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Article ; Online: MRGPRX2-Mediated Degranulation of Human Skin Mast Cells Requires the Operation of G

Wang, Zhao / Franke, Kristin / Bal, Gürkan / Li, Zhuoran / Zuberbier, Torsten / Babina, Magda

2022 Volume 11, Issue 6

Abstract: ... hexosaminidase or histamine release. Phosphorylation events were studied by immunoblotting. As a G protein ... coupled receptor, MRGPRX2 signals by activating G proteins; however, their nature has remained ... controversial. In skin MCs, G ...

Abstract	The recent discovery of MRGPRX2 explains mast cell (MC)-dependent symptoms independently of FcεRI-activation. Because of its novelty, signaling cascades triggered by MRGPRX2 are rudimentarily understood, especially in cutaneous MCs, by which MRGPRX2 is chiefly expressed. Here, MCs purified from human skin were used following preculture or ex vivo and stimulated by FcεRI-aggregation or MRGPRX2 agonists (compound 48/80, Substance P) in the presence/absence of inhibitors. Degranulation was assessed by β-hexosaminidase or histamine release. Phosphorylation events were studied by immunoblotting. As a G protein-coupled receptor, MRGPRX2 signals by activating G proteins; however, their nature has remained controversial. In skin MCs, G
MeSH term(s)	Cell Degranulation ; GTP-Binding Proteins/metabolism ; Humans ; MAP Kinase Signaling System ; Mast Cells/metabolism ; Nerve Tissue Proteins/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Receptors, G-Protein-Coupled/metabolism ; Receptors, IgE/metabolism ; Receptors, Neuropeptide/metabolism
Chemical Substances	MRGPRX2 protein, human ; Nerve Tissue Proteins ; Receptors, G-Protein-Coupled ; Receptors, IgE ; Receptors, Neuropeptide ; GTP-Binding Proteins (EC 3.6.1.-)
Language	English
Publishing date	2022-03-10
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11060953
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Correction to: Role of prothrombin 19,911 A > G polymorphism, blood group and male gender in patients with venous thromboembolism: results of a german cohort study.

Journal of thrombosis and thrombolysis

2023 Volume 56, Issue 1, Page(s) 212

Language	English
Publishing date	2023-04-15
Publishing country	Netherlands
Document type	Published Erratum
ZDB-ID	1230645-9
ISSN	1573-742X ; 0929-5305
ISSN (online)	1573-742X
ISSN	0929-5305
DOI	10.1007/s11239-023-02809-7
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: The N Terminus of Adhesion G Protein-Coupled Receptor GPR126/ADGRG6 as Allosteric Force Integrator.

Mitgau, Jakob / Franke, Julius / Schinner, Camilla / Stephan, Gabriele / Berndt, Sandra / Placantonakis, Dimitris G / Kalwa, Hermann / Spindler, Volker / Wilde, Caroline / Liebscher, Ines

Frontiers in cell and developmental biology

2022 Volume 10, Page(s) 873278

Abstract: The adhesion G protein-coupled receptor (aGPCR) GPR126/ADGRG6 plays an important role ...

Abstract	The adhesion G protein-coupled receptor (aGPCR) GPR126/ADGRG6 plays an important role in several physiological functions, such as myelination or peripheral nerve repair. This renders the receptor an attractive pharmacological target. GPR126 is a mechano-sensor that translates the binding of extracellular matrix (ECM) molecules to its N terminus into a metabotropic intracellular signal. To date, the structural requirements and the character of the forces needed for this ECM-mediated receptor activation are largely unknown. In this study, we provide this information by combining classic second-messenger detection with single-cell atomic force microscopy. We established a monoclonal antibody targeting the N terminus to stimulate GPR126 and compared it to the activation through its known ECM ligands, collagen IV and laminin 211. As each ligand uses a distinct mode of action, the N terminus can be regarded as an allosteric module that can fine-tune receptor activation in a context-specific manner.
Language	English
Publishing date	2022-06-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2022.873278
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Article ; Online: Distinct Longitudinal Changes in Immunoglobulin G N-Glycosylation Associate with Therapy Response in Chronic Inflammatory Diseases.

Štambuk, Jerko / Vučković, Frano / Habazin, Siniša / Hanić, Maja / Novokmet, Mislav / Nikolaus, Susanna / Tran, Florian / Schreiber, Stefan / Franke, Andre / Rosenstiel, Philip / Lauc, Gordan / Aden, Konrad / Pezer, Marija

International journal of molecular sciences

2022 Volume 23, Issue 15

Abstract: ... on serum immunoglobulin G (IgG) glycosylation. We analyzed IgG subclass-specific fragment crystallizable (Fc) N ...

Abstract	Immunosuppressants and biologicals are widely used therapeutics for various chronic inflammatory diseases (CID). To gain more detailed insight into their downstream effects, we examined their impact on serum immunoglobulin G (IgG) glycosylation. We analyzed IgG subclass-specific fragment crystallizable (Fc) N-glycosylation in patients suffering from various CID using the LC-MS approach. Firstly, we compared IgG Fc N-glycosylation between 128 CID patients and 204 healthy controls. Our results replicated previously observed CID-related decrease in IgG Fc galactosylation (adjusted
MeSH term(s)	Chromatography, Liquid ; Glycosylation ; Humans ; Immunoglobulin Fc Fragments/metabolism ; Immunoglobulin Fc Fragments/therapeutic use ; Immunoglobulin G/metabolism ; Mass Spectrometry
Chemical Substances	Immunoglobulin Fc Fragments ; Immunoglobulin G
Language	English
Publishing date	2022-07-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23158473
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Article ; Online: The N Terminus of Adhesion G Protein–Coupled Receptor GPR126/ADGRG6 as Allosteric Force Integrator

Jakob Mitgau / Julius Franke / Camilla Schinner / Gabriele Stephan / Sandra Berndt / Dimitris G. Placantonakis / Hermann Kalwa / Volker Spindler / Caroline Wilde / Ines Liebscher

Frontiers in Cell and Developmental Biology, Vol

2022 Volume 10

Abstract: The adhesion G protein–coupled receptor (aGPCR) GPR126/ADGRG6 plays an important role ...

Abstract	The adhesion G protein–coupled receptor (aGPCR) GPR126/ADGRG6 plays an important role in several physiological functions, such as myelination or peripheral nerve repair. This renders the receptor an attractive pharmacological target. GPR126 is a mechano-sensor that translates the binding of extracellular matrix (ECM) molecules to its N terminus into a metabotropic intracellular signal. To date, the structural requirements and the character of the forces needed for this ECM-mediated receptor activation are largely unknown. In this study, we provide this information by combining classic second-messenger detection with single-cell atomic force microscopy. We established a monoclonal antibody targeting the N terminus to stimulate GPR126 and compared it to the activation through its known ECM ligands, collagen IV and laminin 211. As each ligand uses a distinct mode of action, the N terminus can be regarded as an allosteric module that can fine-tune receptor activation in a context-specific manner.
Keywords	adhesion GPCR ; mechano-activation ; signal transduction ; allosteric modulator ; activating antibody ; extracellular matrix ligand ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
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Article: Successful Treatment of Pediatric Inflammatory Multisystem Syndrome Temporally Associated with COVID-19 (PIMS-TS) with Split Doses of Immunoglobulin G and Estimation of PIMS-TS Incidence in a County District in Southern Germany.

Wehl, Götz / Franke, Jörg / Frühwirth, Martin / Edlinger, Michael / Rauchenzauner, Markus

Healthcare (Basel, Switzerland)

2021 Volume 9, Issue 4

Abstract: Pediatric inflammatory multisystem syndrome temporally associated with SARS Cov2 (PIMS-TS) is a newly encountered disease in children sharing clinical features with Kawasaki disease, toxic shock syndrome, or macrophage-activating syndrome. Pathogenically, ...

Abstract	Pediatric inflammatory multisystem syndrome temporally associated with SARS Cov2 (PIMS-TS) is a newly encountered disease in children sharing clinical features with Kawasaki disease, toxic shock syndrome, or macrophage-activating syndrome. Pathogenically, it is associated with immune-mediated post-infectious hyperinflammation leading to short-term myocardial injury with yet unknown long-term outcome. We herein present three cases of PIMS-TS treated in our institution with divided doses of immunoglobulins and high dose acetyl salicylic acid, according to existing Kawasaki disease guidelines. Due to greater weight in adolescents affected and concerns of rheological sequelae following possible hyperviscosity, doses of immunoglobulins were divided and given 24 h apart with good tolerability. All patients recovered rapidly with normalization of previously encountered cardiac manifestations. As diagnosis of PIMS-TS should be made promptly, timing of therapy is of paramount importance for a favorable outcome. To date, no randomized controlled trial data exist concerning treatment recommendations. 1.8% (95% CI: 1.7% to 2.0%) of all children and adolescents in the county district of Ostallgäu were tested positive for SARS CoV-2, incidence of PIMS-TS was 1.7% (95% CI: 0.9% to 3.1%) among SARS CoV-2 positive tested earlier. As the pandemic is still ongoing, rising numbers of PIMS-TS in children might be expected.
Language	English
Publishing date	2021-04-18
Publishing country	Switzerland
Document type	Case Reports
ZDB-ID	2721009-1
ISSN	2227-9032
ISSN	2227-9032
DOI	10.3390/healthcare9040481
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Article ; Online: Response to: Correspondence on "G-CSF as a suitable alternative to GM-CSF to boost dinutuximab-mediated neutrophil cytotoxicity in neuroblastoma treatment" by Mora

Martinez Sanz, Paula / van Rees, Dieke J / Matlung, Hanke L / Tytgat, Godelieve A M / Franke, Katka

Journal for immunotherapy of cancer

2021 Volume 9, Issue 12

MeSH term(s)	Antibodies, Monoclonal ; Granulocyte Colony-Stimulating Factor ; Granulocyte-Macrophage Colony-Stimulating Factor ; Humans ; Neuroblastoma/drug therapy ; Neutrophils
Chemical Substances	Antibodies, Monoclonal ; Granulocyte Colony-Stimulating Factor (143011-72-7) ; dinutuximab (7SQY4ZUD30) ; Granulocyte-Macrophage Colony-Stimulating Factor (83869-56-1)
Language	English
Publishing date	2021-12-10
Publishing country	England
Document type	Journal Article ; Comment
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2021-003983
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Article ; Online: Role of prothrombin 19911 A>G polymorphism, blood group and male gender in patients with venous thromboembolism: Results of a German cohort study.

Journal of thrombosis and thrombolysis

2020 Volume 51, Issue 2, Page(s) 494–501

Abstract: The role of the A>G polymorphism at position 19911 in the prothrombin gene (factor [F] 2 ...

Abstract	The role of the A>G polymorphism at position 19911 in the prothrombin gene (factor [F] 2 at rs3136516) as a risk factor for venous thromboembolism [VTE] is still unclear. To evaluate the presence of the F2 polymorphism in VTE patients compared to healthy blood donors and to adjust the results for common inherited thrombophilias [IT], age at onset and blood group [BG], and to calculate the risk of VTE recurrence. We investigated 1012 Caucasian patients with a diagnosis of VTE for the presence of the F2 rs3136516 polymorphism and compared these with 902 healthy blood donors. Odds ratios [OR] together with their 95% confidence intervals were calculated adjusted for F5 at rs6025, F2 at rs1799963, blood group, age and gender. In addition, we evaluated the risk of recurrent VTE during patient follow-up calculating hazard ratios [HR] together with their 95% CI. Compared with the AA wildtype, the F2 GG and AG genotypes (rs3136516) were associated with VTE (OR 1.48 and 1.45). The OR in F5 carriers compared to controls was 5.68 and 2.38 in patients with F2 (rs1799963). BG "non-O" was significantly more often diagnosed in patients compared to BG "O" (OR 2.74). VTE recurrence more often occurred in males (HR 2.3) and in carriers with combined thrombophilia (HR 2.11). Noteworthy, the rs3136516 polymorphism alone was not associated significantly with recurrence. In Caucasian patients with VTE the F2 GG/GA genotypes (rs3136516) were moderate risk factors for VTE. Recurrence was associated with male gender and combined thrombophilia.
MeSH term(s)	Adult ; Blood Group Antigens/blood ; Female ; Genetic Predisposition to Disease ; Germany/epidemiology ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Prothrombin/genetics ; Risk Factors ; Sex Factors ; Venous Thromboembolism/blood ; Venous Thromboembolism/etiology ; Venous Thromboembolism/genetics ; Young Adult
Chemical Substances	Blood Group Antigens ; Prothrombin (9001-26-7)
Language	English
Publishing date	2020-05-08
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1230645-9
ISSN	1573-742X ; 0929-5305
ISSN (online)	1573-742X
ISSN	0929-5305
DOI	10.1007/s11239-020-02169-6
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 4352: Show issues

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Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: MRGPRX2-Mediated Degranulation of Human Skin Mast Cells Requires the Operation of G αi , G αq , Ca++ Channels, ERK1/2 and PI3K—Interconnection between Early and Late Signaling

Zhao Wang / Kristin Franke / Gürkan Bal / Zhuoran Li / Torsten Zuberbier / Magda Babina

Cells, Vol 11, Iss 953, p

2022 Volume 953

Abstract	The recent discovery of MRGPRX2 explains mast cell (MC)-dependent symptoms independently of FcεRI-activation. Because of its novelty, signaling cascades triggered by MRGPRX2 are rudimentarily understood, especially in cutaneous MCs, by which MRGPRX2 is chiefly expressed. Here, MCs purified from human skin were used following preculture or ex vivo and stimulated by FcεRI-aggregation or MRGPRX2 agonists (compound 48/80, Substance P) in the presence/absence of inhibitors. Degranulation was assessed by β-hexosaminidase or histamine release. Phosphorylation events were studied by immunoblotting. As a G protein-coupled receptor, MRGPRX2 signals by activating G proteins; however, their nature has remained controversial. In skin MCs, G αi and G αq were required for degranulation, but G αi was clearly more relevant. Ca++ channels were likewise crucial. Downstream, PI3K was essential for granule discharge initiated by MRGPRX2 or FcεRI. ERK1/2 and JNK were additional participants, especially in the allergic route. Addressing possible points of intersection between early and later events, pERK1/2 and pAKT were found to depend on G αi , further highlighting its significance. G αq and Ca++ channels made some contributions to the phosphorylation of ERK. Ca++ differentially affected PI3K activation in FcεRI- vis-à-vis MRGPRX2-signaling, as channel inhibition increased pAKT only when triggered via FcεRI. Collectively, our study significantly extends our understanding of the molecular framework behind granule secretion from skin MCs.
Keywords	mast cells ; MRGPRX2 ; FcεRI ; degranulation ; G proteins ; signal transduction ; Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: G-CSF as a suitable alternative to GM-CSF to boost dinutuximab-mediated neutrophil cytotoxicity in neuroblastoma treatment.

Journal for immunotherapy of cancer

2021 Volume 9, Issue 5

Abstract: ... we have investigated whether clinically well-established granulocyte colony-stimulating factor (G-CSF ... with GM-CSF or G-CSF to kill dinutuximab-opsonized GD2-positive neuroblastoma cell lines and primary ... neuroblastoma interactions.: Results: We found that G-CSF was as potent as GM-CSF in enhancing the killing ...

Abstract	Background: Current immunotherapy for patients with high-risk neuroblastoma involves the therapeutic antibody dinutuximab that targets GD2, a ganglioside expressed on the majority of neuroblastoma tumors. Opsonized tumor cells are killed through antibody-dependent cellular cytotoxicity (ADCC), a process mediated by various immune cells, including neutrophils. The capacity of neutrophils to kill dinutuximab-opsonized tumor cells can be further enhanced by granulocyte-macrophage colony-stimulating factor (GM-CSF), which has been shown in the past to improve responses to anti-GD2 immunotherapy. However, access to GM-CSF (sargramostim) is limited outside of Northern America, creating a high clinical need for an alternative method to stimulate dinutuximab responsiveness in the treatment of neuroblastoma. In this in vitro study, we have investigated whether clinically well-established granulocyte colony-stimulating factor (G-CSF) can be a potentially suitable alternative for GM-CSF in the dinutuximab immunotherapy regimen of patients with neuroblastoma. Methods: We compared the capacity of neutrophils stimulated either in vitro or in vivo with GM-CSF or G-CSF to kill dinutuximab-opsonized GD2-positive neuroblastoma cell lines and primary patient tumor material. Blocking experiments with antibodies inhibiting either respective Fc gamma receptors (FcγR) or neutrophil integrin CD11b/CD18 demonstrated the involvement of these receptors in the process of ADCC. Flow cytometry and live cell microscopy were used to quantify and visualize neutrophil-neuroblastoma interactions. Results: We found that G-CSF was as potent as GM-CSF in enhancing the killing capacity of neutrophils towards neuroblastoma cells. This was observed with in vitro stimulated neutrophils, and with in vivo stimulated neutrophils from both patients with neuroblastoma and healthy donors. Enhanced killing due to GM-CSF or G-CSF stimulation was consistent regardless of dinutuximab concentration, tumor-to-neutrophil ratio and concentration of the stimulating cytokine. Both GM-CSF and G-CSF stimulated neutrophils required FcγRIIa and CD11b/CD18 integrin to perform ADCC, and this was accompanied by trogocytosis of tumor material by neutrophils and tumor cell death in both stimulation conditions. Conclusions: Our preclinical data support the use of G-CSF as an alternative stimulating cytokine to GM-CSF in the treatment of high-risk neuroblastoma with dinutuximab, warranting further testing of G-CSF in a clinical setting.
MeSH term(s)	Adjuvants, Immunologic/pharmacology ; Antibodies, Monoclonal/pharmacology ; Antineoplastic Agents, Immunological/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; CD11b Antigen/metabolism ; CD18 Antigens/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Coculture Techniques ; Cytotoxicity, Immunologic/drug effects ; Granulocyte Colony-Stimulating Factor/pharmacology ; Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology ; Humans ; Neuroblastoma/drug therapy ; Neuroblastoma/immunology ; Neuroblastoma/metabolism ; Neuroblastoma/pathology ; Neutrophils/drug effects ; Neutrophils/immunology ; Neutrophils/metabolism ; Neutrophils/pathology ; Receptors, IgG/metabolism ; Trogocytosis/drug effects ; Tumor Microenvironment
Chemical Substances	Adjuvants, Immunologic ; Antibodies, Monoclonal ; Antineoplastic Agents, Immunological ; CD11b Antigen ; CD18 Antigens ; FCGR2A protein, human ; ITGAM protein, human ; Receptors, IgG ; Granulocyte Colony-Stimulating Factor (143011-72-7) ; dinutuximab (7SQY4ZUD30) ; Granulocyte-Macrophage Colony-Stimulating Factor (83869-56-1)
Language	English
Publishing date	2021-05-26
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2020-002259
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