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1. Reactive oxygen species produced by myeloid cells in psoriasis as a potential biofactor contributing to the development of vascular inflammation

Author

Schaller, Theresa, Ringen, Julia, Fischer, Berenice, Bieler, Tabea, Perius, Katharina, Knopp, Tanja, Kommoss, Katharina S, Korn, Thomas, Heikenwälder, Mathias, Oelze, Matthias, Daiber, Andreas, Münzel, Thomas, Kramer, Daniela, Wenzel, Philip, Wild, Johannes, Karbach, Susanne, and Waisman, Ari

Subjects
Clinical Biochemistry, Molecular Medicine, 610 Medicine & health, General Medicine, Biochemistry
Abstract

Psoriasis is an immune-mediated inflammatory skin disease driven by interleukin-17A (IL-17A) and associated with cardiovascular dysfunction. We used a severe psoriasis mouse model of keratinocyte IL-17A overexpression (K14-IL-17Aind/+ , IL-17Aind/+ control mice) to investigate the activity of neutrophils and a potential cellular interconnection between skin and vasculature. Levels of dermal reactive oxygen species (ROS) and their release by neutrophils were measured by lucigenin-/luminol-based assays, respectively. Quantitative RT-PCR determined neutrophilic activity and inflammation-related markers in skin and aorta. To track skin-derived immune cells, we used PhAM-K14-IL-17Aind/+ mice allowing us to mark all cells in the skin by photoconversion of a fluorescent protein to analyze their migration into spleen, aorta, and lymph nodes by flow cytometry. Compared to controls, K14-IL-17Aind/+ mice exhibited elevated ROS levels in the skin and a higher neutrophilic oxidative burst accompanied by the upregulation of several activation markers. In line with these results psoriatic mice displayed elevated expression of genes involved in neutrophil migration (e.g., Cxcl2 and S100a9) in skin and aorta. However, no direct immune cell migration from the psoriatic skin into the aortic vessel wall was observed. Neutrophils of psoriatic mice showed an activated phenotype, but no direct cellular migration from the skin to the vasculature was observed. This suggests that highly active vasculature-invading neutrophils must originate directly from the bone marrow. Hence, the skin-vasculature crosstalk in psoriasis is most likely based on the systemic effects of the autoimmune skin disease, emphasizing the importance of a systemic therapeutic approach for psoriasis patients.

Published
2023
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2. CD4+ T-cell-derived IL-10 promotes CNS inflammation in mice by sustaining effector T cell survival

Author

Yogev, Nir, Bedke, Tanja, Kobayashi, Yasushi, Brockmann, Leonie, Lukas, Dominika, Regen, Tommy, Croxford, Andrew L, Nikolav, Alexei, Hövelmeyer, Nadine, von Stebut, Esther, Prinz, Marco, Ubeda, Carles, Maloy, Kevin J., Gagliani, Nicola, Flavell, Richard A, Waisman, Ari, and Huber, Samuel

Abstract

Interleukin (IL)-10 is considered a prototypical anti-inflammatory cytokine, significantly contributing to the maintenance and reestablishment of immune homeostasis. Accordingly, it has been shown in the intestine that IL-10 produced by Tregs can act on effector T cells, thereby limiting inflammation. Herein, we investigate whether this role also applies to IL-10 produced by T cells during central nervous system (CNS) inflammation. During neuroinflammation, both CNS-resident and -infiltrating cells produce IL-10; yet, as IL-10 has a pleotropic function, the exact contribution of the different cellular sources is not fully understood. We find that T-cell-derived IL-10, but not other relevant IL-10 sources, can promote inflammation in experimental autoimmune encephalomyelitis. Furthermore, in the CNS, T-cell-derived IL-10 acts on effector T cells, promoting their survival and thereby enhancing inflammation and CNS autoimmunity. Our data indicate a pro-inflammatory role of T-cell-derived IL-10 in the CNS.

Published
2022

4. Repositioning T H cell polarization from single cytokines to complex help

Author

Tuzlak, Selma, Dejean, Anne S, Iannacone, Matteo, Quintana, Francisco J, Waisman, Ari, Ginhoux, Florent, Korn, Thomas, Becher, Burkhard, University of Zurich, Korn, Thomas, and Becher, Burkhard

Subjects
2403 Immunology, 2723 Immunology and Allergy, 570 Life sciences, biology, 610 Medicine & health, 10263 Institute of Experimental Immunology
Published
2021
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5. Microglia as Central Protagonists in the Chronic Stress Response

Author

Schramm, Eva and Waisman, Ari

Subjects
Phagocytosis, Neurology, Humans, Cytokines, Review, Microglia, Neurology (clinical), Reactive Oxygen Species
Abstract

Chronic stress is a major risk factor for developing psychiatric conditions. In addition to elevating the levels of stress hormones released in the body, chronic stress activates the immune system, resulting in increased levels of proinflammatory cytokines and innate immune cells in the circulation of rodents and humans. Furthermore, exposure to chronic stress alters the phenotype of microglia, a population of innate immune cells that reside in the CNS parenchyma. In rodent models, chronic stress activates microglia in defined brain regions and induces changes in their phenotype and functional properties. In this review, we discussed how microglia are activated in stressful situations. Furthermore, we described how microglia affect the CNS environment during chronic stress, through the production of cytokines, the induction of reactive oxygen species, and phagocytosis. We suggested that, due to their strategic location as immune cells within the CNS, microglia are important players in the induction of psychopathologies after chronic stress.

Published
2022
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6. [YIA] Myeloid cell derived Interleukin-6 causes vascular dysfunction, inflammation and endothelin-1 expression in mice

Author

Wild, Johannes, Knopp, Tanja, Jung, Rebecca, Efentakis, Panagiotis, Bochenek, Magdalena, Masri, Joumana, Randriamboavonjy, Voahanginirina, Wunderlich, Thomas, Oelze, Matthias, Daiber, Andreas, Bosmann, Markus, Afer, Kathrin Sch, Fleming, Ingrid, Munzel, Thomas, Philip Wenzel, Waisman, Ari, and Karbach, Susanne

Subjects
Physiology (medical), Biochemistry
Published
2022
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7. Evaluating the IgMi mouse as a novel tool to study B‐cell biology

Author

Sahputra, Rinal, Yam‐Puc, Juan Carlos, Waisman, Ari, Muller, Werner, and Else, Kathryn J

Subjects
B-Lymphocytes, T-Lymphocytes, B-Lymphocyte Subsets, Membrane Proteins, Cell Differentiation, Dendritic Cells, Germinal Center, Lymphocyte Activation, Immunoglobulin Class Switching, Antibodies, Mice, Immunoglobulin M, Antibody Formation, Animals, Letter to the Editor
Abstract

The IgMi mouse fails to secrete antibodies or class switch its BCR from IgM. Our study reveals that other cellular compartments, including B‐cell subsets, DC subsets, GC B cells and TFH cells are perturbed in the IgMi mouse, thus presenting important additional considerations when using the mouse to explore the role of secreted antibody.

Published
2018

8. Interleukin-1β promotes atheroprotective changes of advanced atherosclerotic lesions in mice

Author

Gomez, Delphine, Baylis, Richard A., Durgin, Brittany G., Newman, Alexandra A. C., Alencar, Gabriel F., Mahan, Sidney, St. Hilaire, Cynthia, Muller, Werner, Waisman, Ari, Francis, Sheila E., Pinteaux, Emmanuel, Randolph, Gwendalyn J., Gram, Hermann, and Owens, Gary K.

Subjects
Inflammation, Macrophages, Interleukin-1beta, Myocytes, Smooth Muscle, Cell Polarity, Down-Regulation, Apoptosis, Atherosclerosis, Antibodies, Neutralizing, Article, Monocytes, Mice, Inbred C57BL, Phenotype, Neutralization Tests, Animals, Cell Proliferation, Signal Transduction
Abstract

Despite decades of research, our understanding of the processes controlling late-stage atherosclerotic plaque stability remains poor. Although a prevailing hypothesis is that reducing inflammation may improve advanced plaque stability, direct evidence of this is lacking. Therefore, we performed intervention studies on smooth muscle cell (SMC) lineage tracing Apoe−/− mice with advanced atherosclerosis using anti-IL-1β or IgG control antibodies. Surprisingly, we found that IL-1β antibody treatment between 18 and 26 weeks of Western diet feeding induced a marked reduction in SMC and collagen content, but increased macrophage number in the fibrous cap. There was also no change in lesion size and complete inhibition of beneficial outward remodeling. We also found that SMC-specific Il1r1 KO resulted in smaller lesions nearly devoid of SMC and a fibrous cap whereas macrophage-selective loss of IL-1R1 had no effect on lesion size or composition. Taken together, results show that IL-1β promotes multiple beneficial changes in late-stage murine atherosclerosis including promoting outward remodeling and formation and maintenance of a SMC/collagen-rich fibrous cap.

Published
2018

11. SMAC mimetics promote NIK-dependent inhibition of CD4+ TH17 cell differentiation

Author

Rizk, John, Kaplinsky, Joseph, Agerholm, Rasmus, Kadekar, Darshana, Ivars, Fredrik, Agace, William W, Wong, W Wei-Lynn, Szucs, Matthew J, Myers, Samuel A, Carr, Steven A, Waisman, Ari, Bekiaris, Vasileios, University of Zurich, and Bekiaris, Vasileios

Subjects
1307 Cell Biology, 1303 Biochemistry, 1312 Molecular Biology, 570 Life sciences, biology, 610 Medicine & health, Cell Biology, 10263 Institute of Experimental Immunology, Biochemistry, Molecular Biology
Published
2019

12. Interleukin-1 mediates ischaemic brain injury via distinct actions on endothelial cells and cholinergic neurons

Author

Wong, Raymond, Lénárt, Nikolett, Hill, Laura, Toms, Lauren, Martinecz, Bernadett, Császár, Eszter, Nyiri, Gábor, Papaemmanouil, Athina, Waisman, Ari, Muller, Werner, Schwaninger, Markus, Rothwell, Nancy, Francis, Sheila, Pinteaux, Emmanuel, Denes, Adam, and Allan, Stuart

Abstract

The cytokine interleukin-1 (IL-1) is a key contributor to neuroinflammation and brain injury, yet mechanisms by which IL-1 triggers neuronal injury remain unknown. Here we induced conditional deletion of IL-1R1 in brain endothelial cells, neurons and blood cells to assess site-specific IL-1 actions in a model of cerebral ischaemia in mice. Tamoxifen treatment of IL-1R1 floxed (fl/fl) mice crossed with mice expressing tamoxifen-inducible Cre-recombinase under the Slco1c1 promoter resulted in brain endothelium-specific deletion of IL-1R1 and a significant decrease in infarct size (29%), blood-brain barrier (BBB) breakdown (53%) and neurological deficit (40%) compared to vehicle-treated or control (IL-1R1fl/fl) mice. Absence of brain endothelial IL-1 signalling improved cerebral blood flow, followed by reduced neutrophil infiltration and vascular activation 24 h after brain injury. Conditional IL-1R1 deletion in neurons using tamoxifen inducible nestin-Cre mice resulted in reduced neuronal injury (25%) and altered microglia-neuron interactions, without affecting cerebral perfusion or vascular activation. Deletion of IL-1R1 specifically in cholinergic neurons reduced infarct size, brain oedema and improved functional outcome. Ubiquitous deletion of IL-1R1 had no effect on brain injury, suggesting beneficial compensatory mechanisms on other cells against the detrimental effects of IL-1 on endothelial cells and neurons. We also show that IL-1R1 signalling deletion in platelets or myeloid cells does not contribute to brain injury after experimental stroke. Thus, brain endothelial and neuronal (cholinergic) IL-1R1 mediate detrimental actions of IL-1 in the brain in ischaemic stroke. Cell-specific targeting of IL-1R1 in the brain could therefore have therapeutic benefits in stroke and other cerebrovascular diseases.

Published
2018
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13. Inhibition of experimental autoimmune encephalomyelitis by tolerance-promoting DNA vaccination focused to dendritic cells

Author

Castor, Timo, Yogev, Nir, Blank, Thomas, Barwig, Christina, Prinz, Marco, Waisman, Ari, Bros, Matthias, and Reske-Kunz, Angelika B.

Subjects
Encephalomyelitis, Autoimmune, Experimental, Physiology, Molecular biology, Immune Cells, Immunology, 610 Medizin, lcsh:Medicine, DNA construction, DNA vaccination, Transfection, T-Lymphocytes, Regulatory, White Blood Cells, Mice, Animal Cells, immune system diseases, Immune Physiology, 610 Medical sciences, Medicine and Health Sciences, Immune Tolerance, Vaccines, DNA, Animals, lcsh:Science, Preventive medicine, Innate Immune System, Blood Cells, T Cells, lcsh:R, Biology and Life Sciences, hemic and immune systems, Cell Biology, Regulatory T cells, Dendritic Cells, Molecular Development, Biolistics, Flow Cytometry, nervous system diseases, Research and analysis methods, Public and occupational health, Molecular biology techniques, nervous system, Immune System, Plasmid Construction, Cytokines, Vaccination and immunization, lcsh:Q, Cellular Types, Spleen, Research Article, Developmental Biology
Abstract

In this study we analysed the effects of prophylactic biolistic DNA vaccination with plasmids encoding the encephalitogenic protein myelin oligodendrocyte glycoprotein (MOG) on the severity of a subsequently MOGp35-55-induced EAE and on the underlying immune response. We compared the outcome of vaccination with MOG-encoding plasmids alone or in combination with vectors encoding the regulatory cytokines IL-10 and TGF-ß1, respectively. MOG expression was restricted to skin dendritic cells (DCs) by the use of the DC-specific promoter of the fascin1 gene (pFscn-MOG). For comparison, the strong and ubiquitously active CMV promoter was employed (pCMV-MOG), which allows MOG expression in all transfected cells. Expression of IL-10 and TGF-ß1 was controlled by the CMV promoter to yield maximal synthesis (pCMV-IL10, pCMV-TGFß). Co-application of pFscn-MOG and pCMV-IL10 significantly ameliorated EAE pathology, while vaccination with pCMV-MOG plus pCMV-IL10 did not affect EAE outcome. In contrast, vaccination with either of the two MOG-encoding plasmids in combination with pCMV-TGFß significantly attenuated the clinical EAE symptoms. Mechanistically, we observed diminished infiltration of Th17 and Th1 cells as well as macrophages/DCs into the CNS, which correlated with decreased MOGp35-55-specific production of IL-17 and IFN-ϫ by spleen cells and reduced peptide-specific T cell proliferation. Our findings suggest deletion of or anergy induction in MOG-specific CD4+ T cells by the suppressive vaccination platform employed. MOG expression driven by the DC-specific fascin1 promoter yielded similar inhibitory effects on EAE progression as the ubiquitously active viral CMV promoter, when coapplying pCMV-TGFß. Our finding that pCMV-IL10 promoted tolerogenic effects only, when coapplied with pFscn-MOG, but not pCMV-MOG suggests that IL-10 affected only directly transfected DCs (pFscn-MOG), but not neighbouring DCs that engulfed MOG-containing vesicles derived from transfected keratinocytes (pCMV-MOG). Thus, due to its DC-restricted expression, the fascin1 promoter might be an interesting alternative to ubiquitously expressed promoters for vaccination strategies.

Published
2018
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14. Evaluating the IgMi mouse as a novel tool to study B cell biology

Author

Sahputra, Rinal, Yam-Puc, Juan Carlos, Waisman, Ari, Muller, Werner, and Else, Kathryn

Abstract

The current study aims to provide a detailed characterisation of IgMi mice by comparing them to their wild type controls to evaluate the use of the IgMi mouse as a novel tool to study B cell biology.

Published
2018
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15. Alternative NF-?B signaling regulates mTEC differentiation from podoplanin-expressing presursors in the cortico-medullary junction

Author

Onder Lucas, Nindl Veronika, Scandella Elke, Chai Qian, Cheng Hung-Wei, Caviezel-Firner Sonja, Novkovic Mario, Bomze David, Maier Reinhard, Mair Florian, Ledermann Birgit, Becher Burkhard, Waisman Ari, and Ludewig Burkhard

Abstract

The thymic epithelium forms specialized niches to enable thymocyte differentiation. While the common epithelial progenitor of medullary and cortical thymic epithelial cells (mTECs and cTECs) is well defined early stages of mTEC lineage specification have remained elusive. Here we utilized in vivo targeting of mTECs to resolve their differentiation pathways and to determine whether mTEC progenitors participate in thymocyte education. We found that mTECs descend from a lineage committed podoplanin (PDPN) expressing progenitor located at the cortico medullary junction. PDPN(+) junctional TECs (jTECs) represent a distinct TEC population that builds the thymic medulla but only partially supports negative selection and thymocyte differentiation. Moreover conditional gene targeting revealed that abrogation of alternative NF ?B pathway signaling in the jTEC stage completely blocked mTEC development. Taken together this study identifies jTECs as lineage committed mTEC progenitors and shows that NF ?B dependent progression of jTECs to mTECs is critical to secure central tolerance.

Published
2015
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16. Characterization of a conditional interleukin-1 receptor 1 mouse mutant using the Cre/LoxP system

Author

Abdulaal, Wesam, Walker, Catherine, Costello, Ryan, Redondo Castro, Elena, Mufazalov, Ilgiz A, Papaemmanouil, Athina, Rothwell, Nancy J, Allan, Stuart, Waisman, Ari, Pinteaux, Emmanuel, and Müller, Werner

Subjects
IL-17, Immune regulation, Trichuris muris, Cre/loxP, Infection
Abstract

IL-1 is a key cytokine known to drive chronic inflammation and to regulate many physiological, immunological and neuroimmunological responses via actions on diverse cell types of the body. To determine the mechanisms of IL-1 actions as part of the inflammatory response in vivo, we generated a conditional IL-1 receptor 1 (IL-1R1) mouse mutant using the Cre/LoxP system (IL-1R1(fl/fl) ). In the mutant generated, exon 5, which encodes part of the extracellular binding region of the receptor, is flanked by LoxP sites, thereby inactivating the two previously described functional IL-1R1 gene transcripts after Cre-mediated recombination. Using keratin 14-Cre driver mice, new IL-1R1 deficient (-/-) mice were subsequently generated, in which all signaling IL-1 receptor isoforms are deleted ubiquitously. Furthermore, using vav-iCre driver mice, we deleted IL-1 receptor isoforms in the haematopoietic system. In these mice, we show that both the IL-17 and IL-22 cytokine response is reduced, when mice are challenged by the helminth Trichuris muris. We are currently crossing IL-1R1(fl/fl) mice with different Cre-expressing mice in order to study mechanisms of acute and chronic inflammatory diseases. This article is protected by copyright. All rights reserved.

Published
2016
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17. The nuclear receptor PPARγ selectively inhibits Th17 differentiation in a T cell–intrinsic fashion and suppresses CNS autoimmunity

Author

Klotz, Luisa, Burgdorf, Sven, Dani, Indra, Saijo, Kaoru, Flossdorf, Juliane, Hucke, Stephanie, Alferink, Judith, Nowak, Natalija, Nowak, Nina, Beyer, Marc, Mayer, Gunter, Langhans, Birgit, Klockgether, Thomas, Waisman, Ari, Eberl, Gerard, Schultze, Joachim, Famulok, Michael, Kolanus, Waldemar, Glass, Christopher, Kurts, Christian, Knolle, Percy A, Institutes of Molecular Medicine and Experimental Immunology, Universität Bonn = University of Bonn, Department of Neurology, Department of Cellular and Molecular Medicine (CMM), University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), Department of Psychiatry, Institute of Molecular Psychiatry, Life and Medical Sciences Institute for Molecular Immunology, Rheinische Friedrich-Wilhelms-Universität Bonn, Life and Medical Sciences Institute for Genomics and Immunoregulation, Life and Medical Sciences Institute for Chemical Biology, Deparment of Internal Medicine, Department of Internal Medicine, Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Développement des Tissus Lymphoïdes, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of Bonn, University of California-University of California, Johannes Gutenberg - Universität Mainz (JGU), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Nuclear Receptor Subfamily 1, Group F, Member 3, Helper-Inducer, Receptors, Retinoic Acid, T-Lymphocytes, MESH: Interleukin-17, Cellular differentiation, Retinoic Acid, Peroxisome proliferator-activated receptor, Neurodegenerative, Inbred C57BL, Medical and Health Sciences, Mice, Interleukin 21, 0302 clinical medicine, Group F, RAR-related orphan receptor gamma, MESH: Nuclear Receptor Co-Repressor 2, Receptors, 2.1 Biological and endogenous factors, Thyroid Hormone, Immunology and Allergy, MESH: Animals, Aetiology, Encephalomyelitis, Promoter Regions, Genetic, chemistry.chemical_classification, Orphan receptor, 0303 health sciences, Receptors, Thyroid Hormone, Interleukin-17, Cell Differentiation, T-Lymphocytes, Helper-Inducer, Nuclear Receptor Subfamily 1, Group F, Member 3, 3. Good health, Cell biology, DNA-Binding Proteins, medicine.anatomical_structure, MESH: Repressor Proteins, [SDV.IMM]Life Sciences [q-bio]/Immunology, Interleukin 17, MESH: Cell Differentiation, medicine.medical_specialty, Encephalomyelitis, Autoimmune, Experimental, Multiple Sclerosis, Nuclear Receptor Subfamily 1, Member 3, 1.1 Normal biological development and functioning, T cell, Immunology, Biology, Autoimmune Disease, Promoter Regions, Experimental, 03 medical and health sciences, Genetic, Underpinning research, MESH: Mice, Inbred C57BL, Internal medicine, MESH: Promoter Regions, Genetic, Genetics, medicine, Animals, Humans, Nuclear Receptor Co-Repressor 2, MESH: Receptors, Thyroid Hormone, MESH: T-Lymphocytes, Helper-Inducer, MESH: Encephalomyelitis, Autoimmune, Experimental, MESH: Mice, 030304 developmental biology, MESH: Receptors, Retinoic Acid, MESH: Humans, Inflammatory and immune system, Neurosciences, Brief Definitive Report, Correction, MESH: Multiple Sclerosis, Brain Disorders, Mice, Inbred C57BL, PPAR gamma, Repressor Proteins, Endocrinology, MESH: PPAR gamma, Nuclear receptor, chemistry, MESH: DNA-Binding Proteins, 030217 neurology & neurosurgery, Autoimmune
Abstract

T helper cells secreting interleukin (IL)-17 (Th17 cells) play a crucial role in autoimmune diseases like multiple sclerosis (MS). Th17 differentiation, which is induced by a combination of transforming growth factor (TGF)-beta/IL-6 or IL-21, requires expression of the transcription factor retinoic acid receptor-related orphan receptor gamma t (ROR gamma t). We identify the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) as a key negative regulator of human and mouse Th17 differentiation. PPAR gamma activation in CD4(+) T cells selectively suppressed Th17 differentiation, but not differentiation into Th1, Th2, or regulatory T cells. Control of Th17 differentiation by PPAR gamma involved inhibition of TGF-beta/IL-6-induced expression of ROR gamma t in T cells. Pharmacologic activation of PPAR gamma prevented removal of the silencing mediator for retinoid and thyroid hormone receptors corepressor from the ROR gamma t promoter in T cells, thus interfering with ROR gamma t transcription. Both T cell-specific PPAR gamma knockout and endogenous ligand activation revealed the physiological role of PPAR gamma for continuous T cell-intrinsic control of Th17 differentiation and development of autoimmunity. Importantly, human CD4(+) T cells from healthy controls and MS patients were strongly susceptible to PPAR gamma-mediated suppression of Th17 differentiation. In summary, we report a PPAR gamma-mediated T cell-intrinsic molecular mechanism that selectively controls Th17 differentiation in mice and in humans and that is amenable to pharmacologic modulation. We therefore propose that PPAR gamma represents a promising molecular target for specific immunointervention in Th17-mediated autoimmune diseases such as MS.

Published
2009
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18. Generation of a Novel T Cell Specific Interleukin-1 Receptor Type 1 Conditional Knock Out Mouse Reveals Intrinsic Defects in Survival, Expansion and Cytokine Production of CD4 T Cells

Author

Mufazalov, Ilgiz A, Regen, Tommy, Schelmbauer, Carsten, Kuschmann, Janina, Muratova, Alisa M, Nikolaev, Alexei, Muller, Werner, Pinteaux, Emmanuel, and Waisman, Ari

Subjects
CD4-Positive T-Lymphocytes, CD3 Complex, Physiology, Interleukin-1beta, 610 Medizin, lcsh:Medicine, Lymphocyte Activation, Mice, White Blood Cells, T-Lymphocyte Subsets, Animal Cells, 610 Medical sciences, Immune Physiology, Medicine and Health Sciences, Lymphocytes, lcsh:Science, Mice, Knockout, B-Lymphocytes, Innate Immune System, T Cells, Antibodies, Monoclonal, Cell Differentiation, Animal Models, Phenotype, Gene Targeting, Cytokines, Small Intestine, Cellular Types, Anatomy, Signal Transduction, Research Article, Cell Survival, Immune Cells, Immunology, Mice, Transgenic, Mouse Models, Research and Analysis Methods, Immunophenotyping, Model Organisms, Animals, T Helper Cells, Cell Proliferation, Receptors, Interleukin-1 Type I, Blood Cells, lcsh:R, Biology and Life Sciences, Cell Biology, Molecular Development, Gastrointestinal Tract, Immune System, lcsh:Q, Digestive System, Biomarkers, Spleen, Interleukin-1, Developmental Biology
Abstract

Interleukin-1 (IL-1) plays a crucial role in numerous inflammatory diseases via action on its only known signaling IL-1 receptor type 1 (IL-1R1). To investigate the role of IL-1 signaling in selected cell types, we generated a new mouse strain in which exon 5 of the Il1r1 gene is flanked by loxP sites. Crossing of these mice with CD4-Cre transgenic mice resulted in IL-1R1 loss of function specifically in T cells. These mice, termed IL-1R1ΔT, displayed normal development under steady state conditions. Importantly, isolated CD4 positive T cells retained their capacity to differentiate toward Th1 or Th17 cell lineages in vitro, and strongly proliferated in cultures supplemented with either anti-CD3/CD28 or Concanavalin A, but, as predicted, were completely unresponsive to IL-1β administration. Furthermore, IL-1R1ΔT mice were protected from gut inflammation in the anti-CD3 treatment model, due to dramatically reduced frequencies and absolute numbers of IL-17A and interferon (IFN)-γ producing cells. Taken together, our data shows the necessity of intact IL-1 signaling for survival and expansion of CD4 T cells that were developed in an otherwise IL-1 sufficient environment.

Published
2016
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19. Alternative NF-κB signaling regulates mTEC differentiation from podoplanin-expressing presursors in the cortico-medullary junction

Author

Onder, Lucas, Nindl, Veronika, Scandella, Elke, Chai, Qian, Cheng, Hung-Wei, Caviezel-Firner, Sonja, Novkovic, Mario, Bomze, David, Maier, Reinhard, Mair, Florian, Ledermann, Birgit, Becher, Burkhard, Waisman, Ari, Ludewig, Burkhard, University of Zurich, and Ludewig, Burkhard

Subjects
2403 Immunology, 2723 Immunology and Allergy, 570 Life sciences, biology, 610 Medicine & health, 10263 Institute of Experimental Immunology
Published
2015

21. Mature oligodendrocytes actively increase in vivo cytoskeletal plasticity following CNS damage

Author

Locatelli, Giuseppe, Baggiolini, Arianna, Schreiner, Bettina, Palle, Pushpalatha, Waisman, Ari, Becher, Burkhard, Buch, Thorsten, University of Zurich, and Buch, T

Subjects
Cellular and Molecular Neuroscience, 2403 Immunology, Neurology, 2808 Neurology, Immunology, 2804 Cellular and Molecular Neuroscience, 2800 General Neuroscience, 10239 Institute of Laboratory Animal Science, 610 Medicine & health, 10040 Clinic for Neurology
Abstract

BACKGROUND Oligodendrocytes are myelinating cells of the central nervous system which support functionally, structurally, and metabolically neurons. Mature oligodendrocytes are generally believed to be mere targets of destruction in the context of neuroinflammation and tissue damage, but their real degree of in vivo plasticity has become a matter of debate. We thus investigated the in vivo dynamic, actin-related response of these cells under different kinds of demyelinating stress. METHODS We used a novel mouse model (oLucR) expressing luciferase in myelin oligodendrocyte glycoprotein-positive oligodendrocytes under the control of a β-actin promoter. Activity of this promoter served as surrogate for dynamics of the cytoskeleton gene transcription through recording of in vivo bioluminescence following diphtheria toxin-induced oligodendrocyte death and autoimmune demyelination. Cytoskeletal gene expression was quantified from mature oligodendrocytes directly isolated from transgenic animals through cell sorting. RESULTS Experimental demyelinating setups augmented oligodendrocyte-specific in vivo bioluminescence. These changes in luciferase signal were confirmed by further ex vivo analysis of the central nervous system tissue from oLucR mice. Increase in bioluminescence upon autoimmune inflammation was parallel to an oligodendrocyte-specific increased transcription of β-tubulin. CONCLUSIONS Mature oligodendrocytes acutely increase their cytoskeletal plasticity in vivo during demyelination. They are therefore not passive players under demyelinating conditions but can rather react dynamically to external insults.

Published
2015
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22. Non-Redundant Roles for B Cell-Derived IL-10 in Immune Counter-Regulation1

Author

Madan, Rajat, Demircik, Filiz, Surianarayanan, Sangeetha, Allen, Jessica L., Divanovic, Senad, Trompette, Aurelien, Yogev, Nir, Gu, Yuanyuan, Khodoun, Marat, Hildeman, David, Boespflug, Nicholas, Fogolin, Mariela B., Gröbe, Lothar, Greweling, Marina, Finkelman, Fred D., Cardin, Rhonda, Mohrs, Markus, Müller, Werner, Waisman, Ari, Roers, Axel, and Karp, Christopher L.

Subjects
Lipopolysaccharides, Male, Mice, Knockout, Muromegalovirus, Lymphoid Tissue, B-Lymphocyte Subsets, Mice, Transgenic, Herpesviridae Infections, CD8-Positive T-Lymphocytes, Article, Interleukin-10, Mice, Inbred C57BL, Disease Models, Animal, Mice, NIH 3T3 Cells, Animals, Female, Inflammation Mediators
Abstract

IL-10 plays a central role in restraining the vigor of inflammatory responses, but the critical cellular sources of this counter-regulatory cytokine remain speculative in many disease models. Using a novel IL-10 transcriptional reporter mouse, we found an unexpected predominance of B cells (including plasma cells) among IL-10 expressing cells in peripheral lymphoid tissues at baseline and during diverse models of in vivo immunological challenge. Use of a novel B cell-specific IL-10 knockout mouse revealed that B cell-derived IL-10 non-redundantly decreases virus-specific CD8+ T cell responses and plasma cell expansion during murine cytomegalovirus (MCMV4) infection and modestly restrains immune activation after challenge with foreign antibodies to IgD. In contrast, no role for B cell-derived IL-10 was evident during endotoxemia; however, while B cells dominated lymphoid tissue IL-10 production in this model, myeloid cells were dominant in blood and liver. These data suggest that B cells are an under-appreciated source of counter-regulatory IL-10 production in lymphoid tissues, provide a clear rationale for testing the biological role of B cell-derived IL-10 in infectious and inflammatory disease, and underscore the utility of cell type-specific knockouts for mechanistic limning of immune counter-regulation.

Published
2009

24. Cardiac pacemaker function of HCN4 channels in mice is confined to embryonic development and requires cyclic AMP

Author

Harzheim, Dagmar, Pfeiffer, K Holger, Fabritz, Larissa, Kremmer, Elisabeth, Buch, Thorsten, Waisman, Ari, Kirchhof, Paulus, Kaupp, U Benjamin, Seifert, Reinhard, University of Zurich, and Kaupp, U Benjamin

Subjects
General Immunology and Microbiology, 1300 General Biochemistry, Genetics and Molecular Biology, 2400 General Immunology and Microbiology, General Neuroscience, General Biochemistry, 1312 Molecular Biology, 570 Life sciences, biology, 2800 General Neuroscience, 610 Medicine & health, Genetics and Molecular Biology, 10263 Institute of Experimental Immunology, Molecular Biology
Abstract

Important targets for cAMP signalling in the heart are hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels that underlie the depolarizing 'pacemaker' current, If. We studied the role of If in mice, in which binding of cAMP to HCN4 channels was abolished by a single amino-acid exchange (R669Q). Homozygous HCN4(R669Q/R669Q) mice die during embryonic development. Prior to E12, homozygous and heterozygous embryos display reduced heart rates and show no or attenuated responses to catecholaminergic stimulation. Adult heterozygous mice display normal heart rates at rest and during exercise. However, following beta-adrenergic stimulation, hearts exhibit pauses and sino-atrial node block. Our results demonstrate that in the embryo, HCN4 is a true cardiac pacemaker and elevation of HCN4 channel activity by cAMP is essential for viability. In adult mice, an important function of HCN4 channels is to prevent sinus pauses during and after stress while their role as a pacemaker of the murine heart is put into question. Most importantly, our results indicate that HCN4 channels can fulfil their physiological function only when cAMP is bound

Published
2008

25. MHC class II expression through a hitherto unknown pathway supports T helper cell dependent immune responses: implications for MHC class II deficiency

Author

Buch, Thorsten, Polić, Bojan, Clausen, Bjoern E., Weiss, Susanne, Akilli, Ozlem, Chang, Cheong-Hee, Flavell, Richard, Schulz, Ansgar, Jonjić, Stipan, Waisman, Ari, and Foerster, Irmgard

Subjects
chemical and pharmacologic phenomena, respiratory system, Bare Lymphocyte Syndrome, MHC class II, RFX5, CIITA, T helper cells
Abstract

MHC class II (MHCII) deficiency of Bare Lymphocyte Syndrome (BLS) is a severe immunodeficiency characterized by deficient T helper (Th) cell dependent immunity. The disease is caused by defects of the MHCII promoter complex resulting in low or absent MHCII expression. We demonstrate in a murine model of MHCII deficiency (RFX5- or CIITA-deficient mice) that residual MHCII expression by professional APC is sufficient to support activation of adoptively transferred Th cells. Furthermore, upon transplantation of WT thymic epithelium we observed development of endogenous Th cells with restoration of Th cell dependent antibody responses and immunity to cytomegalovirus infection, thus opening the posssibility of an alternative treatment regimen for BLS. Residual MHCII expression was further induced by the presence of Th cells and also other stimuli. Analysis of CIITA/RFX5 double deficient animals revealed that this inducible MHCII expression is genetically independent of the known promoter complex and thus constitutes an alternative MHCII expression pathway. In these experiments, we also detected a novel repressive function of the RFX complex in the absence of CIITA.

Published
2006

26. Efficient B Cell Depletion via Diphtheria Toxin in CD19-Cre/iDTR Mice

Author

Demircik, Filiz, Buch, Thorsten, and Waisman, Ari

Subjects
B Cells, Mouse, Science, Immune Cells, Antigens, CD19, Plasma Cells, Immunology, Toxic Agents, 610 Medizin, Immunoglobulins, Mice, Transgenic, Toxicology, Lymphocyte Depletion, Mice, Model Organisms, Bacterial Proteins, 610 Medical sciences, Animals, Diphtheria Toxin, Lymphocyte Count, Antibody-Producing Cells, Biology, B-Lymphocytes, Integrases, Animal Models, Mice, Inbred C57BL, Luminescent Proteins, Medicine, Intercellular Signaling Peptides and Proteins, Syndecan-1, Heparin-binding EGF-like Growth Factor, Research Article
Abstract

B cells were first discovered as antibody producing cells, as B-1 B cells and finally as effector cells. In recent years their capacity to serve as antigen presenting cells is increasingly appreciated, and better tools are needed to study their function. We have previously described a new mouse model, the iDTR mice, that allow for the Cre-mediated expression of the diphtheria toxin receptor, thus rendering cells that express the Cre-recombinase sensitivity to diphtheria toxin. Herein we describe a new mouse line, the B-DTR mice, where the CD19-Cre was crossed to the iDTR mice. B-DTR allows for the efficient and cost-effective depletion of different B cell subpopulations, but only partially plasma cells. These mice can therefore be used to study the importance of B cells versus plasma cells in different immune responses and autoimmune diseases.

Published
2013

27. Interleukin-1 mediates ischaemic brain injury via distinct actions on endothelial cells and cholinergic neurons

Author

Wong, Raymond, Lénárt, Nikolett, Hill, Laura, Toms, Lauren, Coutts, Graham, Martinecz, Bernadett, Császár, Eszter, Nyiri, Gábor, Papaemmanouil, Athina, Waisman, Ari, Müller, Werner, Schwaninger, Markus, Rothwell, Nancy, Francis, Sheila, Pinteaux, Emmanuel, Denés, Adam, and Allan, Stuart M.

Abstract

The cytokine interleukin-1 (IL-1) is a key contributor to neuroinflammation and brain injury, yet mechanisms by which IL-1 triggers neuronal injury remain unknown. Here we induced conditional deletion of IL-1R1 in brain endothelial cells, neurons and blood cells to assess site-specific IL-1 actions in a model of cerebral ischaemia in mice. Tamoxifen treatment of IL-1R1 floxed (fl/fl) mice crossed with mice expressing tamoxifen-inducible Cre-recombinase under the Slco1c1 promoter resulted in brain endothelium-specific deletion of IL-1R1 and a significant decrease in infarct size (29%), blood-brain barrier (BBB) breakdown (53%) and neurological deficit (40%) compared to vehicle-treated or control (IL-1R1fl/fl) mice. Absence of brain endothelial IL-1 signalling improved cerebral blood flow, followed by reduced neutrophil infiltration and vascular activation 24 h after brain injury. Conditional IL-1R1 deletion in neurons using tamoxifen inducible nestin-Cre mice resulted in reduced neuronal injury (25%) and altered microglia-neuron interactions, without affecting cerebral perfusion or vascular activation. Deletion of IL-1R1 specifically in cholinergic neurons reduced infarct size, brain oedema and improved functional outcome. Ubiquitous deletion of IL-1R1 had no effect on brain injury, suggesting beneficial compensatory mechanisms on other cells against the detrimental effects of IL-1 on endothelial cells and neurons. We also show that IL-1R1 signalling deletion in platelets or myeloid cells does not contribute to brain injury after experimental stroke. Thus, brain endothelial and neuronal (cholinergic) IL-1R1 mediate detrimental actions of IL-1 in the brain in ischaemic stroke. Cell-specific targeting of IL-1R1 in the brain could therefore have therapeutic benefits in stroke and other cerebrovascular diseases.

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28. Interleukin-1 promotes autoimmune neuroinflammation by suppressing endothelial heme oxygenase-1 at the blood–brain barrier

Author

Hauptmann, Judith, Johann, Lisa, Marini, Federico, Kitic, Maja, Colombo, Elisa, Mufazalov, Ilgiz A., Krueger, Martin, Karram, Khalad, Moos, Sonja, Wanke, Florian, Kurschus, Florian C., Klein, Matthias, Cardoso, Silvia, Strauß, Judith, Bolisetty, Subhashini, Lühder, Fred, Schwaninger, Markus, Binder, Harald, Bechman, Ingo, Bopp, Tobias, Agarwal, Anupam, Soares, Miguel P., Regen, Tommy, and Waisman, Ari

Subjects
610 Medical sciences, 610 Medizin, 3. Good health

29. IL-17 controls central nervous system autoimmunity through the intestinal microbiome

Author

Regen, Tommy, Isaac, Sandrine, Amorim, Ana, Núñez, Nicolás Gonzalo, Hauptmann, Judith, Shanmugavadivu, Arthi, Klein, Matthias, Sankowski, Roman, Mufazalov, Ilgiz A, Yogev, Nir, Huppert, Jula, Wanke, Florian, Witting, Michael, Grill, Alexandra, Gálvez, Eric J C, Nikolaev, Alexei, Blanfeld, Michaela, Prinz, Immo, Schmitt-Kopplin, Philippe, Strowig, Till, Reinhardt, Christoph, Prinz, Marco, Bopp, Tobias, Becher, Burkhard, Ubeda, Carles, and Waisman, Ari

Subjects
3. Good health

30. Guidelines for the use of flow cytometry and cell sorting in immunological studies

Author

Cossarizza, Andrea, Chang, Hyun-Dong, Radbruch, Andreas, Akdis, Mübeccel, Andrä, Immanuel, Annunziato, Francesco, Bacher, Petra, Barnaba, Vincenzo, Battistini, Luca, Bauer, Wolfgang M, Baumgart, Sabine, Becher, Burkhard, Beisker, Wolfgang, Berek, Claudia, Blanco, Alfonso, Borsellino, Giovanna, Boulais, Philip E, Brinkman, Ryan R, Büscher, Martin, Busch, Dirk H, Bushnell, Timothy P, Cao, Xuetao, Cavani, Andrea, Chattopadhyay, Pratip K, Cheng, Qingyu, Chow, Sue, Clerici, Mario, Cooke, Anne, Cosma, Antonio, Cosmi, Lorenzo, Cumano, Ana, Dang, Van Duc, Davies, Derek, De Biasi, Sara, Del Zotto, Genny, Della Bella, Silvia, Dellabona, Paolo, Deniz, Günnur, Dessing, Mark, Diefenbach, Andreas, Di Santo, James, Dieli, Francesco, Dolf, Andreas, Donnenberg, Vera S, Dörner, Thomas, Ehrhardt, Götz R A, Endl, Elmar, Engel, Pablo, Engelhardt, Britta, Esser, Charlotte, Everts, Bart, Dreher, Anita, Falk, Christine S, Fehniger, Todd A, Filby, Andrew, Fillatreau, Simon, Follo, Marie, Förster, Irmgard, Foster, John, Foulds, Gemma A, Frenette, Paul S, Galbraith, David, Garbi, Natalio, García-Godoy, Maria Dolores, Geginat, Jens, Ghoreschi, Kamran, Gibellini, Lara, Goettlinger, Christoph, Goodyear, Carl S, Gori, Andrea, Grogan, Jane, Gross, Mor, Grützkau, Andreas, Grummitt, Daryl, Hahn, Jonas, Hammer, Quirin, Hauser, Anja E, Haviland, David L, Hedley, David, Herrera, Guadalupe, Herrmann, Martin, Hiepe, Falk, Holland, Tristan, Hombrink, Pleun, Houston, Jessica P, Hoyer, Bimba F, Huang, Bo, Hunter, Christopher A, Iannone, Anna, Jäck, Hans-Martin, Jávega, Beatriz, Jonjic, Stipan, Juelke, Kerstin, Jung, Steffen, Kaiser, Toralf, Kalina, Tomas, Keller, Baerbel, Khan, Srijit, Kienhöfer, Deborah, Kroneis, Thomas, Kunkel, Désirée, Kurts, Christian, Kvistborg, Pia, Lannigan, Joanne, Lantz, Olivier, Larbi, Anis, LeibundGut-Landmann, Salome, Leipold, Michael D, Levings, Megan K, Litwin, Virginia, Liu, Yanling, Lohoff, Michael, Lombardi, Giovanna, Lopez, Lilly, Lovett-Racke, Amy, Lubberts, Erik, Ludewig, Burkhard, Lugli, Enrico, Maecker, Holden T, Martrus, Glòria, Matarese, Giuseppe, Maueröder, Christian, McGrath, Mairi, McInnes, Iain, Mei, Henrik E, Melchers, Fritz, Melzer, Susanne, Mielenz, Dirk, Mills, Kingston, Mirrer, David, Mjösberg, Jenny, Moore, Jonni, Moran, Barry, Moretta, Alessandro, Moretta, Lorenzo, Mosmann, Tim R, Müller, Susann, Müller, Werner, Münz, Christian, Multhoff, Gabriele, Munoz, Luis Enrique, Murphy, Kenneth M, Nakayama, Toshinori, Nasi, Milena, Neudörfl, Christine, Nolan, John, Nourshargh, Sussan, O'Connor, José-Enrique, Ouyang, Wenjun, Oxenius, Annette, Palankar, Raghav, Panse, Isabel, Peterson, Pärt, Peth, Christian, Petriz, Jordi, Philips, Daisy, Pickl, Winfried, Piconese, Silvia, Pinti, Marcello, Pockley, A Graham, Podolska, Malgorzata Justyna, Pucillo, Carlo, Quataert, Sally A, Radstake, Timothy R D J, Rajwa, Bartek, Rebhahn, Jonathan A, Recktenwald, Diether, Remmerswaal, Ester B M, Rezvani, Katy, Rico, Laura G, Robinson, J Paul, Romagnani, Chiara, Rubartelli, Anna, Ruckert, Beate, Ruland, Jürgen, Sakaguchi, Shimon, Sala-De-Oyanguren, Francisco, Samstag, Yvonne, Sanderson, Sharon, Sawitzki, Birgit, Scheffold, Alexander, Schiemann, Matthias, Schildberg, Frank, Schimisky, Esther, Schmid, Stephan A, Schmitt, Steffen, Schober, Kilian, Schüler, Thomas, Schulz, Axel Ronald, Schumacher, Ton, Scotta, Cristiano, Shankey, T Vincent, Shemer, Anat, Simon, Anna-Katharina, Spidlen, Josef, Stall, Alan M, Stark, Regina, Stehle, Christina, Stein, Merle, Steinmetz, Tobit, Stockinger, Hannes, Takahama, Yousuke, Tarnok, Attila, Tian, ZhiGang, Toldi, Gergely, Tornack, Julia, Traggiai, Elisabetta, Trotter, Joe, Ulrich, Henning, Van Der Braber, Marlous, Van Lier, René A W, Veldhoen, Marc, Vento-Asturias, Salvador, Vieira, Paulo, Voehringer, David, Volk, Hans-Dieter, Von Volkmann, Konrad, Waisman, Ari, Walker, Rachael, Ward, Michael D, Warnatz, Klaus, Warth, Sarah, Watson, James V, Watzl, Carsten, Wegener, Leonie, Wiedemann, Annika, Wienands, Jürgen, Willimsky, Gerald, Wing, James, Wurst, Peter, Yu, Liping, Yue, Alice, Zhang, Qianjun, Zhao, Yi, Ziegler, Susanne, and Zimmermann, Jakob

Subjects
610 Medicine & health, 3. Good health

31. Psoriasis and Vascular Dysfunction in Mice and Patients

Author

Karbach, Susanne H., Croxford, Andrew, Oelze, Mathias, Minwegen, Daniel, Wegner-Kops, Joanna, Koukes, Lija, Ullmann, Alexander, Muxel, Selina, Yogev, Nir, Li, Huige, Wild, Philipp, Gori, Tommaso, Daiber, Andreas, Stebut, Esther, Wenzel, Philip, Waisman, Ari, and Thomas Muenzel

35. Skin Sodium Accumulates in Psoriasis and Reflects Disease Severity

Author

Marcus Kelm, Andreas Krause, Peter Linz, Vladimir-Andrey Gimenez-Rivera, Florian C. Kurschus, Joanna Wegner, András Maifeld, Elisa Wistorf, Lajos Markó, Dominik N. Müller, Theda Bartolomaeus, Anna Brand, Ralf Dechend, Susanne Karbach, Georgios Kokolakis, Nicola Wilck, Johannes Wild, Natalia Rakova, Ari Waisman, Tine V. Karlsen, Markus Kleinewietfeld, Sandra Philipp, Michael Boschmann, Anna Birukov, Helge Wiig, Björn E. Clausen, Sofia K. Forslund, Michael Schultheis, Titus Kuehne, Friedrich C. Luft, Rebecca Jung, Wild, Johannes/0000-0002-1446-8101, Wilck, Nicola/0000-0003-3189-5364, Birukov, Anna/0000-0002-8306-3351, Karlsen, Tine, Veronica/0000-0002-1512-2479, Gimenez RIvera, Vladimir, Andrey/0000-0001-5055-208X, Maifeld, Andras, Wild, Johannes, Karlsen, Tine, V, Rakova, Natalia, Wistorf, Elisa, Linz, Peter, Jung , Rebecca, Birukov, Anna, Gimenez-Rivera, Vladimir-Andrey, Wilck, Nicola, Bartolomaeus, Theda, Dechend, Ralf, KLEINEWIETFELD, Markus, Forslund, Sofia K., Krause, Andreas, Kokolakis, Georgios, Philipp, Sandra, Clausen, Bjoern E., Brand , Anna, Waisman, Ari, Kurschus, Florian C., Wegner, Joanna, Schultheis, Michael, Luft, Friedrich C., Boschmann, Michael, Kelm, Marcus, Wiig, Helge, Kuehne, Titus, Muller, Dominik N., Karbach, Susanne, and Marko, Lajos

Subjects
Male, medicine.medical_specialty, Sodium, chemistry.chemical_element, Inflammation, Imiquimod, Dermatology, Sodium Chloride, Lymphocyte Activation, Severity of Illness Index, Biochemistry, Article, Mice, Internal medicine, Psoriasis, medicine, Extracellular, Animals, Humans, T helper 17 cell, Molecular Biology, Cells, Cultured, Skin, integumentary system, business.industry, Spectrophotometry, Atomic, Spectrum Analysis, Interleukin-17, Cell Differentiation, Cell Biology, medicine.disease, Pathophysiology, Mice, Inbred C57BL, Endocrinology, chemistry, Cardiovascular and Metabolic Diseases, Th17 Cells, medicine.symptom, business, Intracellular, medicine.drug
Abstract

Sodium can accumulate in the skin at concentrations exceeding serum levels. A high sodium environment can lead to pathogenic T helper 17 cell expansion. Psoriasis is a chronic inflammatory skin disease in which IL-17. producing T helper 17 cells play a crucial role. In an observational study, we measured skin sodium content in patients with psoriasis and in age-matched healthy controls by Sodium-23 magnetic resonance imaging. Patients with PASI > 5 showed significantly higher sodium and water content in the skin but not in other tissues than those with lower PASI or healthy controls. Skin sodium concentrations measured by Sodium-23 spectroscopy or by atomic absorption spectrometry in ashed-skin biopsies verified the findings with Sodium-23 magnetic resonance imaging. In vitro T helper 17 cell differentiation of naive CD4(+) cells from patients with psoriasis markedly induced IL-17A expression under increased sodium chloride concentrations. The imiquimod-induced psoriasis mouse model replicated the human findings. Extracellular tracer Chromium-51-EDTA measurements in imiquimod- and sham-treated skin showed similar extracellular volumes, rendering excessive water of intracellular origin. Chronic genetic IL-17A-driven psoriasis mouse models underlined the role of IL-17A in dermal sodium accumulation and inflammation. Our data describe skin sodium as a pathophysiological feature of psoriasis, which could open new avenues for its treatment.

Published
2022
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36. Innate and adaptive immune responses in the CNS

Author

Roland S. Liblau, Burkhard Becher, Ari Waisman, University of Zurich, and Waisman, Ari

Subjects
Central Nervous System, Innate immunology, Autoimmunity, Inflammation, Context (language use), 610 Medicine & health, Adaptive Immunity, Biology, medicine.disease_cause, 10263 Institute of Experimental Immunology, 03 medical and health sciences, 0302 clinical medicine, Immune system, Central Nervous System Diseases, Response to injury, Immunity, medicine, Animals, Humans, 030304 developmental biology, 0303 health sciences, Immunity, Innate, 2728 Neurology (clinical), Immunology, 570 Life sciences, biology, Neurology (clinical), medicine.symptom, Neuroscience, 030217 neurology & neurosurgery, Homeostasis
Abstract

Almost every disorder of the CNS is said to have an inflammatory component, but the precise nature of inflammation in the CNS is often imprecisely defined, and the role of CNS-resident cells is uncertain compared with that of cells that invade the tissue from the systemic immune compartment. To understand inflammation in the CNS, the term must be better defined, and the response of tissue to disturbances in homoeostasis (eg, neurodegenerative processes) should be distinguished from disorders in which aberrant immune responses lead to CNS dysfunction and tissue destruction (eg, autoimmunity). Whether the inflammatory tissue response to injury is reparative or degenerative seems to be dependent on context and timing, as are the windows of opportunity for therapeutic intervention in inflammatory CNS diseases.

Published
2015
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37. Homeostasis of Microglia in the Adult Brain: Review of Novel Microglia Depletion Systems

Author

Melanie Greter, Julia Bruttger, Florent Ginhoux, Ari Waisman, University of Zurich, and Waisman, Ari

Subjects
Neuroimmunomodulation, Cellular differentiation, Mesenchyme, Immunology, Central nervous system, Embryonic Development, Inflammation, 610 Medicine & health, Biology, Blood–brain barrier, 10263 Institute of Experimental Immunology, medicine, Immunology and Allergy, Animals, Homeostasis, Humans, Neuroinflammation, 2403 Immunology, Microglia, Macrophages, Brain, Cell Differentiation, Embryonic stem cell, Disease Models, Animal, medicine.anatomical_structure, Models, Animal, 2723 Immunology and Allergy, 570 Life sciences, biology, medicine.symptom
Abstract

Microglia are brain macrophages that emerge from early erythro-myeloid precursors in the embryonic yolk sac and migrate to the brain mesenchyme before the blood brain barrier is formed. They seed the brain, and proliferate until they have formed a grid-like distribution in the central nervous system that is maintained throughout lifespan. The mechanisms through which these embryonic-derived cells contribute to microglia homoeostasis at steady state and upon inflammation are still not entirely clear. Here we review recent studies that provided insight into the contribution of embryonically-derived microglia and of adult 'microglia-like' cells derived from monocytes during inflammation. We examine different microglia depletion models, and discuss the origin of their rapid repopulation after depletion and outline important areas of future research.

Published
2015

38. Guidelines for the use of flow cytometry and cell sorting in immunological studies

Author

Guadalupe Herrera, Jens Geginat, Daryl Grummitt, Vincenzo Barnaba, Joanne Lannigan, Beate Rückert, Elisabetta Traggiai, Christian Münz, Susanne Melzer, Ari Waisman, Pratip K. Chattopadhyay, Jonas Hahn, T. Vincent Shankey, S Schmid, Julia Tornack, David W. Hedley, Paolo Dellabona, Jürgen Wienands, Ana Cumano, Ester B. M. Remmerswaal, Christopher A. Hunter, Van Duc Dang, Anis Larbi, Timothy P. Bushnell, Mor Gross, Wenjun Ouyang, Vera S. Donnenberg, Lilly Lopez, Holden T. Maecker, Jenny Mjösberg, Christina Stehle, Yanling Liu, Alan M. Stall, Anja E. Hauser, Yousuke Takahama, Mark C. Dessing, Gergely Toldi, Klaus Warnatz, Raghav Palankar, Sussan Nourshargh, Enrico Lugli, Bimba F. Hoyer, Pleun Hombrink, Bartek Rajwa, Sarah Warth, Isabel Panse, Rachael C. Walker, Silvia Piconese, Andrew Filby, Pärt Peterson, Kilian Schober, Silvia Della Bella, Leonie Wegener, Merle Stein, Anne Cooke, Alessandro Moretta, Deborah Kienhöfer, Andrea Cossarizza, Hyun-Dong Chang, Konrad von Volkmann, Jessica P. Houston, Mübeccel Akdis, Andreas Grützkau, Tristan Holland, Jakob Zimmermann, Jonni S. Moore, Dirk Mielenz, Iain B. McInnes, Bo Huang, Paulo Vieira, Thomas Kroneis, Tobit Steinmetz, Kerstin Juelke, Sharon Sanderson, James V. Watson, Srijit Khan, Sally A. Quataert, Winfried F. Pickl, Annika Wiedemann, Sara De Biasi, Andreas Radbruch, James B. Wing, Susann Müller, Ton N. Schumacher, Katy Rezvani, Gloria Martrus, Alexander Scheffold, Toralf Kaiser, Carlo Pucillo, Lara Gibellini, Anna Rubartelli, Qingyu Cheng, Luca Battistini, David Mirrer, David W. Galbraith, Giovanna Borsellino, Ryan R. Brinkman, Tim R. Mosmann, Laura G. Rico, Anita Dreher, Désirée Kunkel, Francesco Annunziato, Pia Kvistborg, Andrea Gori, Chiara Romagnani, Anat Shemer, Toshinori Nakayama, Francisco Sala-de-Oyanguren, Attila Tárnok, Alfonso Blanco, Anna Iannone, Giuseppe Matarese, Thomas Dörner, Virginia Litwin, Michael Lohoff, Petra Bacher, Jordi Petriz, Lorenzo Moretta, Götz R. A. Ehrhardt, Qianjun Zhang, Andrea Cavani, Barry Moran, Christian Maueröder, Immanuel Andrä, Dirk H. Busch, Joe Trotter, Timothy R D J Radstake, Stipan Jonjić, Fritz Melchers, Hans-Martin Jäck, Beatriz Jávega, Gerald Willimsky, Martin Büscher, Henrik E. Mei, Christine S. Falk, Zhigang Tian, Martin Herrmann, Alice Yue, Steffen Jung, Bart Everts, Frank A. Schildberg, John Bellamy Foster, Giovanna Lombardi, Milena Nasi, John P. Nolan, Todd A. Fehniger, Francesco Dieli, Steffen Schmitt, Andreas Dolf, A. Graham Pockley, Claudia Berek, Josef Spidlen, Megan K. Levings, Werner Müller, Baerbel Keller, René A. W. van Lier, Daisy Philips, Susanne Ziegler, Christian Kurts, Malgorzata J. Podolska, Jürgen Ruland, David Voehringer, Kenneth M. Murphy, Marlous van der Braber, Maria Dolores García-Godoy, Sabine Baumgart, Yi Zhao, Antonio Cosma, Falk Hiepe, Charlotte Esser, Pablo Engel, Marcello Veldhoen, Irmgard Förster, Amy E. Lovett-Racke, Günnur Deniz, Burkhard Ludewig, Esther Schimisky, Cristiano Scottà, Marcello Pinti, Jonathan Rebhahn, Regina Stark, Mario Clerici, Liping Yu, Shimon Sakaguchi, Derek Davies, Anna Katharina Simon, Lorenzo Cosmi, Gabriele Multhoff, Kamran Ghoreschi, Quirin Hammer, Henning Ulrich, J. Paul Robinson, Yvonne Samstag, Olivier Lantz, Hannes Stockinger, Xuetao Cao, Simon Fillatreau, David L. Haviland, Natalio Garbi, C. Neudörfl, Kingston H. G. Mills, Salvador Vento-Asturias, Christian Peth, Philip E. Boulais, Diether J. Recktenwald, Burkhard Becher, Tomas Kalina, Michael D. Leipold, Christoph Goettlinger, Gemma A. Foulds, Jane L. Grogan, Axel R. Schulz, James P. Di Santo, Matthias Schiemann, Michael D. Ward, Britta Engelhardt, Birgit Sawitzki, Annette Oxenius, Carl S. Goodyear, Salomé LeibundGut-Landmann, Wolfgang Beisker, Sue Chow, Carsten Watzl, Marie Follo, Erik Lubberts, Peter Wurst, Thomas Schüler, Andreas Diefenbach, Wolfgang Bauer, Hans-Dieter Volk, Luis E. Muñoz, Elmar Endl, Genny Del Zotto, José-Enrique O'Connor, Mairi McGrath, Paul S. Frenette, Dipartimento di Scienze Biomediche, Università degli Studi di Modena e Reggio Emilia (UNIMORE), Cell Biology, Klinik für Dermatologie, Venerologie und Allergologie, Department of Internal Medicine, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI)-DENOTHE Center, Neuroimmunology Unit, Santa Lucia Foundation (IRCCS), Inorganic Chemistry II, Universität Bayreuth, Caprotec Bioanalytics GmbH, International Occultation Timing Association European Section (IOTA ES), International Occultation Timing Association European Section, Institut der Leibniz-Gemeinschaft, Berlin, Fondazione Santa Lucia (IRCCS), Terry Fox Laboratory, BC Cancer Agency (BCCRC)-British Columbia Cancer Agency Research Centre, Department of Immunology, Chinese Academy of Medical Sciences, Fondazione Don Carlo Gnocchi, Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Experimental Immunology Unit, Dept. of Oncology, DIBIT San Raffaele Scientific Institute, Département d'Immunologie - Department of Immunology, Institut Pasteur [Paris], Charité Hospital, Humboldt-Universität zu Berlin, Universitat de Barcelona (UB), Rheumatologie, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Department of Histology and Embryology, University of Rijeka, Weizmann Institute of Science [Rehovot, Israël], Régulation des Infections Rétrovirales, Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), Institute of Virology [Zürich], College of Food Science and Technology [Shangai], Shanghai Ocean University, Institute for Medical Microbiology and Hygiene, University of Marburg, Centre for Transplantation, King's College London (MRC), Guy's Hospital [London], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Institute, Heinrich Pette Institute [Hamburg], Institute of Translational Medicine, Department of Medicine Huddinge, Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm]-Lipid Laboratory, Università di Genova, Dipartimento di Medicina Sperimentale, Department of Environmental Microbiology, Helmholtz Zentrum für Umweltforschung = Helmholtz Centre for Environmental Research (UFZ), Experimental Immunology, Helmholtz Centre for Infection Research (HZI), Viral Immunobiology, Universität Zürich [Zürich] = University of Zurich (UZH)-Institute of Experimental Immunology [Zurich], Department of Radiation Oncology [Munich], Ludwig-Maximilians-Universität München (LMU), Department of Mathematics and Statistics, American University, William Harvey Research Institute, Barts and the London Medical School, Cytometry Laboratories and School of Veterinary Medicine, Purdue University [West Lafayette], Osaka University [Osaka], FACS and Array Core Facility, Johannes Gutenberg - Universität Mainz (JGU), Institute for Cognitive Science, University of Osnabrueck, Department of Molecular Immunology, Medizinische Universität Wien = Medical University of Vienna, Universität Leipzig [Leipzig], Institute of Immunology, School of Life Sciences-University of Science & Technology of China [Suzhou], Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Immunology, Processus de Transfert et d'Echanges dans l'Environnement - EA 3819 (PROTEE), Université de Toulon (UTLN), Heinrich-Pette-Institut, Leibniz Institute for Experimental Virology, Enrico Lugli and Pratip K. Chattopadhyay were supported by grants from the Fondazione Cariplo (Grant Ricerca Biomedica 2012/0683), the Italian Ministry of Health (Bando Giovani Ricercatori GR-2011-02347324) and the European Union Marie Curie Career Integration Grant 322093 (all to E.L.). E.L. and P.K.C. are International Society for the Advancement of Cytometry (ISAC) Marylou Ingram scholars. Alice Yue and Ryan R. Brinkman were funded by Genome BC and NSERC. Klaus Warnatz received funding from the German Federal Ministry of Education and Research (BMBF 01EO1303) and the Deutsche Forschungsgemeinschaft (DECIDE, DFG WA 1597/4-1 and the TRR130). The Jung laboratory is supported by funds of the ERC and ISF. Henrik Mei is a 2017-2021 ISAC scholar. Antonio Cosma is supported by the French government program: 'Investissement d'avenir: Equipements d'Excellence' (EQUIPEX)-2010 FlowCyTech, Grant number: ANR-10-EQPX-02-01. Henrik Mei is supported by the Deutsche Forschungsgemeinschaft (DFG, grants Me3644/5-1 and TRR130/TP24)., Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), Università degli Studi di Firenze = University of Florence (UniFI)-DENOTHE Center, Institut Pasteur [Paris] (IP), Humboldt University Of Berlin, Universität Bonn = University of Bonn, Università degli studi di Genova = University of Genoa (UniGe), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Universität Leipzig, Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Obstetrics & Gynecology, Rheumatology, Pediatrics, Landsteiner Laboratory, Other departments, AII - Inflammatory diseases, Università di Modena e Reggio Emilia, DENOTHE Center-University of Florence, Santa Lucia Foundation ( IRCCS ), International Occultation Timing Association European Section ( IOTA ES ), Fondazione Santa Lucia ( IRCCS ), BC Cancer Agency ( BCCRC ) -British Columbia Cancer Agency Research Centre, Fondazione don Carlo Gnocchi, Fondazione IRCCS, Immunologie des Maladies Virales et Autoimmunes ( IMVA - U1184 ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Département d'Immunologie, Humboldt Universität zu Berlin, Universitat de Barcelona ( UB ), Charité, Weizmann Institute of Science, Université de Bonn, Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Singapore Immunology Network ( SIgN ), Agency for Science Technology and Research, College of Food Science and Technology, Centre for Transplantation, King's College London ( MRC ), Erasmus MC University Medical Center, Helmholtz Centre for Environmental Research ( UFZ ), Helmholtz Centre for Infection Research ( HZI ), University of Zürich [Zürich] ( UZH ) -Institute of Experimental Immunology [Zurich], Ludwig-Maximilians-Universität München, Johannes Gutenberg - Universität Mainz ( JGU ), Medical University of Vienna, Lymphopoïèse, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Johannes Gutenberg - University of Mainz ( JGU ), Processus de Transfert et d'Echanges dans l'Environnement - EA 3819 ( PROTEE ), Université de Toulon ( UTLN ), Universita degli studi di Genova, Cossarizza, Andrea, Chang, Hyun-Dong, Radbruch, Andrea, Akdis, Mübeccel, Andrä, Immanuel, Annunziato, Francesco, Bacher, Petra, Barnaba, Vincenzo, Battistini, Luca, Bauer, Wolfgang M., Baumgart, Sabine, Becher, Burkhard, Beisker, Wolfgang, Berek, Claudia, Blanco, Alfonso, Borsellino, Giovanna, Boulais, Philip E., Brinkman, Ryan R., Büscher, Martin, Busch, Dirk H., Bushnell, Timothy P., Cao, Xuetao, Cavani, Andrea, Chattopadhyay, Pratip K., Cheng, Qingyu, Chow, Sue, Clerici, Mario, Cooke, Anne, Cosma, Antonio, Cosmi, Lorenzo, Cumano, Ana, Dang, Van Duc, Davies, Derek, De Biasi, Sara, Del Zotto, Genny, Della Bella, Silvia, Dellabona, Paolo, Deniz, Günnur, Dessing, Mark, Diefenbach, Andrea, Di Santo, Jame, Dieli, Francesco, Dolf, Andrea, Donnenberg, Vera S., Dörner, Thoma, Ehrhardt, Götz R. A., Endl, Elmar, Engel, Pablo, Engelhardt, Britta, Esser, Charlotte, Everts, Bart, Dreher, Anita, Falk, Christine S., Fehniger, Todd A., Filby, Andrew, Fillatreau, Simon, Follo, Marie, Förster, Irmgard, Foster, John, Foulds, Gemma A., Frenette, Paul S., Galbraith, David, Garbi, Natalio, García-Godoy, Maria Dolore, Geginat, Jen, Ghoreschi, Kamran, Gibellini, Lara, Goettlinger, Christoph, Goodyear, Carl S., Gori, Andrea, Grogan, Jane, Gross, Mor, Grützkau, Andrea, Grummitt, Daryl, Hahn, Jona, Hammer, Quirin, Hauser, Anja E., Haviland, David L., Hedley, David, Herrera, Guadalupe, Herrmann, Martin, Hiepe, Falk, Holland, Tristan, Hombrink, Pleun, Houston, Jessica P., Hoyer, Bimba F., Huang, Bo, Hunter, Christopher A., Iannone, Anna, Jäck, Hans-Martin, Jávega, Beatriz, Jonjic, Stipan, Juelke, Kerstin, Jung, Steffen, Kaiser, Toralf, Kalina, Toma, Keller, Baerbel, Khan, Srijit, Kienhöfer, Deborah, Kroneis, Thoma, Kunkel, Désirée, Kurts, Christian, Kvistborg, Pia, Lannigan, Joanne, Lantz, Olivier, Larbi, Ani, LeibundGut-Landmann, Salome, Leipold, Michael D., Levings, Megan K., Litwin, Virginia, Liu, Yanling, Lohoff, Michael, Lombardi, Giovanna, Lopez, Lilly, Lovett-Racke, Amy, Lubberts, Erik, Ludewig, Burkhard, Lugli, Enrico, Maecker, Holden T., Martrus, Glòria, Matarese, Giuseppe, Maueröder, Christian, Mcgrath, Mairi, Mcinnes, Iain, Mei, Henrik E., Melchers, Fritz, Melzer, Susanne, Mielenz, Dirk, Mills, Kingston, Mirrer, David, Mjösberg, Jenny, Moore, Jonni, Moran, Barry, Moretta, Alessandro, Moretta, Lorenzo, Mosmann, Tim R., Müller, Susann, Müller, Werner, Münz, Christian, Multhoff, Gabriele, Munoz, Luis Enrique, Murphy, Kenneth M., Nakayama, Toshinori, Nasi, Milena, Neudörfl, Christine, Nolan, John, Nourshargh, Sussan, O'Connor, José-Enrique, Ouyang, Wenjun, Oxenius, Annette, Palankar, Raghav, Panse, Isabel, Peterson, Pärt, Peth, Christian, Petriz, Jordi, Philips, Daisy, Pickl, Winfried, Piconese, Silvia, Pinti, Marcello, Pockley, A. Graham, Podolska, Malgorzata Justyna, Pucillo, Carlo, Quataert, Sally A., Radstake, Timothy R. D. J., Rajwa, Bartek, Rebhahn, Jonathan A., Recktenwald, Diether, Remmerswaal, Ester B. M., Rezvani, Katy, Rico, Laura G., Robinson, J. Paul, Romagnani, Chiara, Rubartelli, Anna, Ruckert, Beate, Ruland, Jürgen, Sakaguchi, Shimon, Sala-de-Oyanguren, Francisco, Samstag, Yvonne, Sanderson, Sharon, Sawitzki, Birgit, Scheffold, Alexander, Schiemann, Matthia, Schildberg, Frank, Schimisky, Esther, Schmid, Stephan A., Schmitt, Steffen, Schober, Kilian, Schüler, Thoma, Schulz, Axel Ronald, Schumacher, Ton, Scotta, Cristiano, Shankey, T. Vincent, Shemer, Anat, Simon, Anna-Katharina, Spidlen, Josef, Stall, Alan M., Stark, Regina, Stehle, Christina, Stein, Merle, Steinmetz, Tobit, Stockinger, Hanne, Takahama, Yousuke, Tarnok, Attila, Tian, Zhigang, Toldi, Gergely, Tornack, Julia, Traggiai, Elisabetta, Trotter, Joe, Ulrich, Henning, van der Braber, Marlou, van Lier, René A. W., Veldhoen, Marcello, Vento-Asturias, Salvador, Vieira, Paulo, Voehringer, David, Volk, Hans-Dieter, von Volkmann, Konrad, Waisman, Ari, Walker, Rachael, Ward, Michael D., Warnatz, Klau, Warth, Sarah, Watson, James V., Watzl, Carsten, Wegener, Leonie, Wiedemann, Annika, Wienands, Jürgen, Willimsky, Gerald, Wing, Jame, Wurst, Peter, Yu, Liping, Yue, Alice, Zhang, Qianjun, Zhao, Yi, Ziegler, Susanne, Zimmermann, Jakob, Cossarizza, A., Chang, H., Radbruch, A., Akdis, M., Andrã¤, I., Annunziato, F., Bacher, P., Barnaba, V., Battistini, L., Bauer, W., Baumgart, S., Becher, B., Beisker, W., Berek, C., Blanco, A., Borsellino, G., Boulais, P., Brinkman, R., Bã¼scher, M., Busch, D., Bushnell, T., Cao, X., Cavani, A., Chattopadhyay, P., Cheng, Q., Chow, S., Clerici, M., Cooke, A., Cosma, A., Cosmi, L., Cumano, A., Dang, V., Davies, D., De Biasi, S., Del Zotto, G., Della Bella, S., Dellabona, P., Deniz, G., Dessing, M., Diefenbach, A., Di Santo, J., Dieli, F., Dolf, A., Donnenberg, V., Dã¶rner, T., Ehrhardt, G., Endl, E., Engel, P., Engelhardt, B., Esser, C., Everts, B., Dreher, A., Falk, C., Fehniger, T., Filby, A., Fillatreau, S., Follo, M., Fã¶rster, I., Foster, J., Foulds, G., Frenette, P., Galbraith, D., Garbi, N., García-Godoy, M., Geginat, J., Ghoreschi, K., Gibellini, L., Goettlinger, C., Goodyear, C., Gori, A., Grogan, J., Gross, M., Grã¼tzkau, A., Grummitt, D., Hahn, J., Hammer, Q., Hauser, A., Haviland, D., Hedley, D., Herrera, G., Herrmann, M., Hiepe, F., Holland, T., Hombrink, P., Houston, J., Hoyer, B., Huang, B., Hunter, C., Iannone, A., Jã¤ck, H., Jã¡vega, B., Jonjic, S., Juelke, K., Jung, S., Kaiser, T., Kalina, T., Keller, B., Khan, S., Kienhã¶fer, D., Kroneis, T., Kunkel, D., Kurts, C., Kvistborg, P., Lannigan, J., Lantz, O., Larbi, A., LeibundGut-Landmann, S., Leipold, M., Levings, M., Litwin, V., Liu, Y., Lohoff, M., Lombardi, G., Lopez, L., Lovett-Racke, A., Lubberts, E., Ludewig, B., Lugli, E., Maecker, H., Martrus, G., Matarese, G., Mauerã¶der, C., Mcgrath, M., Mcinnes, I., Mei, H., Melchers, F., Melzer, S., Mielenz, D., Mills, K., Mirrer, D., Mjã¶sberg, J., Moore, J., Moran, B., Moretta, A., Moretta, L., Mosmann, T., Mã¼ller, S., Mã¼ller, W., Mã¼nz, C., Multhoff, G., Munoz, L., Murphy, K., Nakayama, T., Nasi, M., Neudã¶rfl, C., Nolan, J., Nourshargh, S., O'Connor, J., Ouyang, W., Oxenius, A., Palankar, R., Panse, I., Peterson, P., Peth, C., Petriz, J., Philips, D., Pickl, W., Piconese, S., Pinti, M., Pockley, A., Podolska, M., Pucillo, C., Quataert, S., Radstake, T., Rajwa, B., Rebhahn, J., Recktenwald, D., Remmerswaal, E., Rezvani, K., Rico, L., Robinson, J., Romagnani, C., Rubartelli, A., Ruckert, B., Ruland, J., Sakaguchi, S., Sala-de-Oyanguren, F., Samstag, Y., Sanderson, S., Sawitzki, B., Scheffold, A., Schiemann, M., Schildberg, F., Schimisky, E., Schmid, S., Schmitt, S., Schober, K., Schã¼ler, T., Schulz, A., Schumacher, T., Scotta, C., Shankey, T., Shemer, A., Simon, A., Spidlen, J., Stall, A., Stark, R., Stehle, C., Stein, M., Steinmetz, T., Stockinger, H., Takahama, Y., Tarnok, A., Tian, Z., Toldi, G., Tornack, J., Traggiai, E., Trotter, J., Ulrich, H., van der Braber, M., van Lier, R., Veldhoen, M., Vento-Asturias, S., Vieira, P., Voehringer, D., Volk, H., von Volkmann, K., Waisman, A., Walker, R., Ward, M., Warnatz, K., Warth, S., Watson, J., Watzl, C., Wegener, L., Wiedemann, A., Wienands, J., Willimsky, G., Wing, J., Wurst, P., Liping, Y., Yue, A., Zhang, Q., Zhao, Y., Ziegler, S., and Zimmermann, J.

Subjects
0301 basic medicine, T-Lymphocytes, Cell Separation, T cell precursors, 0302 clinical medicine, Immunophenotyping, Human lymphopoiesis, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, Non-U.S. Gov't, Immunologic Technique, medicine.diagnostic_test, Research Support, Non-U.S. Gov't, virus diseases, hemic and immune systems, False Positive Reaction, Cell sorting, Flow Cytometry, natural killer and innate lymphoid cells differentiation, 3. Good health, Research Design, [SDV.IMM]Life Sciences [q-bio]/Immunology, Human, Quality Control, medicine.drug_class, Immunology, Animals, Cell Proliferation, DNA, False Positive Reactions, Humans, RNA, Software, Guidelines as Topic, Immunologic Techniques, chemical and pharmacologic phenomena, Computational biology, Biology, Monoclonal antibody, Research Support, Article, Flow cytometry, N.I.H, 03 medical and health sciences, Immune system, Research Support, N.I.H., Extramural, medicine, early lymphoid progenitors, Journal Article, Mass cytometry, IMUNOLOGIA, Animal, Extramural, B cell ontogeny, 030104 developmental biology, T-Lymphocyte, Cytometry, 030215 immunology
Abstract

The marriage between immunology and cytometry is one of the most stable and productive in the recent history of science. A rapid search in PubMed shows that, as of July 2017, using “flow cytometry immunology” as a search term yields more than 68 000 articles, the first of which, interestingly, is not about lymphocytes. It might be stated that, after a short engagement, the exchange of the wedding rings between immunology and cytometry officially occurred when the idea to link fluorochromes to monoclonal antibodies came about. After this, recognizing different types of cells became relatively easy and feasible not only by using a simple fluorescence microscope, but also by a complex and sometimes esoteric instrument, the flow cytometer that is able to count hundreds of cells in a single second, and can provide repetitive results in a tireless manner. Given this, the possibility to analyse immune phenotypes in a variety of clinical conditions has changed the use of the flow cytometer, which was incidentally invented in the late 1960s to measure cellular DNA by using intercalating dyes, such as ethidium bromide. The epidemics of HIV/AIDS in the 1980s then gave a dramatic impulse to the technology of counting specific cells, since it became clear that the quantification of the number of peripheral blood CD4+ T cells was crucial to follow the course of the infection, and eventually for monitoring the therapy. As a consequence, the development of flow cytometers that had to be easy-to-use in all clinical laboratories helped to widely disseminate this technology. Nowadays, it is rare to find an immunological paper or read a conference abstract in which the authors did not use flow cytometry as the main tool to dissect the immune system and identify its fine and complex functions. Of note, recent developments have created the sophisticated technology of mass cytometry, which is able to simultaneously identify dozens of molecules at the single cell level and allows us to better understand the complexity and beauty of the immune system.

Published
2017
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39. T-helper cells: methods and protocols / Preface

Author

Burkhard Becher, Waisman, A., University of Zurich, Becher, Burkhard, and Waisman, Ari

Subjects
1311 Genetics, 1312 Molecular Biology, 570 Life sciences, biology, 610 Medicine & health, 10263 Institute of Experimental Immunology
Published
2014
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40. Isolation of Leukocytes from Mouse Central Nervous System

Author

Melanie Greter, Iva Lelios, University of Zurich, Waisman, Ari, and Becher, Burkhard

Subjects
Isolation (health care), medicine.diagnostic_test, Central nervous system, 610 Medicine & health, Inflammation, Biology, 10263 Institute of Experimental Immunology, Cell biology, Flow cytometry, medicine.anatomical_structure, Immune system, 1311 Genetics, 1312 Molecular Biology, medicine, 570 Life sciences, biology, medicine.symptom
Abstract

During neuroinflammatory or neurodegenerative diseases, it is often critical to characterize the composition of infiltrating immune cells. This protocol describes a reliable, fast, and simple method for the isolation of leukocytes from murine central nervous system (CNS) during steady state or inflammation for analysis by flow cytometry or other techniques.

Published
2014
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41. Tolerance without clonal expansion: self-antigen-expressing B cells program self-reactive T cells for future deletion

Author

Thorsten Buch, Ari Waisman, F. Thomas Wunderlich, Tobias J. A. J. Heinen, Werner Müller, Nir Yogev, Axel Roers, Friederike Frommer, Stephen M. Anderton, Estelle Bettelli, University of Zurich, and Waisman, Ari

Subjects
T-Lymphocytes, Programmed Cell Death 1 Receptor, Autoimmunity, Antigens, CD/biosynthesis, Antigens, CD5/genetics, Autoantigens, Interleukin 21, Mice, Immunology and Allergy, Cytotoxic T cell, Homeostasis, CTLA-4 Antigen, IL-2 receptor, Antigens, Differentiation/biosynthesis, B-Lymphocytes, Antigens, CD/genetics, B-Lymphocytes/immunology, T-Lymphocytes/metabolism, Natural killer T cell, Cell biology, medicine.anatomical_structure, Homeostasis/immunology, 2723 Immunology and Allergy, Antigens, CD5/biosynthesis, Antigens, Differentiation/genetics, Antigens, CD5/immunology, T cell, Immunology, Antigens, CD/immunology, Clonal Deletion, 610 Medicine & health, chemical and pharmacologic phenomena, Mice, Transgenic, Biology, Autoantigens/biosynthesis, CD5 Antigens, Autoimmunity/physiology, Autoantigens/immunology, Antigens, CD, medicine, Animals, B-Lymphocytes/metabolism, Antigen-presenting cell, Cell Proliferation, 2403 Immunology, Antigens, Differentiation/immunology, Gene Expression Regulation/immunology, CD40, Clonal Deletion/physiology, T-Lymphocytes/immunology, Antigens, Differentiation, 10040 Clinic for Neurology, B-1 cell, Gene Expression Regulation, biology.protein
Abstract

B cells have been shown in various animal models to induce immunological tolerance leading to reduced immune responses and protection from autoimmunity. We show that interaction of B cells with naive T cells results in T cell triggering accompanied by the expression of negative costimulatory molecules such as PD-1, CTLA-4, B and T lymphocyte attenuator, and CD5. Following interaction with B cells, T cells were not induced to proliferate, in a process that was dependent on their expression of PD-1 and CTLA-4, but not CD5. In contrast, the T cells became sensitive to Ag-induced cell death. Our results demonstrate that B cells participate in the homeostasis of the immune system by ablation of conventional self-reactive T cells.

42. IL-17 controls central nervous system autoimmunity through the intestinal microbiome

Author

Ana Amorim, Immo Prinz, Alexandra Grill, Jula Huppert, Philippe Schmitt-Kopplin, Tobias Bopp, Ari Waisman, Sandrine Isaac, Till Strowig, Michael Witting, Marco Prinz, Arthi Shanmugavadivu, Ilgiz A. Mufazalov, Nir Yogev, Judith Hauptmann, Michaela Blanfeld, Matthias Klein, Florian Wanke, Christoph Reinhardt, Roman Sankowski, Alexei Nikolaev, Eric J. C. Gálvez, Nicolás Gonzalo Núñez, Burkhard Becher, Carles Ubeda, Tommy Regen, University of Zurich, and Waisman, Ari

Subjects
0301 basic medicine, Central Nervous System, Male, Encephalomyelitis, Autoimmune, Experimental, Multiple Sclerosis, receptor, Immunology, Central nervous system, 610 Medicine & health, Gut flora, 10263 Institute of Experimental Immunology, medicine.disease_cause, Autoimmunity, interleukin-17, 03 medical and health sciences, Mice, 0302 clinical medicine, medicine, cytokine, Animals, Humans, cns, t-cells, Mice, Knockout, 2403 Immunology, biology, gut microbiota, Multiple sclerosis, Experimental autoimmune encephalomyelitis, General Medicine, Fecal Microbiota Transplantation, neutralization, medicine.disease, biology.organism_classification, Adoptive Transfer, 3. Good health, Gut Epithelium, Gastrointestinal Microbiome, 030104 developmental biology, Neuroimmunology, medicine.anatomical_structure, 2723 Immunology and Allergy, 570 Life sciences, Th17 Cells, sequences, Female, Interleukin 17, 030217 neurology & neurosurgery
Abstract

Interleukin-17A- (IL-17A) and IL-17F-producing CD4(+) T helper cells (T(H)17 cells) are implicated in the development of chronic inflammatory diseases, such as multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). T-H 17 cells also orchestrate leukocyte invasion of the central nervous system (CNS) and subsequent tissue damage. However, the role of IL-17A and IL-17F as effector cytokines is still confused with the encephalitogenic function of the cells that produce these cytokines, namely, T-H 17 cells, fueling a long-standing debate in the neuroimmunology field. Here, we demonstrated that mice deficient for IL-17A/F lose their susceptibility to EAE, which correlated with an altered composition of their gut microbiota. However, loss of IL-17A/F in T-H cells did not diminish their encephalitogenic capacity. Reconstitution of a wild-type-like intestinal microbiota or reintroduction of IL-17A specifically into the gut epithelium of IL-17A/F-deficient mice reestablished their susceptibility to EAE. Thus, our data demonstrated that IL-17A and IL-17F are not encephalitogenic mediators but rather modulators of intestinal homeostasis that indirectly alter CNS-directed autoimmunity.

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