37 results on '"HAGN, M."'
Search Results
2. INFRAFRONTIER-providing mutant mouse resources as research tools for the international scientific community
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Meehan, TF, Chen, CK, Koscielny, G, Relac, M, Wilkinson, P, Flicek, P, Parkinson, H, Castro, A, Fessele, S, Steinkamp, R, Hagn, M, Raess, M, de Angelis, MH, Bottomley, J, Ramirez-Solis, R, Smedley, D, Ball, S, Blake, A, Fray, M, Kenyon, J, Mallon, AM, Brown, S, Massimi, M, Matteoni, R, Tocchini-Valentini, G, Herault, Y, Kollias, G, Ulfhake, B, Demengeot, J, Fremond, C, Bosch, F, Montoliu, L, Soininen, R, Schughart, K, Brakebusch, C, Sedlacek, R, Rulicke, T, McKerlie, C, Malissen, B, Iraqi, F, Jonkers, J, Russig, H, Huylebroeck, Danny, Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany., and Cell biology
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Internet ,business.industry ,Knowledge Bases ,Mutant ,Biology ,Mice, Mutant Strains ,Biotechnology ,World Wide Web ,Phenotype ,SDG 3 - Good Health and Well-being ,Databases, Genetic ,Models, Animal ,Genetics ,Database Issue ,Animals ,The Internet ,business ,Embryonic Stem Cells - Abstract
This deposit is composed by a publication in which the IGC' authors have had the role of collaboration (it's a collaboration publication). This type of deposit in ARCA is in restrictedAccess (it can't be in open access to the public), and could only be accessed by two ways: either by requesting a legal copy to the author (the email contact present in this deposit) or by visiting the following link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383977/ The laboratory mouse is a key model organism to investigate mechanism and therapeutics of human disease. The number of targeted genetic mouse models of disease is growing rapidly due to high-throughput production strategies employed by the International Mouse Phenotyping Consortium (IMPC) and the development of new, more efficient genome engineering techniques such as CRISPR based systems. We have previously described the European Mouse Mutant Archive (EMMA) resource and how this international infrastructure provides archiving and distribution worldwide for mutant mouse strains. EMMA has since evolved into INFRAFRONTIER (http://www.infrafrontier.eu), the pan-European research infrastructure for the systemic phenotyping, archiving and distribution of mouse disease models. Here we describe new features including improved search for mouse strains, support for new embryonic stem cell resources, access to training materials via a comprehensive knowledgebase and the promotion of innovative analytical and diagnostic techniques. European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI).
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- 2015
3. Size distribution of coherently strained InAs quantum dots
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Schmidt, K.H., Mederios-Ribeiro, G., Kunze, U., Abstreiter, G., Hagn, M., and Petroff, P.M.
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Photoluminescence -- Observations ,Spectrum analysis -- Usage ,Gaussian distribution -- Observations ,Physics - Abstract
InAs quantum dots (QDs) are used to fabricate good electrical and optical quality zero-dimensional systems. Size distribution dependence of coherently strained islands on InAs deposited on a GaAs substrate has been studied, using photoluminescence (PL) and photovoltage (PV) spectroscopy. Quantum dot photoluminescence is described at low InAs by a broad Gaussian peak, while the PL signal moves to lower energies with increasing INAs coverage. The energetic position remains constant. A simple accumulation model confirms the interpretation.
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- 1998
4. B cell-derived circulating granzyme B is a feature of acute infectious mononucleosis
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Hagn, M, Panikkar, A, Smith, C, Balfour, HH, Khanna, R, Voskoboinik, I, Trapani, JA, Hagn, M, Panikkar, A, Smith, C, Balfour, HH, Khanna, R, Voskoboinik, I, and Trapani, JA
- Abstract
Granzyme B (GzmB) is a serine protease best known for inducing target cell apoptosis when released by cytotoxic T lymphocytes (CTLs) or natural killer cells with pore-forming perforin. As a result, GzmB detected in the serum of virus-infected individuals has typically been attributed to these sources. Here, we show that patients with recently diagnosed infectious mononucleosis caused by Epstein-Barr virus (EBV) have high circulating levels of GzmB that may be derived from infected B cells early in course of disease. We recently reported that human B cells from healthy donors secrete active GzmB when stimulated in vitro through B-cell receptor (BCR) ligation and interleukin (IL)-21. We found that infecting B cells with EBV greatly amplified GzmB secretion in response to the same stimuli, but the expression was terminated once the infection had become latent. Our results represent a rare instance of GzmB expression by non-CTL/natural killer cells in the context of infection with a human pathogen.
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- 2015
5. EMMA - European Mouse Mutant Archive
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Hagn M., Tocchini-Valentini G., Brown S., Lendahl U., Demengeot J., Birney E., Ramirez-Solis R., Herault Y., Montoliu L., Kollias G., Ruelicke T., Sedlacek R., Soininen R., and Hrabe de Angelis M.
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Mouse mutant ,Disease model - Published
- 2011
6. EMMA - The EUROPEAN MOUSE MUTANT ARCHIVE
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Hagn M et al. (EMMA Consortium)
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- 2009
7. THE EUROPEAN MOUSE MUTANT ARCHIVE (EMMA)
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Hagn M. et al.
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disease model ,mouse mutant - Published
- 2008
8. EMMA Cre-driver line archiving
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Hagn M. and Matteoni R.
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- 2007
9. Mouse granzyme A induces a novel death with writhing morphology that is mechanistically distinct from granzyme B-induced apoptosis
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Susanto, O, primary, Stewart, S E, additional, Voskoboinik, I, additional, Brasacchio, D, additional, Hagn, M, additional, Ellis, S, additional, Asquith, S, additional, Sedelies, K A, additional, Bird, P I, additional, Waterhouse, N J, additional, and Trapani, J A, additional
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- 2013
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10. Strong magnetic field dependence of laser emission from quantum wires formed by cleaved edge overgrowth
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Wegscheider, Werner, Pfeiffer, Loren N., West, Kenneth W., Littlewood, P., Narayan, O., Hagn, M., Dignam, M. M., and Leibenguth, R. E.
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Condensed Matter::Mesoscopic Systems and Quantum Hall Effect ,530 Physik - Abstract
Characteristics of GaAs/AlGaAs quantum wire (QWR) lasers are studied for the first time under strong magnetic fields up to 12T. The QWR laser diodes have been fabricated by the molecular beam epitaxy technique, we call “cleaved edge overgrowth” (CEO), which combines conventional layer growth along the [001] crystal axis with high-quality regrowth on the (110) crystal face formed by an in situ cleave. The active region of our lasers consists of atomically precise QWRs that form at the T-shaped intersections of 7 nm wide GaAs quantum wells (QWs). The origin of the quantum mechanical bound state is the relaxation of quantum well confinement at this intersection, which limits free carrier motion to one-dimension, i.e. to the line defined by the intersection of the two QWs. Applying a magnetic field parallel to the QWR axis we observe a pronounced increase in the laser emission intensity of more than one order of magnitude while the electrical diode characteristic remains unaffected. This effect mainly occurs for field strengths of 5 to 9 T where the magnetic length becomes comparable to the QWR dimensions. For a magnetic field direction oriented perpendicular to the QWR axis and parallel to the [110] overgrowth direction, a completely different behavior is observed. Although the absolute intensity increase is comparable to the previous case, the emitted intensity is already doubled for a magnetic field below 1 T, and magnetic fields exceeding 4 T show only a weak effect on the emitted intensity for this field direction. The origin of such a strong magnetic field dependence of the QWR emission, not previously observed for QW lasers, is discussed in the context of excitonic lasing.
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- 1996
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11. EMMA--mouse mutant resources for the international scientific community
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Wilkinson, P., primary, Sengerova, J., additional, Matteoni, R., additional, Chen, C.-K., additional, Soulat, G., additional, Ureta-Vidal, A., additional, Fessele, S., additional, Hagn, M., additional, Massimi, M., additional, Pickford, K., additional, Butler, R. H., additional, Marschall, S., additional, Mallon, A.-M., additional, Pickard, A., additional, Raspa, M., additional, Scavizzi, F., additional, Fray, M., additional, Larrigaldie, V., additional, Leyritz, J., additional, Birney, E., additional, Tocchini-Valentini, G. P., additional, Brown, S., additional, Herault, Y., additional, Montoliu, L., additional, de Angelis, M. H., additional, and Smedley, D., additional
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- 2009
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12. EMMA The European mouse mutant archive
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Hagn, M., primary, Marschall, S., additional, and Hrabe de Angelis, M., additional
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- 2007
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13. Spatially resolved optical spectroscopy on natural quantum dots
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Zrenner, A., primary, Schaller, A., additional, Markmann, M., additional, Hagn, M., additional, Arzberger, M., additional, Henry, D., additional, Abstreiter, G., additional, Böhm, G., additional, and Weimann, G., additional
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- 1998
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14. Evidence for condensation of excitons in double quantum wells
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Butov, L V, primary, Zrenner, A, additional, Hagn, M, additional, Abstreiter, G, additional, Boehm, G, additional, and Weimann, G, additional
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- 1996
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15. Anomalous transport of indirect excitons in coupled AlAs/GaAs quantum wells
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Butov, L.V., primary, Zrenner, A., additional, Hagn, M., additional, Abstreiter, G., additional, Böhm, G., additional, and Weimann, G., additional
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- 1996
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16. Strong magnetic field dependence of laser emission from quantum wires formed by cleaved edge overgrowth
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Wegscheider, W., primary, Pfeiffer, L.N., additional, West, K.W., additional, Littlewood, P., additional, Narayan, O., additional, Hagn, M., additional, Dignam, M.M., additional, and Leibenguth, R.E., additional
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- 1996
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17. Electric-field-induced exciton transport in coupled quantum well structures
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Hagn, M, primary, Zrenner, A, additional, Böhm, G, additional, and Weimann, G, additional
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- 1996
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18. Evidence for condensation of excitons in double quantum wells
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Butov, L.V., primary, Zrenner, A., additional, Hagn, M., additional, Abstreiter, G., additional, Boehm, G., additional, and Weimann, G., additional
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- 1996
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19. Electric‐field‐induced exciton transport in coupled quantum well structures
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Hagn, M., primary, Zrenner, A., additional, Böhm, G., additional, and Weimann, G., additional
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- 1995
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20. Long-lived excitonic ground states in GaAs/AlAs coupled quantum well structures
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Zrenner, A, primary, Butov, L V, additional, and Hagn, M, additional
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- 1994
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21. Quantum dots formed by interface fluctuations in AlAs/GaAs coupled quantum well structures
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Zrenner, A., primary, Butov, L. V., additional, Hagn, M., additional, Abstreiter, G., additional, Böhm, G., additional, and Weimann, G., additional
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- 1994
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22. Electric field induced [MATH]-X transition in GaAs-AlAs coupled quantum well structures
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HAGN, M., primary, ZRENNER, A., additional, BÖHM, G., additional, and WEIMANN, G., additional
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- 1993
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23. PATHBIO: an international training program for precision mouse phenotyping.
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Ruberte J, Schofield PN, Brakebusch C, Vogel P, Herault Y, Gracia G, McKerlie C, Hrabĕ de Angelis M, Hagn M, and Sundberg JP
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- Animals, Animals, Genetically Modified, Biomedical Research organization & administration, Curriculum, Disease Models, Animal, Humans, Mice, Research Personnel education, Biomedical Research education, Phenotype
- Abstract
Design and production of genetically engineered mouse strains by individual research laboratories, research teams, large-scale consortia, and the biopharmaceutical industry have magnified the need for qualified personnel to identify, annotate, and validate (phenotype) these potentially new mouse models of human disease. The PATHBIO project has been recently established and funded by the European Union's ERASMUS+ Knowledge Alliance program to address the current shortfall in formally trained personnel. A series of teaching workshops will be given by experts on anatomy, histology, embryology, imaging, and comparative pathology to increase the availability of individuals with formal training to contribute to this important niche of Europe's biomedical research enterprise. These didactic and hands-on workshops are organized into three modules: (1) embryology, anatomy, histology, and the anatomical basis of imaging, (2) image-based phenotyping, and (3) pathology. The workshops are open to all levels of participants from recent graduates to Ph.D., M.D., and veterinary scientists. Participation is available on a competitive basis at no cost for attending. The first series of Workshop Modules was held in 2019 and these will continue for the next 2 years.
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- 2020
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24. B cell-derived circulating granzyme B is a feature of acute infectious mononucleosis.
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Hagn M, Panikkar A, Smith C, Balfour HH Jr, Khanna R, Voskoboinik I, and Trapani JA
- Abstract
Granzyme B (GzmB) is a serine protease best known for inducing target cell apoptosis when released by cytotoxic T lymphocytes (CTLs) or natural killer cells with pore-forming perforin. As a result, GzmB detected in the serum of virus-infected individuals has typically been attributed to these sources. Here, we show that patients with recently diagnosed infectious mononucleosis caused by Epstein-Barr virus (EBV) have high circulating levels of GzmB that may be derived from infected B cells early in course of disease. We recently reported that human B cells from healthy donors secrete active GzmB when stimulated in vitro through B-cell receptor (BCR) ligation and interleukin (IL)-21. We found that infecting B cells with EBV greatly amplified GzmB secretion in response to the same stimuli, but the expression was terminated once the infection had become latent. Our results represent a rare instance of GzmB expression by non-CTL/natural killer cells in the context of infection with a human pathogen.
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- 2015
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25. A method for detecting intracellular perforin in mouse lymphocytes.
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Brennan AJ, House IG, Oliaro J, Ramsbottom KM, Hagn M, Yagita H, Trapani JA, and Voskoboinik I
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- Animals, Cell Separation, Cells, Cultured, Flow Cytometry, Fluorescent Antibody Technique, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Perforin genetics, Protein Transport, Granzymes metabolism, Immunological Synapses metabolism, Intracellular Space metabolism, Perforin metabolism, T-Lymphocytes, Cytotoxic immunology
- Abstract
Cytotoxic lymphocytes destroy pathogen-infected and transformed cells through the cytotoxic granule exocytosis death pathway, which is dependent on the delivery of proapoptotic granzymes into the target cell cytosol by the pore-forming protein, perforin. Despite the importance of mouse models in understanding the role of cytotoxic lymphocytes in immune-mediated disease and their role in cancer immune surveillance, no reliable intracellular detection method exists for mouse perforin. Consequently, rapid, flow-based assessment of cytotoxic potential has been problematic, and complex assays of function are generally required. In this study, we have developed a novel method for detecting perforin in primary mouse cytotoxic T lymphocytes by immunofluorescence and flow cytometry. We used this new technique to validate perforin colocalization with granzyme B in cytotoxic granules polarized to the immunological synapse, and to assess the expression of perforin in cytotoxic T lymphocytes at various stages of activation. The sensitivity of this technique also allowed us to distinguish perforin levels in Prf1(+/+) and Prf1(+/-) mice. This new methodology will have broad applications and contribute to advances within the fields of lymphocyte biology, infectious disease, and cancer., (Copyright © 2014 by The American Association of Immunologists, Inc.)
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- 2014
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26. A colorimetric assay that specifically measures Granzyme B proteolytic activity: hydrolysis of Boc-Ala-Ala-Asp-S-Bzl.
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Hagn M, Sutton VR, and Trapani JA
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- Animals, Apoptosis physiology, Aspartic Acid metabolism, Formic Acid Esters metabolism, Granzymes analysis, Humans, Hydrolysis, Killer Cells, Natural cytology, Killer Cells, Natural enzymology, Killer Cells, Natural metabolism, Mice, Oligopeptides analysis, Proteolysis, Rats, Serine Endopeptidases analysis, Serine Endopeptidases metabolism, T-Lymphocytes, Cytotoxic cytology, T-Lymphocytes, Cytotoxic enzymology, T-Lymphocytes, Cytotoxic metabolism, Colorimetry methods, Granzymes metabolism, Oligopeptides metabolism
- Abstract
The serine protease Granzyme B (GzmB) mediates target cell apoptosis when released by cytotoxic T lymphocytes (CTL) or natural killer (NK) cells. GzmB is the most studied granzyme in humans and mice and therefore, researchers need specific and reliable tools to study its function and role in pathophysiology. This especially necessitates assays that do not recognize proteases such as caspases or other granzymes that are structurally or functionally related. Here, we apply GzmB's preference for cleavage after aspartic acid residues in a colorimetric assay using the peptide thioester Boc-Ala-Ala-Asp-S-Bzl. GzmB is the only mammalian serine protease capable of cleaving this substrate. The substrate is cleaved with similar efficiency by human, mouse and rat GzmB, a property not shared by other commercially available peptide substrates, even some that are advertised as being suitable for this purpose. This protocol is demonstrated using unfractionated lysates from activated NK cells or CTL and is also suitable for recombinant proteases generated in a variety of prokaryotic and eukaryotic systems, provided the correct controls are used. This assay is a highly specific method to ascertain the potential pro-apoptotic activity of cytotoxic molecules in mammalian lymphocytes, and of their recombinant counterparts expressed by a variety of methodologies.
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- 2014
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27. CD27(+)IgD(-) B cells in the peripheral blood of colorectal cancer patients: on anti-tumor or tumor-protective mission?
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Jahrsdörfer B, Lindner S, Hagn M, and Schrezenmeier H
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- 2014
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28. B-CLL cells acquire APC- and CTL-like phenotypic characteristics after stimulation with CpG ODN and IL-21.
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Hagn M, Blackwell SE, Beyer T, Ebel V, Fabricius D, Lindner S, Stilgenbauer S, Simmet T, Tam C, Neeson P, Trapani JA, Schrezenmeier H, Weiner GJ, and Jahrsdörfer B
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- Aged, Aged, 80 and over, Antigen-Presenting Cells immunology, Antigen-Presenting Cells pathology, Apoptosis drug effects, B-Lymphocytes immunology, B-Lymphocytes pathology, Chemokine CXCL10 genetics, Chemokine CXCL10 immunology, Cytotoxicity, Immunologic drug effects, Female, Gene Expression Regulation, Leukemic, Granzymes genetics, Granzymes immunology, Humans, Immunophenotyping, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Middle Aged, Perforin genetics, Perforin immunology, Primary Cell Culture, Recombinant Proteins pharmacology, Signal Transduction, T-Box Domain Proteins genetics, T-Box Domain Proteins immunology, Antigen-Presenting Cells drug effects, B-Lymphocytes drug effects, Interleukins pharmacology, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Lymphocyte Activation drug effects, Oligodeoxyribonucleotides pharmacology
- Abstract
CpG oligodeoxynucleotides (CpG) and IL-21 are two promising agents for the treatment of B-cell chronic lymphocytic leukemia (B-CLL). Recently, we reported that the combination of CpG and IL-21 (CpG/IL-21) can induce granzyme B (GrB)-dependent apoptosis in B-CLL cells. Here, we demonstrate that treatment of B-CLL cells with CpG and IL-21 results in the development of antigen-presenting cell (APC)-like cells with cytotoxic features. These properties eventually give rise to B-CLL cell apoptosis, independently of their cytogenetic phenotype, whereas normal B-cell survival is not negatively affected by CpG/IL-21. APC- and CTL-typical molecules found to be up-regulated in CpG/IL-21-stimulated B-CLL cells include GrB, perforin, T-bet, monokine-induced by IFN-γ and IFN-γ-inducible protein 10 (IP-10), as well as molecules important for cell adhesion, antigen cross-presentation and costimulation. Also induced are molecules involved in GrB induction, trafficking and processing, whereas the GrB inhibitor Serpin B9 [formerly proteinase inhibitor-9 (PI-9)] is down-modulated by CpG/IL-21. In conclusion, CpG/IL-21-stimulated B-CLL cells acquire features that are reminiscent of killer dendritic cells, and which result in enhanced immunogenicity, cytotoxicity and apoptosis. Our results provide novel insights into the aberrant immune state of B-CLL cells and may establish a basis for the development of an innovative cellular vaccination approach in B-CLL., (© The Japanese Society for Immunology. 2014. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2014
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29. Interleukin 21-induced granzyme B-expressing B cells infiltrate tumors and regulate T cells.
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Lindner S, Dahlke K, Sontheimer K, Hagn M, Kaltenmeier C, Barth TF, Beyer T, Reister F, Fabricius D, Lotfi R, Lunov O, Nienhaus GU, Simmet T, Kreienberg R, Möller P, Schrezenmeier H, and Jahrsdörfer B
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- Apoptosis drug effects, B-Lymphocytes, Regulatory metabolism, CD5 Antigens metabolism, Cell Communication drug effects, Cells, Cultured, Humans, Immunophenotyping, Lymphocyte Activation drug effects, Lymphocyte Activation immunology, Lymphocytes, Tumor-Infiltrating drug effects, Lymphocytes, Tumor-Infiltrating enzymology, Lymphocytes, Tumor-Infiltrating immunology, Phenotype, Receptors, Antigen, T-Cell, gamma-delta metabolism, Signal Transduction drug effects, T-Lymphocyte Subsets metabolism, Toll-Like Receptors metabolism, Tumor Microenvironment drug effects, Tumor Microenvironment immunology, B-Lymphocytes, Regulatory drug effects, B-Lymphocytes, Regulatory immunology, Granzymes metabolism, Interleukins pharmacology, Neoplasms enzymology, Neoplasms immunology, T-Lymphocyte Subsets immunology
- Abstract
The pathogenic impact of tumor-infiltrating B cells is unresolved at present, however, some studies suggest that they may have immune regulatory potential. Here, we report that the microenvironment of various solid tumors includes B cells that express granzyme B (GrB, GZMB), where these B cells can be found adjacent to interleukin (IL)-21-secreting regulatory T cells (Treg) that contribute to immune tolerance of tumor antigens. Because Tregs and plasmacytoid dendritic cells are known to modulate T-effector cells by a GrB-dependent mechanism, we hypothesized that a similar process may operate to modulate regulatory B cells (Breg). IL-21 induced outgrowth of B cells expressing high levels of GrB, which thereby limited T-cell proliferation by a GrB-dependent degradation of the T-cell receptor ζ-chain. Mechanistic investigations into how IL-21 induced GrB expression in B cells to confer Breg function revealed a CD19(+)CD38(+)CD1d(+)IgM(+)CD147(+) expression signature, along with expression of additional key regulatory molecules including IL-10, CD25, and indoleamine-2,3-dioxygenase. Notably, induction of GrB by IL-21 integrated signals mediated by surface immunoglobulin M (B-cell receptor) and Toll-like receptors, each of which were enhanced with expression of the B-cell marker CD5. Our findings show for the first time that IL-21 induces GrB(+) human Bregs. They also establish the existence of human B cells with a regulatory phenotype in solid tumor infiltrates, where they may contribute to the suppression of antitumor immune responses. Together, these findings may stimulate novel diagnostic and cell therapeutic approaches to better manage human cancer as well as autoimmune and graft-versus-host pathologies., (©2013 AACR.)
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- 2013
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30. Why do human B cells secrete granzyme B? Insights into a novel B-cell differentiation pathway.
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Hagn M and Jahrsdörfer B
- Abstract
B cells are generally believed to operate as producers of high affinity antibodies to defend the body against microorganisms, whereas cellular cytotoxicity is considered as an exclusive prerogative of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). In conflict with this dogma, recent studies have demonstrated that the combination of interleukin-21 (IL-21) and B-cell receptor (BCR) stimulation enables B cells to produce and secrete the active form of the cytotoxic serine protease granzyme B (GrB). Although the production of GrB by B cells is not accompanied by that of perforin as in the case of many other GrB-secreting cells, recent findings suggest GrB secretion by B cells may play a significant role in early antiviral immune responses, in the regulation of autoimmune responses, and in cancer immunosurveillance. Here, we discuss in detail how GrB-secreting B cells may influence a variety of immune processes. A better understanding of the role that GrB-secreting B cells are playing in the immune system may allow for the development and improvement of novel immunotherapeutic approaches against infectious, autoimmune and malignant diseases.
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- 2012
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31. Centralized mouse repositories.
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Donahue LR, Hrabe de Angelis M, Hagn M, Franklin C, Lloyd KC, Magnuson T, McKerlie C, Nakagata N, Obata Y, Read S, Wurst W, Hörlein A, and Davisson MT
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- Animals, Quality Control, Species Specificity, Mice genetics
- Abstract
Because the mouse is used so widely for biomedical research and the number of mouse models being generated is increasing rapidly, centralized repositories are essential if the valuable mouse strains and models that have been developed are to be securely preserved and fully exploited. Ensuring the ongoing availability of these mouse strains preserves the investment made in creating and characterizing them and creates a global resource of enormous value. The establishment of centralized mouse repositories around the world for distributing and archiving these resources has provided critical access to and preservation of these strains. This article describes the common and specialized activities provided by major mouse repositories around the world.
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- 2012
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32. Activated mouse B cells lack expression of granzyme B.
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Hagn M, Belz GT, Kallies A, Sutton VR, Thia KY, Tarlinton DM, Hawkins ED, and Trapani JA
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- Animals, Antibodies, Viral biosynthesis, Antibodies, Viral immunology, B-Lymphocytes metabolism, B-Lymphocytes virology, Cells, Cultured, Gammaherpesvirinae, Granzymes immunology, Haptens, Hemocyanins pharmacology, Herpesviridae Infections enzymology, Humans, Immunity, Humoral, Interleukins pharmacology, Lymphocyte Activation, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Transgenic, Orthomyxoviridae, Orthomyxoviridae Infections enzymology, Receptors, Antigen, B-Cell immunology, Receptors, Antigen, B-Cell metabolism, Species Specificity, T-Lymphocytes, Cytotoxic metabolism, T-Lymphocytes, Cytotoxic virology, B-Lymphocytes immunology, Granzymes metabolism, Herpesviridae Infections immunology, Orthomyxoviridae Infections immunology, T-Lymphocytes, Cytotoxic immunology
- Abstract
Recently, it has been reported that human B cells express and secrete the cytotoxic protease granzyme B (GrB) after stimulation with IL-21 and BCR cross-linking. To date, there are few clues on the function of GrB in B cell biology. As experimental transgenic murine systems should provide insights into these issues, we assayed for GrB in C57BL/6 B cells using an extensive array of physiologically relevant stimuli but were unable to detect either GrB expression or its proteolytic activity, even when Ag-specific transgenic BCRs were engaged. Similar results were also obtained with B cells from DBA/2, CBA, or BALB/c mice. In vivo, infection with either influenza virus or murine γ-herpesvirus induced the expected expression of GrB in CTLs, but not in B cell populations. We also investigated a possible role of GrB on the humoral immune response to the model Ag 4-hydroxy-3-nitrophenylacetyl-keyhole limpet hemocyanin, but GrB-deficient mice produced normal amounts of Ab with typical affinity maturation and a heightened secondary response, demonstrating conclusively the redundancy of GrB for Ab responses. Our results highlight the complex evolutionary differences that have shaped the immune systems of mice and humans. The physiological consequences of GrB expression in human B cells remain unclear, and the current study suggests that experimental mouse models will not be helpful in addressing this issue.
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- 2012
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33. Human B cells differentiate into granzyme B-secreting cytotoxic B lymphocytes upon incomplete T-cell help.
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Hagn M, Sontheimer K, Dahlke K, Brueggemann S, Kaltenmeier C, Beyer T, Hofmann S, Lunov O, Barth TF, Fabricius D, Tron K, Nienhaus GU, Simmet T, Schrezenmeier H, and Jahrsdörfer B
- Subjects
- B-Lymphocytes metabolism, CD40 Ligand, Cells, Cultured, Humans, Immunity, Cellular, Interleukin-2 pharmacology, Interleukins pharmacology, B-Lymphocytes cytology, Cell Differentiation immunology, Granzymes metabolism, T-Lymphocytes, Helper-Inducer immunology
- Abstract
Recently, CD4(+) T helper cells were shown to induce differentiation of human B cells into plasma cells by expressing interleukin (IL-)21 and CD40 ligand (CD40L). In the present study we show, that in the absence of CD40L, CD4(+) T cell-derived IL-21 induces differentiation of B cells into granzyme B (GzmB)-secreting cytotoxic cells. Using fluorescence-activated cell sorting (FACS) analysis, ELISpot and confocal microscopy, we demonstrate that CD4(+) T cells, activated via their T-cell receptor without co-stimulation, can produce IL-21, but do not express CD40L and rapidly induce GzmB in co-cultured B cells in an IL-21 receptor-dependent manner. Of note, we confirmed these results with recombinant reagents, highlighting that CD40L suppresses IL-21-induced GzmB induction in B cells in a dose-dependent manner. Surprisingly, although GzmB-secreting B cells did not express perforin, they were able to transfer active GzmB to tumor cell lines, thereby effectively inducing apoptosis. In contrast, no cytotoxic effects were found when effector B cells were activated with IL-2 instead of IL-21 or when target cells were cultured with IL-21 alone. Our findings suggest GzmB(+) cytotoxic B cells may have a role in early cellular immune responses including tumor immunosurveillance, before fully activated, antigen-specific cytotoxic T cells are on the spot. CD40 ligand determines whether IL-21 induces differentiation of B cells into plasma cells or into granzyme B-secreting cytotoxic cells.
- Published
- 2012
- Full Text
- View/download PDF
34. CD5+ B cells from individuals with systemic lupus erythematosus express granzyme B.
- Author
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Hagn M, Ebel V, Sontheimer K, Schwesinger E, Lunov O, Beyer T, Fabricius D, Barth TF, Viardot A, Stilgenbauer S, Hepp J, Scharffetter-Kochanek K, Simmet T, and Jahrsdörfer B
- Subjects
- Adolescent, Adult, Aged, B-Lymphocytes immunology, B-Lymphocytes pathology, CD5 Antigens biosynthesis, Cell Proliferation, Cell Survival immunology, Female, Granzymes genetics, Humans, Immune Tolerance, Interleukins blood, Interleukins genetics, Interleukins immunology, Lupus Erythematosus, Systemic blood, Male, Middle Aged, Receptor Cross-Talk immunology, Receptors, Antigen, B-Cell immunology, Receptors, Interleukin-21 biosynthesis, Receptors, Interleukin-21 genetics, B-Lymphocytes metabolism, Granzymes metabolism, Interleukins biosynthesis, Lupus Erythematosus, Systemic immunology, Receptors, Antigen, B-Cell metabolism
- Abstract
Recently, we reported that IL-21 induces granzyme B (GzmB) and GzmB-dependent apoptosis in malignant CD5(+) B cells from patients with chronic lymphocytic leukemia. Several autoimmune diseases (AD) are associated with enhanced frequencies of CD5(+) B cells. Since AD are also associated with elevated IL-21 and GzmB levels, we postulated a link between CD5(+) B cells, IL-21 and GzmB. Here, we demonstrate that IL-21 and GzmB serum levels are highly correlated in subjects with systemic lupus erythematosus (SLE) and that freshly isolated CD5(+) SLE B cells constitutively express GzmB. IL-21 directly induced GzmB expression and secretion by CD5(+) B cells from several AD and from cord blood in vitro, and the simultaneous presence of BCR stimulation strongly enhanced this process. Furthermore, IL-21 suppressed both viability and expansion of CD5(+) B cells from SLE individuals. In summary, our study may explain the elevated levels of IL-21 and GzmB in SLE and other AD. Moreover, our data suggest that IL-21 may have disease-modifying characteristics by inducing GzmB in CD5(+) B cells and by suppressing their expansion. Our results provide the rationale for further evaluation of the therapeutic potential of IL-21 in certain AD such as SLE.
- Published
- 2010
- Full Text
- View/download PDF
35. EMMA--mouse mutant resources for the international scientific community.
- Author
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Wilkinson P, Sengerova J, Matteoni R, Chen CK, Soulat G, Ureta-Vidal A, Fessele S, Hagn M, Massimi M, Pickford K, Butler RH, Marschall S, Mallon AM, Pickard A, Raspa M, Scavizzi F, Fray M, Larrigaldie V, Leyritz J, Birney E, Tocchini-Valentini GP, Brown S, Herault Y, Montoliu L, de Angelis MH, and Smedley D
- Subjects
- Animals, Chromosomes, Computational Biology trends, Databases, Protein, Information Storage and Retrieval methods, Internet, Mice, Mice, Inbred C57BL, Mice, Knockout, Models, Genetic, Protein Structure, Tertiary, Software, User-Computer Interface, Computational Biology methods, Databases, Genetic, Databases, Nucleic Acid
- Abstract
The laboratory mouse is the premier animal model for studying human disease and thousands of mutants have been identified or produced, most recently through gene-specific mutagenesis approaches. High throughput strategies by the International Knockout Mouse Consortium (IKMC) are producing mutants for all protein coding genes. Generating a knock-out line involves huge monetary and time costs so capture of both the data describing each mutant alongside archiving of the line for distribution to future researchers is critical. The European Mouse Mutant Archive (EMMA) is a leading international network infrastructure for archiving and worldwide provision of mouse mutant strains. It operates in collaboration with the other members of the Federation of International Mouse Resources (FIMRe), EMMA being the European component. Additionally EMMA is one of four repositories involved in the IKMC, and therefore the current figure of 1700 archived lines will rise markedly. The EMMA database gathers and curates extensive data on each line and presents it through a user-friendly website. A BioMart interface allows advanced searching including integrated querying with other resources e.g. Ensembl. Other resources are able to display EMMA data by accessing our Distributed Annotation System server. EMMA database access is publicly available at http://www.emmanet.org.
- Published
- 2010
- Full Text
- View/download PDF
36. Human B cells secrete granzyme B when recognizing viral antigens in the context of the acute phase cytokine IL-21.
- Author
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Hagn M, Schwesinger E, Ebel V, Sontheimer K, Maier J, Beyer T, Syrovets T, Laumonnier Y, Fabricius D, Simmet T, and Jahrsdörfer B
- Subjects
- Acute-Phase Proteins, B-Lymphocytes immunology, Endosomes virology, Humans, Immunity, Immunophenotyping, Signal Transduction, Vaccination, Virus Internalization, Antigens, Viral immunology, B-Lymphocytes metabolism, Granzymes metabolism, Interleukins immunology
- Abstract
Human B cells are currently not known to produce the proapoptotic protease granzyme B (GrB) in physiological settings. We have discovered that BCR stimulation with either viral Ags or activating Abs in the context of the acute phase cytokine IL-21 can induce the secretion of substantial amounts of GrB by human B cells. Importantly, GrB response to viral Ags was significantly stronger in B cells from subjects recently vaccinated against the corresponding viruses as compared with unvaccinated subjects. GrB-secreting B cells featured a homogeneous CD19(+)CD20(+)CD27(-)CD38(-)IgD(-) phenotype, improved survival, and enhanced expression of costimulatory, Ag-presenting and cell-adhesion molecules. B cell-derived GrB was enzymatically active and its induction required the activation of similar signaling pathways as those in CTLs. Our findings suggest that GrB-secreting B cells support the early antiviral immune response against viruses with endosomal entry pathways, thereby counteracting overwhelming viral replication at the beginning of an infection until virus-specific T cells from draining lymph nodes arrive at the site of infection. Our data may also explain the elevated serum GrB levels found in the early phase of various viral diseases.
- Published
- 2009
- Full Text
- View/download PDF
37. [Scientific activities in nursing. Nursing research has grown up in Germany].
- Author
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Majoros M, Hagn M, and Knipfer E
- Subjects
- Germany, Humans, Nursing Research
- Published
- 1995
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