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  • 1
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    Online Resource
    Validation of the Asthma Severity Scoring System (ASSESS) in the ALLIANCE Cohort
    Elsevier BV ; 2023
    In:  Journal of Allergy and Clinical Immunology Vol. 151, No. 6 ( 2023-06), p. 1525-1535.e4
    Details
    In: Journal of Allergy and Clinical Immunology, Elsevier BV, Vol. 151, No. 6 ( 2023-06), p. 1525-1535.e4
    Type of Medium: Online Resource
    ISSN: 0091-6749
    URL: Article
    DOI: 10.1016/j.jaci.2023.01.027
    RVK:
    XA 52000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 2006613-2
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  • 2
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    T2-high asthma phenotypes across lifespan
    European Respiratory Society (ERS) ; 2022
    In:  European Respiratory Journal Vol. 60, No. 3 ( 2022-09), p. 2102288-
    Details
    In: European Respiratory Journal, European Respiratory Society (ERS), Vol. 60, No. 3 ( 2022-09), p. 2102288-
    Abstract: In adults, personalised asthma treatment targets patients with type 2 (T2)-high and eosinophilic asthma phenotypes. It is unclear whether such classification is achievable in children. Objectives To define T2-high asthma with easily accessible biomarkers and compare resulting phenotypes across all ages. Methods In the multicentre clinical All Age Asthma Cohort (ALLIANCE), 1125 participants (n=776 asthmatics, n=349 controls) were recruited and followed for 2 years (1 year in adults). Extensive clinical characterisation (questionnaires, blood differential count, allergy testing, lung function and sputum induction (in adults)) was performed at baseline and follow-ups. Interleukin (IL)-4, IL-5 and IL-13 were measured after stimulation of whole blood with lipopolysaccharide (LPS) or anti-CD3/CD28. Measurements and main results Based on blood eosinophil counts and allergen-specific serum IgE antibodies, patients were categorised into four mutually exclusive phenotypes: “atopy-only”, “eosinophils-only”, “T2-high” (eosinophilia + atopy) and “T2-low” (neither eosinophilia nor atopy). The T2-high phenotype was found across all ages, even in very young children in whom it persisted to a large degree even after 2 years of follow-up. T2-high asthma in adults was associated with childhood onset, suggesting early origins of this asthma phenotype. In both children and adults, the T2-high phenotype was characterised by excessive production of specific IgE to allergens (p 〈 0.0001) and, from school age onwards, by increased production of IL-5 after anti-CD3/CD28 stimulation of whole blood. Conclusions Using easily accessible biomarkers, patients with T2-high asthma can be identified across all ages delineating a distinct phenotype. These patients may benefit from therapy with biologicals even at a younger age.
    Type of Medium: Online Resource
    ISSN: 0903-1936 , 1399-3003
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.1183/13993003.02288-2021
    DOI: 10.1183/13993003.02288-2021.Supp1
    DOI: 10.1183/13993003.02288-2021.Shareable1
    Language: English
    Publisher: European Respiratory Society (ERS)
    Publication Date: 2022
    detail.hit.zdb_id: 2834928-3
    detail.hit.zdb_id: 1499101-9
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  • 3
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    IgA + memory B-cells are significantly increased in patients with asthma and small airway dysfunction
    European Respiratory Society (ERS) ; 2022
    In:  European Respiratory Journal Vol. 60, No. 5 ( 2022-11), p. 2102130-
    Details
    In: European Respiratory Journal, European Respiratory Society (ERS), Vol. 60, No. 5 ( 2022-11), p. 2102130-
    Abstract: Comprehensive studies investigated the role of T-cells in asthma which led to personalised treatment options targeting severe eosinophilic asthma. However, little is known about the contribution of B-cells to this chronic inflammatory disease. In this study we investigated the contribution of various B-cell populations to specific clinical features in asthma. Methods In the All Age Asthma Cohort (ALLIANCE), a subgroup of 154 adult asthma patients and 28 healthy controls were included for B-cell characterisation by flow cytometry. Questionnaires, lung function measurements, blood differential counts and allergy testing of participants were analysed together with comprehensive data on B-cells using association studies and multivariate linear models. Results Patients with severe asthma showed decreased immature B-cell populations while memory B-cells were significantly increased compared with both mild–moderate asthma patients and healthy controls. Furthermore, increased frequencies of IgA + memory B-cells were associated with impaired lung function and specifically with parameters indicative for augmented resistance in the peripheral airways. Accordingly, asthma patients with small airway dysfunction (SAD) defined by impulse oscillometry showed increased frequencies of IgA + memory B-cells, particularly in patients with mild–moderate asthma. Additionally, IgA + memory B-cells significantly correlated with clinical features of SAD such as exacerbations. Conclusions With this study we demonstrate for the first time a significant association of increased IgA + memory B-cells with asthma and SAD, pointing towards future options for B-cell-directed strategies in preventing and treating asthma.
    Type of Medium: Online Resource
    ISSN: 0903-1936 , 1399-3003
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.1183/13993003.02130-2021
    DOI: 10.1183/13993003.02130-2021.Supp1
    DOI: 10.1183/13993003.02130-2021.Shareable1
    Language: English
    Publisher: European Respiratory Society (ERS)
    Publication Date: 2022
    detail.hit.zdb_id: 2834928-3
    detail.hit.zdb_id: 1499101-9
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  • 4
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    Image_2.pdf
    Frontiers Media SA ; 2023
    In:  Frontiers in Immunology Vol. 14 ( 2023-5-12)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 14 ( 2023-5-12)
    Abstract: A single population of interferon-regulatory factor 8 (Irf8)-dependent conventional dendritic cell (cDC type1) is considered to be responsible for both immunogenic and tolerogenic responses depending on the surrounding cytokine milieu . Here, we challenge this concept of an omnipotent single Irf8-dependent cDC1 cluster through analysis of pulmonary cDCs at single cell resolution. We report existence of a pulmonary cDC1 cluster lacking Xcr1 with an immunogenic signature that clearly differs from the Xcr1 positive cDC1 cluster. The Irf8 + Batf3 + Xcr1 - cluster expresses high levels of pro-inflammatory genes associated with antigen presentation, migration and co-stimulation such as Ccr7 , Cd74 , MHC-II , Ccl5 , Il12b and Relb while, the Xcr1 + cDC1 cluster expresses genes corresponding to immune tolerance mechanisms like Clec9a , Pbx1 , Cadm1 , Btla and Clec12a . In concordance with their pro-inflammatory gene expression profile, the ratio of Xcr1 - cDC1s but not Xcr1 + cDC1 is increased in the lungs of allergen-treated mice compared to the control group, in which both cDC1 clusters are present in comparable ratios. The existence of two distinct Xcr1 + and Xcr1 - cDC1 clusters is furthermore supported by velocity analysis showing markedly different temporal patterns of Xcr1 - and Xcr1 + cDC1s. In summary, we present evidence for the existence of two different cDC1 clusters with distinct immunogenic profiles in vivo . Our findings have important implications for DC-targeting immunomodulatory therapies.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2023.1127485
    DOI: 10.3389/fimmu.2023.1127485.s001
    DOI: 10.3389/fimmu.2023.1127485.s002
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 2606827-8
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  • 5
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    The Cystic Fibrosis Upper and Lower Airway Metagenome
    American Society for Microbiology ; 2023
    In:  Microbiology Spectrum Vol. 11, No. 2 ( 2023-04-13)
    Details
    In: Microbiology Spectrum, American Society for Microbiology, Vol. 11, No. 2 ( 2023-04-13)
    Abstract: The microbial metagenome in cystic fibrosis (CF) airways was investigated by whole-genome shotgun sequencing of total DNA isolated from nasal lavage samples, oropharyngeal swabs, and induced sputum samples collected from 65 individuals with CF aged 7 to 50 years. Each patient harbored a personalized microbial metagenome unique in microbial load and composition, the exception being monocultures of the most common CF pathogens Staphylococcus aureus and Pseudomonas aeruginosa from patients with advanced lung disease. The sampling of the upper airways by nasal lavage uncovered the fungus Malassezia restricta and the bacterium Staphylococcus epidermidis as prominent species. Healthy and CF donors harbored qualitatively and quantitatively different spectra of commensal bacteria in their sputa, even in the absence of any typical CF pathogen. If P. aeruginosa , S. aureus , or Stenotrophomonas maltophilia belonged to the trio of the most abundant species in the CF sputum metagenome, common inhabitants of the respiratory tract of healthy subjects, i.e., Eubacterium sulci , Fusobacterium periodonticum , and Neisseria subflava , were present only in low numbers or not detectable. Random forest analysis identified the numerical ecological parameters of the bacterial community, such as Shannon and Simpson diversity, as the key parameters that globally distinguish sputum samples from CF and healthy donors. IMPORTANCE Cystic fibrosis (CF) is the most common life-limiting monogenetic disease in European populations and is caused by mutations in the CFTR gene. Chronic airway infections with opportunistic pathogens are the major morbidity that determines prognosis and quality of life in most people with CF. We examined the composition of the microbial communities of the oral cavity and upper and lower airways in CF patients across all age groups. From early on, the spectrum of commensals is different in health and CF. Later on, when the common CF pathogens take up residence in the lungs, we observed differential modes of depletion of the commensal microbiota in the presence of S. aureus , P. aeruginosa , S. maltophilia , or combinations thereof. It remains to be seen whether the implementation of lifelong CFTR (cystic fibrosis transmembrane conductance regulator) modulation will change the temporal evolution of the CF airway metagenome.
    Type of Medium: Online Resource
    ISSN: 2165-0497
    URL: Article
    DOI: 10.1128/spectrum.03633-22
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2023
    detail.hit.zdb_id: 2807133-5
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  • 6
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    Interleukin‐17A and interleukin‐22 production by conventional and non‐conventional lymphocytes in three different end‐stage lung diseases
    Wiley ; 2022
    In:  Clinical & Translational Immunology Vol. 11, No. 6 ( 2022-01)
    Details
    In: Clinical & Translational Immunology, Wiley, Vol. 11, No. 6 ( 2022-01)
    Abstract: The contribution of adaptive vs. innate lymphocytes to IL‐17A and IL‐22 secretion at the end stage of chronic lung diseases remains largely unexplored. In order to uncover tissue‐ and disease‐specific secretion patterns, we compared production patterns of IL‐17A and IL‐22 in three different human end‐stage lung disease entities. Methods Production of IL‐17A, IL‐22 and associated cytokines was assessed in supernatants of re‐stimulated lymphocytes by multiplex assays and multicolour flow cytometry of conventional T cells, iNKT cells, γδ T cells and innate lymphoid cells in bronchial lymph node and lung tissue from patients with emphysema ( n  = 19), idiopathic pulmonary fibrosis ( n  = 14) and cystic fibrosis ( n  = 23), as well as lung donors ( n  = 17). Results We detected secretion of IL‐17A and IL‐22 by CD4 + T cells, CD8 + T cells, innate lymphoid cells, γδ T cells and iNKT cells in all end‐stage lung disease entities. Our analyses revealed disease‐specific contributions of individual lymphocyte subpopulations to cytokine secretion patterns. We furthermore found the high levels of microbial detection in CF samples to associate with a more pronounced IL‐17A signature upon antigen‐specific and unspecific re‐stimulation compared to other disease entities and lung donors. Conclusion Our results show that both adaptive and innate lymphocyte populations contribute to IL‐17A‐dependent pathologies in different end‐stage lung disease entities, where they establish an IL‐17A‐rich microenvironment. Microbial colonisation patterns and cytokine secretion upon microbial re‐stimulation suggest that pathogens drive IL‐17A secretion patterns in end‐stage lung disease.
    Type of Medium: Online Resource
    ISSN: 2050-0068 , 2050-0068
    URL: Issue
    URL: Article
    DOI: 10.1002/cti2.v11.6
    DOI: 10.1002/cti2.1398
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2694482-0
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  • 7
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    Online Resource
    Peritoneal dialysate‐range hypertonic glucose promotes T‐cell IL‐17 production that induces mesothelial inflammation
    Wiley ; 2021
    In:  European Journal of Immunology Vol. 51, No. 2 ( 2021-02), p. 354-367
    Details
    In: European Journal of Immunology, Wiley, Vol. 51, No. 2 ( 2021-02), p. 354-367
    Abstract: Peritoneal dialysis (PD) employs hypertonic glucose to remove excess water and uremic waste. Peritoneal membrane failure limits its long‐term use. T‐cell cytokines promote this decline. T‐cell differentiation is critically determined by the microenvironment. We here study how PD‐range hypertonic glucose regulates T‐cell polarization and IL‐17 production. In the human peritoneal cavity, CD3 + cell numbers increased in PD. Single cell RNA sequencing detected expression of T helper (Th) 17 signature genes RORC and IL23R . In vitro, PD‐range glucose stimulated spontaneous and amplified cytokine‐induced Th17 polarization. Osmotic controls l ‐glucose and d ‐mannose demonstrate that induction of IL‐17A is a substance‐independent, tonicity dose‐dependent process. PD‐range glucose upregulated glycolysis and increased the proportion of dysfunctional mitochondria. Blockade of reactive‐oxygen species (ROS) prevented IL‐17A induction in response to PD‐range glucose. Peritoneal mesothelium cultured with IL‐17A or IL17F produced pro‐inflammatory cytokines IL‐6, CCL2, and CX3CL1. In PD patients, peritoneal IL‐17A positively correlated with CX3CL1 concentrations. PD‐range glucose‐stimulated, but neither identically treated Il17a −/− Il17f −/− nor T cells cultured with the ROS scavenger N‐acetylcysteine enhanced mesothelial CX3CL1 expression. Our data delineate PD‐range hypertonic glucose as a novel inducer of Th17 polarization in a mitochondrial‐ROS‐dependent manner. Modulation of tonicity‐mediated effects of PD solutions may improve membrane survival.
    Type of Medium: Online Resource
    ISSN: 0014-2980 , 1521-4141
    URL: Issue
    URL: Article
    DOI: 10.1002/eji.v51.2
    DOI: 10.1002/eji.202048733
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 1491907-2
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  • 8
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    Online Resource
    DataSheet_1.pdf
    Frontiers Media SA ; 2023
    In:  Frontiers in Oncology Vol. 13 ( 2023-4-26)
    Details
    In: Frontiers in Oncology, Frontiers Media SA, Vol. 13 ( 2023-4-26)
    Abstract: Multi-professional interdisciplinary tumor boards (ITB) are essential institutions to discuss all newly diagnosed, relapsed or complex cancer patients in a team of specialists to find an optimal cancer care plan for each individual patient with regard to national and international clinical practice guidelines, patient´s preference and comorbidities. In a high-volume cancer center, entity-specific ITBs take place at least once a week discussing a large number of patients. To a high level of expertise and dedication, this also requires an enormous amount of time for physicians, cancer specialists and administrative support colleagues, especially for radiologists, pathologists, medical oncologists and radiation oncologists, who must attend all cancer-specific boards according to certification requirements. Methods In this 15-month prospective German single-center analysis, we examined the established structures of 12 different cancer-specific ITBs at the certified Oncology Center and demonstrate tools helping to optimize processes before, during and after the boards for optimal, time-saving procedures. Results By changing pathways, introducing revised registration protocols and new digital supports we could show that the workload of preparation by radiologists and pathologists could be reduced significantly by 22.9% (p= & lt;0.0001) and 52.7% (p= & lt;0.0001), respectively. Furthermore, two questions were added to all registration forms about the patient´s need for specialized palliative care support that should lead to more awareness and early integration of specialized help. Discussion There are several ways to reduce the workload of all ITB team members while maintaining high quality recommendations and adherence to national and international guidelines.
    Type of Medium: Online Resource
    ISSN: 2234-943X
    URL: Article
    URL: Article
    DOI: 10.3389/fonc.2023.1072652
    DOI: 10.3389/fonc.2023.1072652.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 2649216-7
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  • 9
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    Online Resource
    Single cell versus single nucleus: transcriptome differences in the murine kidney after ischemia-reperfusion injury
    American Physiological Society ; 2022
    In:  American Journal of Physiology-Renal Physiology Vol. 323, No. 2 ( 2022-08-01), p. F171-F181
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 323, No. 2 ( 2022-08-01), p. F171-F181
    Abstract: The kidney is a complex organ, which consists of multiple components with highly diverse cell types. A detailed understanding of these cell types in health and disease is crucial for the future development of preventive and curative treatment strategies. In recent years, single-cell RNA sequencing (scRNAseq) and single-nucleus RNA sequencing (snRNAseq) technology has opened up completely new possibilities in investigating the variety of renal cell populations in physiological and pathological states. Here, we systematically assessed differences between scRNAseq and snRNAseq approaches in transcriptome analysis of murine kidneys after ischemia-reperfusion injury. We included tissues from control kidneys and from kidneys harvested 1 wk after mild (17-min clamping time) and severe (27-min clamping time) transient unilateral ischemia. Our findings revealed important methodological differences in the discovery of inflammatory cells, tubular cells, and other specialized cell types. Although the scRNAseq approach was advantageous for investigating immune cells, the snRNAseq approach allowed superior insights into healthy and damaged tubular cells. Apart from differences in the quantitative discovery rate, we found important qualitative discrepancies in the captured transcriptomes with crucial consequences for the interpretation of cell states and molecular functions. Together, we provide an overview of method-dependent differences between scRNAseq and snRNAseq results from identical postischemic kidney tissues. Our results highlight the importance of choosing the right approach for specific research questions. NEW & NOTEWORTHY Single-cell and single-nucleus RNA sequencing technologies provide powerful new tools to examine complex tissues such as the kidney. This research reference paper provides practical information on the differences between the two technologies when examining murine kidneys after ischemia-reperfusion injury. The results will serve those who are debating which protocols to use in their given study.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00453.2021
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2022
    detail.hit.zdb_id: 1477287-5
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  • 10
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    Online Resource
    Myeloid CCR2 Promotes Atherosclerosis after AKI
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Journal of the American Society of Nephrology Vol. 33, No. 8 ( 2022-08), p. 1487-1500
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 33, No. 8 ( 2022-08), p. 1487-1500
    Abstract: AKI impairs excretory function, but also leaves a damaged kidney. We demonstrate that a single episode of unilateral ischemia-reperfusion injury significantly promotes atherosclerotic plaque formation in mice. Renal inflammation preceded expression of myeloid and T cell genes in the atherosclerotic aorta. The chemokine receptor CCR2 was instrumental in inflammatory monocyte recruitment to the kidney, renal and aortic inflammatory macrophage marker CD11c expression, and enhanced aortic plaque formation after AKI. Delineating underlying mechanisms in atherosclerosis support the concept of a “toxic kidney” that promotes remote inflammation after ischemic reperfusion injury. Background The risk of cardiovascular events rises after AKI. Leukocytes promote atherosclerotic plaque growth and instability. We established a model of enhanced remote atherosclerosis after renal ischemia-reperfusion (IR) injury and investigated the underlying inflammatory mechanisms. Methods Atherosclerotic lesions and inflammation were investigated in native and bone marrow–transplanted LDL receptor–deficient ( LDLr−/− ) mice after unilateral renal IR injury using histology, flow cytometry, and gene expression analysis. Results Aortic root atherosclerotic lesions were significantly larger after renal IR injury than in controls. A gene expression screen revealed enrichment for chemokines and their cognate receptors in aortas of IR-injured mice in early atherosclerosis, and of T cell–associated genes in advanced disease. Confocal microscopy revealed increased aortic macrophage proximity to T cells. Differential aortic inflammatory gene regulation in IR-injured mice largely paralleled the pattern in the injured kidney. Single-cell analysis identified renal cell types that produced soluble mediators upregulated in the atherosclerotic aorta. The analysis revealed a marked early increase in Ccl2 , which CCR2 + myeloid cells mainly expressed. CCR2 mediated myeloid cell homing to the post-ischemic kidney in a cell-individual manner. Reconstitution with Ccr2−/− bone marrow dampened renal post-ischemic inflammation, reduced aortic Ccl2 and inflammatory macrophage marker CD11c, and abrogated excess aortic atherosclerotic plaque formation after renal IR. Conclusions Our data introduce an experimental model of remote proatherogenic effects of renal IR and delineate myeloid CCR2 signaling as a mechanistic requirement. Monocytes should be considered as mobile mediators when addressing systemic vascular sequelae of kidney injury.
    Type of Medium: Online Resource
    ISSN: 1046-6673 , 1533-3450
    URL: Article
    DOI: 10.1681/ASN.2022010048
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 2029124-3
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