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  1. Article ; Online: MASP-1 and MASP-3 Bind Directly to Aspergillus fumigatus and Promote Complement Activation and Phagocytosis

    Anne Rosbjerg / Reinhard Würzner / Peter Garred / Mikkel-Ole Skjoedt

    Journal of Innate Immunity, Pp 1-

    2021  Volume 14

    Abstract: Activation of the complement system is mediated by the interaction between pathogens and pattern recognition molecules (PRMs); mannose-binding lectin (MBL), ficolins, and collectin-10/-11 from the lectin pathway and C1q from the classical pathway. Lectin ...

    Abstract Activation of the complement system is mediated by the interaction between pathogens and pattern recognition molecules (PRMs); mannose-binding lectin (MBL), ficolins, and collectin-10/-11 from the lectin pathway and C1q from the classical pathway. Lectin pathway activation specifically depends on proteases named MBL-associated serine proteases (MASPs) that are found in complexes with PRMs. In this study, we hypothesize that MASPs can recognize selected pathogens independently of PRMs. Using different clinical strains of opportunistic fungi, we have observed that MASPs directly recognize certain fungal pathogens in a way that can facilitate complement activation. Among these were Aspergillus fumigatus – a dangerous pathogen, especially for immunocompromised patients. In flow cytometry and fluorescence microscopy, we found that MASP-1 and -3 bound to all A. fumigatus growth stages (conidia, germ tubes, and hyphae), whereas rMASP-2 and the nonproteolytic rMAP-1 did not. Bound rMASPs could recruit rMBL and rficolin-3 to A. fumigatus conidia in a nonclassical manner and activate complement via rMASP-2. In experiments using recombinant and purified components, rMASP-1 increased the neutrophilic phagocytosis of conidia. In serum where known complement activation pathways were blocked, phagocytosis could be mediated by rMASP-3. We have encountered an unknown pathway for complement activation and found that MASP-1 and MASP-3 have dual functions as enzymes and as PRMs.
    Keywords lectin pathway ; mannose-binding lectin-associated serine protease ; pattern recognition molecules ; fungi ; aspergillosis ; Medicine ; R ; Internal medicine ; RC31-1245
    Subject code 570
    Language English
    Publishing date 2021-03-01T00:00:00Z
    Publisher Karger Publishers
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Functional Analysis of a Novel Complement C5a Receptor 1-Blocking Monoclonal Antibody

    Leon Cyranka / Ida Mariegaard / Mikkel-Ole Skjødt / Rafael Bayarri-Olmos / Tom Eirik Mollnes / Peter Garred / Anne Rosbjerg

    Journal of Innate Immunity, Vol 15, Iss 1, Pp 836-

    2023  Volume 849

    Abstract: Introduction: The complement system anaphylatoxin C5a is a critical player in inflammation. By binding to complement C5a receptor 1 (C5aR1/CD88), C5a regulates many cellular functions, mainly as a potent pro-inflammatory inducer. We describe the ... ...

    Abstract Introduction: The complement system anaphylatoxin C5a is a critical player in inflammation. By binding to complement C5a receptor 1 (C5aR1/CD88), C5a regulates many cellular functions, mainly as a potent pro-inflammatory inducer. We describe the generation and selection of a potent antagonistic C5aR1 mouse monoclonal antibody (mAb). Methods: Initial C5aR1 hybridoma clone selection was performed with a cell-binding study in human whole blood. In-house C5aR1 mAb assessment for C5aR1 inhibition was done via the iLite® C5a assay. C5aR1 mAb specificity was investigated on C5aR1his- and C5aR2his-expressing Flp-In™-CHO cells. Physiological C5aR1 inhibition was assessed via a C5a-driven calcium flux assay and stimulation assay based on isolated polymorphonuclear leukocytes (PMNs) and a whole blood model stimulated with Escherichia coli. Results: The supernatant of hybridoma clones targeting the N-terminal section of C5aR1 displayed efficient binding to C5aR1 in whole blood, which was confirmed for purified mAbs. The C5aR1 mAb 18-41-6 was selected following the assay of in-house C5aR1 mAbs via the iLite® C5a assay. The mAb 18-41-6 was specific for C5aR1. Full-size and/or F(ab’)2 preparations of mAb 18-41-6 were found to efficiently abrogate C5a-induced calcium flux in neutrophils and to significantly reduce the upregulation of the activation markers CD11b (neutrophils, monocytes) and CD66b (neutrophils). Conclusion: Our results demonstrate that mAb 18-41-6 is a valuable tool for investigating the C5a-C5aR1 axis and a potential therapeutic candidate for inflammatory disease treatment.
    Keywords complement system ; c5ar1 ; c5a ; inflammation ; monoclonal antibody ; Medicine ; R ; Internal medicine ; RC31-1245
    Subject code 630
    Language English
    Publishing date 2023-11-01T00:00:00Z
    Publisher Karger Publishers
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Lectin Pathway Enzyme MASP-2 and Downstream Complement Activation in COVID-19

    Maximilian Peter Götz / Mikkel-Ole Skjoedt / Rafael Bayarri-Olmos / Cecilie Bo Hansen / Laura Pérez-Alós / Ida Jarlhelt / Thomas Benfield / Anne Rosbjerg / Peter Garred

    Journal of Innate Immunity, Pp 1-

    2022  Volume 14

    Abstract: Mannose-binding lectin-associated serine protease 2 (MASP-2) is the main activator of the lectin complement pathway and has been suggested to be involved in the pathophysiology of coronavirus disease 2019 (COVID-19). To study a possible association ... ...

    Abstract Mannose-binding lectin-associated serine protease 2 (MASP-2) is the main activator of the lectin complement pathway and has been suggested to be involved in the pathophysiology of coronavirus disease 2019 (COVID-19). To study a possible association between MASP-2 and COVID-19, we aimed at developing a sensitive and reliable MASP-2 ELISA. From an array of novel mouse-monoclonal antibodies using recombinant MASP-2 as antigen, two clones were selected to create a sandwich ELISA. Plasma samples were obtained from 216 healthy controls, 347 convalescent COVID-19 patients, and 147 prospectively followed COVID-19 patients. The assay was specific towards MASP-2 and did not recognize the truncated MASP2 splice variant MAP-2 (MAp19). The limit of quantification was shown to be 0.1 ng/mL. MASP-2 concentration was found to be stable after multiple freeze-thaw cycles. In healthy controls, the mean MASP-2 concentration was 524 ng/mL (95% CI: 496.5–551.6). No significant difference was found in the MASP-2 concentrations between COVID-19 convalescent samples and controls. However, a significant increase was observed in prospectively followed COVID-19 patients (mean: 834 ng/mL [95% CI: 765.3–902.7, p < 0.0001]). In these patients, MASP-2 concentration correlated significantly with the concentrations of the terminal complement complex (ρ = 0.3596, p < 0.0001), with the lectin pathway pattern recognition molecules ficolin-2 (ρ = 0.2906, p = 0.0004) and ficolin-3 (ρ = 0.3952, p < 0.0001) and with C-reactive protein (ρ = 0.3292, p = 0.0002). Overall, we developed a specific quantitative MASP-2 sandwich ELISA. MASP-2 correlated with complement activation and inflammatory markers in COVID-19 patients, underscoring a possible role of MASP-2 in COVID-19 pathophysiology.
    Keywords mannose-binding lectin-associated serine protease 2 ; masp-2 ; assay ; covid-19 ; inflammation ; outcome ; Medicine ; R ; Internal medicine ; RC31-1245
    Subject code 616
    Language English
    Publishing date 2022-07-01T00:00:00Z
    Publisher Karger Publishers
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: The alpha/B.1.1.7 SARS-CoV-2 variant exhibits significantly higher affinity for ACE-2 and requires lower inoculation doses to cause disease in K18-hACE2 mice

    Rafael Bayarri-Olmos / Laust Bruun Johnsen / Manja Idorn / Line S Reinert / Anne Rosbjerg / Søren Vang / Cecilie Bo Hansen / Charlotte Helgstrand / Jais Rose Bjelke / Theresa Bak-Thomsen / Søren R Paludan / Peter Garred / Mikkel-Ole Skjoedt

    eLife, Vol

    2021  Volume 10

    Abstract: The alpha/B.1.1.7 SARS-CoV-2 lineage emerged in autumn 2020 in the United Kingdom and transmitted rapidly until winter 2021 when it was responsible for most new COVID-19 cases in many European countries. The incidence domination was likely due to a ... ...

    Abstract The alpha/B.1.1.7 SARS-CoV-2 lineage emerged in autumn 2020 in the United Kingdom and transmitted rapidly until winter 2021 when it was responsible for most new COVID-19 cases in many European countries. The incidence domination was likely due to a fitness advantage that could be driven by the receptor-binding domain (RBD) residue change (N501Y), which also emerged independently in other variants of concern such as the beta/B.1.351 and gamma/P.1 strains. Here, we present a functional characterization of the alpha/B.1.1.7 variant and show an eightfold affinity increase towards human angiotensin-converting enzyme-2 (ACE-2). In accordance with this, transgenic hACE2 mice showed a faster disease progression and severity after infection with a low dose of B.1.1.7, compared to an early 2020 SARS-CoV-2 isolate. When challenged with sera from convalescent individuals or anti-RBD monoclonal antibodies, the N501Y variant showed a minor, but significant elevated evasion potential of ACE-2/RBD antibody neutralization. The data suggest that the single asparagine to tyrosine substitution remarkable rise in affinity may be responsible for the higher transmission rate and severity of the B.1.1.7 variant.
    Keywords immunology ; epidemiology ; SARS-CoV-2 ; mouse model ; human ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2021-11-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Modeling of waning immunity after SARS-CoV-2 vaccination and influencing factors

    Laura Pérez-Alós / Jose Juan Almagro Armenteros / Johannes Roth Madsen / Cecilie Bo Hansen / Ida Jarlhelt / Sebastian Rask Hamm / Line Dam Heftdal / Mia Marie Pries-Heje / Dina Leth Møller / Kamille Fogh / Rasmus Bo Hasselbalch / Anne Rosbjerg / Søren Brunak / Erik Sørensen / Margit Anita Hørup Larsen / Sisse Rye Ostrowski / Ruth Frikke-Schmidt / Rafael Bayarri-Olmos / Linda Maria Hilsted /
    Kasper Karmark Iversen / Henning Bundgaard / Susanne Dam Nielsen / Peter Garred

    Nature Communications, Vol 13, Iss 1, Pp 1-

    2022  Volume 11

    Abstract: This study investigates the dynamics of immunological markers after first SARS-CoV-2 vaccination dose in cohort of healthcare professionals in Denmark. Natural infection was associated with higher antibody responses, and IgG decline varied by age, sex, T- ...

    Abstract This study investigates the dynamics of immunological markers after first SARS-CoV-2 vaccination dose in cohort of healthcare professionals in Denmark. Natural infection was associated with higher antibody responses, and IgG decline varied by age, sex, T-cell response, previous infection, and interval between vaccine doses.
    Keywords Science ; Q
    Language English
    Publishing date 2022-03-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: miR-122 regulates p53/Akt signalling and the chemotherapy-induced apoptosis in cutaneous T-cell lymphoma.

    Valentina Manfè / Edyta Biskup / Anne Rosbjerg / Maria Kamstrup / Anne Guldhammer Skov / Catharina Margrethe Lerche / Britt Thyssing Lauenborg / Niels Odum / Robert Gniadecki

    PLoS ONE, Vol 7, Iss 1, p e

    2012  Volume 29541

    Abstract: Advanced cutaneous T-cell lymphoma (CTCL) is resistant to chemotherapy and presents a major area of medical need. In view of the known role of microRNAs (miRNAs) in the regulation of cellular signalling, we aimed to identify the functionally important ... ...

    Abstract Advanced cutaneous T-cell lymphoma (CTCL) is resistant to chemotherapy and presents a major area of medical need. In view of the known role of microRNAs (miRNAs) in the regulation of cellular signalling, we aimed to identify the functionally important miRNA species, which regulate apoptosis in CTCL. Using a recently established model in which apoptosis of CTCL cell lines is induced by Notch-1 inhibition by γ-secretase inhibitors (GSIs), we found that miR-122 was significantly increased in the apoptotic cells. miR-122 up-regulation was not specific for GSI-1 but was also seen during apoptosis induced by chemotherapies including doxorubicin and proteasome blockers (bortezomib, MG132). miR-122 was not expressed in quiescent T-cells, but was detectable in CTCL: in lesional skin in mycosis fungoides and in Sézary cells purified from peripheral blood. In situ hybridization results showed that miR-122 was expressed in the malignant T-cell infiltrate and increased in the advanced stage mycosis fungoides. Surprisingly, miR-122 overexpression decreased the sensitivity to the chemotherapy-induced apoptosis via a signaling circuit involving the activation of Akt and inhibition of p53. We have also shown that induction of miR-122 occurred via p53 and that p53 post-transcriptionally up-regulated miR-122. miR-122 is thus an amplifier of the antiapoptotic Akt/p53 circuit and it is conceivable that a pharmacological intervention in this pathway may provide basis for novel therapies for CTCL.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2012-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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