igniting translational research on their potential use as an immunomodulatory therapy. For busy transplant clinicians, the vast amount of information in the literature on regulatory T cells can be overwhelming. This paper aims to highlight the most applicable research findings on the use of regulatory T cells in the immune diagnosis and potential immunomodulatory therapy of kidney transplant patients. However, can we yet rely on differential regulatory T-cell profiles for the identification of rejection or to tailor patient's immunosuppression? Are we ready to administer regulatory T cells as inductive or adjunctive therapy for kidney transplantation?
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Little is known about genome-wide changes in the atrial transcriptome as a cause or consequence of atrial fibrillation (AF), and the effect of its common and clinically relevant comorbidity—heart ...failure (HF).
The purpose of this study was to explore candidate disease processes for AF by investigating gene expression changes in atrial tissue samples from patients with and without AF, stratified by HF.
RNA sequencing was performed in right and left atrial appendage tissue in 195 patients undergoing open heart surgery from centers participating in the CATCH-ME consortium (no history of AF, n = 91; paroxysmal AF, n = 53; persistent/permanent AF, n = 51). Analyses were stratified into patients with/without HF (n = 75/120) and adjusted for age, sex, atrial side, and a combination of clinical characteristics.
We identified 35 genes associated with persistent AF compared to patients without a history of AF, both in the presence or absence of HF (false discovery rate <0.05). These were mostly novel associations, including 13 long noncoding RNAs. Genes were involved in regulation of cardiomyocyte structure, conduction properties, fibrosis, inflammation, and endothelial dysfunction. Gene set enrichment analysis identified mainly inflammatory gene sets to be enriched in AF patients without HF, and gene sets involved in cellular respiration in AF patients with HF.
Analysis of atrial gene expression profiles identified numerous novel genes associated with persistent AF, in the presence or absence of HF. Interestingly, no consistent transcriptional changes were associated with paroxysmal AF, suggesting that AF-induced changes in gene expression predominate other changes.
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