ORCID Profile
0000-0002-1541-7867
Current Organisations
University of Zurich
,
Universität Zürich
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Publisher: Wiley
Date: 10-2017
Publisher: Rockefeller University Press
Date: 08-2011
DOI: 10.1084/JEM.20110128
Abstract: The canonical NF-κB pathway is a driving force for virtually all aspects of inflammation. Conversely, the role of the noncanonical NF-κB pathway and its central mediator NF-κB–inducing kinase (NIK) remains poorly defined. NIK has been proposed to be involved in the formation of TH17 cells, and its absence in TH cells renders them incapable of inducing autoimmune responses, suggesting a T cell–intrinsic role for NIK. Upon systematic analysis of NIK function in cell-mediated immunity, we found that NIK signaling is dispensable within CD4+ T cells but played a pivotal role in dendritic cells (DCs). We discovered that NIK signaling is required in DCs to deliver co-stimulatory signals to CD4+ T cells and that DC-restricted expression of NIK is sufficient to restore TH1 and TH17 responses as well as cell-mediated immunity in NIK−/− mice. When CD4+ T cells developed in the absence of NIK-sufficient DCs, they were rendered anergic. Reintroduction of NIK into DCs allowed developing NIK−/− CD4+ T cells to become functional effector populations and restored the development of autoimmune disease. Therefore, our data suggest that a population of thymic DCs requires NIK to shape the formation of most αβ CD4+ T effector lineages during early development.
Publisher: Rockefeller University Press
Date: 07-11-2016
DOI: 10.1084/JEM.20160897
Abstract: Narcolepsy type 1 is a devastating neurological sleep disorder resulting from the destruction of orexin-producing neurons in the central nervous system (CNS). Despite its striking association with the HLA-DQB1*06:02 allele, the autoimmune etiology of narcolepsy has remained largely hypothetical. Here, we compared peripheral mononucleated cells from narcolepsy patients with HLA-DQB1*06:02-matched healthy controls using high-dimensional mass cytometry in combination with algorithm-guided data analysis. Narcolepsy patients displayed multifaceted immune activation in CD4+ and CD8+ T cells dominated by elevated levels of B cell–supporting cytokines. Additionally, T cells from narcolepsy patients showed increased production of the proinflammatory cytokines IL-2 and TNF. Although it remains to be established whether these changes are primary to an autoimmune process in narcolepsy or secondary to orexin deficiency, these findings are indicative of inflammatory processes in the pathogenesis of this enigmatic disease.
Publisher: American Chemical Society (ACS)
Date: 03-10-2023
Publisher: Springer Science and Business Media LLC
Date: 02-07-2018
DOI: 10.1038/S41591-018-0094-7
Abstract: In the version of this article initially published, Figs. 5a,c and 6a were incorrect because of an error in a metadata spreadsheet that led to the healthy donor patient 2 (HD2) s les being used twice in the analysis of baseline s les and in the analysis at 12 weeks of anti-PD-1 therapy, while HD3 s les had not been used.
Publisher: Springer Science and Business Media LLC
Date: 08-01-2018
DOI: 10.1038/NM.4466
Abstract: Immune-checkpoint blockade has revolutionized cancer therapy. In particular, inhibition of programmed cell death protein 1 (PD-1) has been found to be effective for the treatment of metastatic melanoma and other cancers. Despite a dramatic increase in progression-free survival, a large proportion of patients do not show durable responses. Therefore, predictive biomarkers of a clinical response are urgently needed. Here we used high-dimensional single-cell mass cytometry and a bioinformatics pipeline for the in-depth characterization of the immune cell subsets in the peripheral blood of patients with stage IV melanoma before and after 12 weeks of anti-PD-1 immunotherapy. During therapy, we observed a clear response to immunotherapy in the T cell compartment. However, before commencing therapy, a strong predictor of progression-free and overall survival in response to anti-PD-1 immunotherapy was the frequency of CD14
Publisher: F1000 Research Ltd
Date: 14-11-2017
DOI: 10.12688/F1000RESEARCH.11622.2
Abstract: High dimensional mass and flow cytometry (HDCyto) experiments have become a method of choice for high throughput interrogation and characterization of cell populations.Here, we present an R-based pipeline for differential analyses of HDCyto data, largely based on Bioconductor packages. We computationally define cell populations using FlowSOM clustering, and facilitate an optional but reproducible strategy for manual merging of algorithm-generated clusters. Our workflow offers different analysis paths, including association of cell type abundance with a phenotype or changes in signaling markers within specific subpopulations, or differential analyses of aggregated signals. Importantly, the differential analyses we show are based on regression frameworks where the HDCyto data is the response thus, we are able to model arbitrary experimental designs, such as those with batch effects, paired designs and so on. In particular, we apply generalized linear mixed models to analyses of cell population abundance or cell-population-specific analyses of signaling markers, allowing overdispersion in cell count or aggregated signals across s les to be appropriately modeled. To support the formal statistical analyses, we encourage exploratory data analysis at every step, including quality control (e.g. multi-dimensional scaling plots), reporting of clustering results (dimensionality reduction, heatmaps with dendrograms) and differential analyses (e.g. plots of aggregated signals).
Publisher: Springer Science and Business Media LLC
Date: 23-06-2020
Publisher: Springer Science and Business Media LLC
Date: 12-10-2014
DOI: 10.1038/NI.3006
Abstract: Advances in cell-fate mapping have revealed the complexity in phenotype, ontogeny and tissue distribution of the mammalian myeloid system. To capture this phenotypic ersity, we developed a 38-antibody panel for mass cytometry and used dimensionality reduction with machine learning-aided cluster analysis to build a composite of murine (mouse) myeloid cells in the steady state across lymphoid and nonlymphoid tissues. In addition to identifying all previously described myeloid populations, higher-order analysis allowed objective delineation of otherwise ambiguous subsets, including monocyte-macrophage intermediates and an array of granulocyte variants. Using mice that cannot sense granulocyte macrophage-colony stimulating factor GM-CSF (Csf2rb(-/-)), which have discrete alterations in myeloid development, we confirmed differences in barrier tissue dendritic cells, lung macrophages and eosinophils. The methodology further identified variations in the monocyte and innate lymphoid cell compartment that were unexpected, which confirmed that this approach is a powerful tool for unambiguous and unbiased characterization of the myeloid system.
Publisher: Society for Neuroscience
Date: 04-02-2020
DOI: 10.1523/JNEUROSCI.2268-19.2020
Abstract: The interaction between the immune system and the nervous system has been at the center of multiple research studies in recent years. Whereas the role played by cytokines as neuronal mediators is no longer contested, the mechanisms by which cytokines modulate pain processing remain to be elucidated. In this study, we have analyzed the involvement of granulocyte-macrophage colony stimulating factor (GM-CSF) in nociceptor activation in male and female mice. Previous studies have suggested GM-CSF might directly activate neurons. However, here we established the absence of a functional GM-CSF receptor in murine nociceptors, and suggest an indirect mechanism of action, via immune cells. We report that GM-CSF applied directly to magnetically purified nociceptors does not induce any transcriptional changes in nociceptive genes. In contrast, conditioned medium from GM-CSF-treated murine macrophages was able to drive nociceptor transcription. We also found that conditioned medium from nociceptors treated with the well established pain mediator, nerve growth factor, could also modify macrophage gene transcription, providing further evidence for a bidirectional crosstalk. SIGNIFICANCE STATEMENT The interaction of the immune system and the nervous system is known to play an important role in the development and maintenance of chronic pain disorders. Elucidating the mechanisms of these interactions is an important step toward understanding, and therefore treating, chronic pain disorders. This study provides evidence for a two-way crosstalk between macrophages and nociceptors in the peripheral nervous system, which may contribute to the sensitization of nociceptors by cytokines in pain development.
Publisher: Elsevier BV
Date: 04-2010
Abstract: A fundamental tenet of immunology is that adaptive immune responses are initiated in secondary lymphoid tissues. This dogma has been challenged by several recent reports. We discuss how successful T cell-mediated immunity can be initiated outside of such dedicated structures, whereas they are required for adaptive humoral immunity. This resembles an ancient immune pathway in the oldest cold-blooded vertebrates, which lack lymph nodes and sophisticated B-cell responses including optimal affinity maturation. The T-cell, however, has retained the capacity to recognize antigen in a lymph node-free environment. Besides bone marrow and lung, the liver is one organ that can potentially serve as a surrogate lymphoid organ and could represent a remnant from the time before lymph nodes developed.
Publisher: Research Square Platform LLC
Date: 10-07-2023
DOI: 10.21203/RS.3.RS-3062506/V1
Abstract: Immune checkpoint inhibitors (ICIs) are standard-of-care for the treatment of advanced melanoma, but their use is limited by immune-related adverse events (irAEs). Proteomic analysis and multiplex cytokine/chemokine assay from serum at baseline and at irAEs onset in 82 patients indicated aberrant T-cell activity with differential expression of Type I and III immune signatures. This was in line with an increase in the proportions of monocytes and decrease of IL-17A producing CD4+ T-cells in the peripheral blood in single cell RNA sequencing. Multiplex immunohistochemistry and spatial transcriptomics on ICI-induced skin rash and colitis showed increase in the proportion of CD4+ T-cells with IL-17A expression. Anti-IL17A mAbs were administered in two patients with myocarditis, colitis and skin rash with resolution of the irAE. This study demonstrates the potential role of Type III CD4+ T-cells in the irAEs development and provides proof-of-principle evidence to support a clinical trial examining anti-IL17A in their management.
Publisher: Oxford University Press (OUP)
Date: 23-04-2010
Publisher: Proceedings of the National Academy of Sciences
Date: 12-12-2017
Abstract: How autoreactive CD4 + T cells recognize their target antigen and induce sustained inflammation in organ-specific autoimmune diseases is incompletely understood. In an experimental model of multiple sclerosis, we show that accumulation of myelin-specific CD4 + T cells within the CNS and subsequent clinical disease development requires autophagy protein (ATG)-dependent phagocytosis in dendritic cells (DCs). Absence of ATG-dependent phagocytosis in DCs abrogates myelin presentation to CD4 + T cells following phagocytosis of oligodendroglial cells, and its pharmacological inhibition delays the onset and reduces the clinical severity of experimental autoimmune encephalomyelitis. Thus, DCs use ATG-dependent phagocytosis for enhanced presentation of myelin antigen during autoimmune CNS inflammation, thereby linking oligodendrocyte injury with antigen processing and autoimmune T cell pathogenicity.
Publisher: Public Library of Science (PLoS)
Date: 26-05-2009
Publisher: Oxford University Press (OUP)
Date: 31-01-2011
Publisher: Wiley
Date: 10-2019
Abstract: These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring ex les of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer‐reviewed by leading experts in the field, making this an essential research companion.
Publisher: Proceedings of the National Academy of Sciences
Date: 28-12-2020
Abstract: Infection/inflammation is a major contributor to male infertility, and macrophages are likely to be key players in both pathological progression and resolution of the inflammation. We report that macrophage populations in the epididymis and testis are derived from fetal and neonatal monocytes, which are self-maintaining during adulthood. Furthermore, during inflammation, circulating monocytes recruited to the epididymis and testis give rise to inflammatory macrophages that promote tissue damage. These data are significant for our understanding of the origins and maintenance of macrophage subpopulations in both organs our results point to a fundamental mechanism underpinning male infertility by infection and inflammation, and pave the way for the development of innovative therapeutics to treat this important and common condition.
Publisher: Public Library of Science (PLoS)
Date: 30-05-2019
Publisher: Springer Science and Business Media LLC
Date: 03-04-2020
DOI: 10.1038/S41467-020-15497-1
Abstract: Oncogenic Ras mutations occur in various leukemias. It was unclear if, besides the direct transforming effect via constant RAS/MEK/ERK signaling, an inflammation-related effect of KRAS contributes to the disease. Here, we identify a functional link between oncogenic Kras G12D and NLRP3 inflammasome activation in murine and human cells. Mice expressing active Kras G12D in the hematopoietic system developed myeloproliferation and cytopenia, which is reversed in Kras G12D mice lacking NLRP3 in the hematopoietic system. Therapeutic IL-1-receptor blockade or NLRP3-inhibition reduces myeloproliferation and improves hematopoiesis. Mechanistically, Kras G12D -RAC1 activation induces reactive oxygen species (ROS) production causing NLRP3 inflammasome-activation. In agreement with our observations in mice, patient-derived myeloid leukemia cells exhibit KRAS/RAC1/ROS/NLRP3/IL-1β axis activity. Our findings indicate that oncogenic KRAS not only act via its canonical oncogenic driver function, but also enhances the activation of the pro-inflammatory RAC1/ROS/NLRP3/IL-1β axis. This paves the way for a therapeutic approach based on immune modulation via NLRP3 blockade in KRAS-mutant myeloid malignancies.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2010
DOI: 10.1161/ATVBAHA.109.201079
Abstract: Objective— Enhanced endothelial permeability leading to intimal accumulation of low-density lipoproteins (LDL) stimulates the formation of atherosclerotic lesions. Histamine is known to increase vascular permeability. Whether this affects the formation of atherosclerotic lesions, however, remains elusive. Methods and Results— Apolipoprotein E–null ( ApoE −/− ) mice treated with a histamine H1 receptor but not an H2 receptor antagonist developed 40% fewer atherosclerotic lesions in the aorta than placebo-treated controls. Similarly, genetic deletion of the H1 but not the H2 receptor resulted in a 60% reduction of lesions compared with ApoE −/− controls. The H1 receptor enhanced LDL permeability and lipid accumulation in the aorta, whereas plasma lipoprotein levels remained unaltered. In contrast, the H1 receptor did not affect proliferation and migration of vascular smooth muscle cells. Bone marrow transplantation confirmed that the formation of atherosclerotic lesions depended on the H1 receptor in vascular cells, whereas its presence in bone marrow-derived cells was irrelevant for plaque development. Mice expressing the H1 receptor exhibited higher levels of the chemokine (C-C motif) ligand 5 and higher numbers of macrophages and T-helper lymphocytes in plaques, higher numbers of circulating lymphocytes, and larger spleens. Conclusion— These data indicate that H1 but not H2 receptor activation drives the formation of atherosclerotic lesions through an increased vascular permeability for LDL, which is associated with an enhanced secondary aortic and systemic inflammation. These data open novel perspectives for the prevention and treatment of atherosclerotic vascular disease.
Location: United States of America
No related grants have been discovered for Burkhard Becher.