Publications by authors named "Christian Kurts"

173 Publications

Survival Factors and Metabolic Pathogenesis in Elderly Patients (≥65) With COVID-19: A Multi-Center Study.

Front Med (Lausanne) 2020 7;7:595503. Epub 2021 Jan 7.

Institute of Experimental Immunology, University Clinic of Rheinische Friedrich-Wilhelms-University, Bonn, Germany.

Elderly patients infected with COVID-19 are reported to be facing a substantially increased risk of mortality. Clinical characteristics, treatment options, and potential survival factors remain under investigation. This study aimed to fill this gap and provide clinically relevant factors associated with survival of elderly patients with COVID-19. In this multi-center study, elderly patients (age ≥65 years old) with laboratory-confirmed COVID-19 from 4 Wuhan hospitals were included. The clinical end point was hospital discharge or deceased with last date of follow-up on Jul. 08, 2020. Clinical, demographic, and laboratory data were collected. Univariate and multivariate analysis were performed to analyze survival and risk factors. A metabolic flux analysis using a large-scale molecular model was applied to investigate the pathogenesis of SARS-CoV-2 with regard to metabolism pathways. A total of 223 elderly patients infected with COVID-19 were included, 91 (40.8%) were discharged and 132 (59.2%) deceased. Acute respiratory distress syndrome (ARDS) developed in 140 (62.8%) patients, 23 (25.3%) of these patients survived. Multivariate analysis showed that potential risk factors for mortality were elevated D-Dimer (odds ratio: 1.13 [95% CI 1.04 - 1.22], = 0.005), high immune-related metabolic index (6.42 [95% CI 2.66-15.48], < 0.001), and increased neutrophil-to-lymphocyte ratio (1.08 [95% 1.03-1.13], < 0.001). Elderly patients receiving interferon atmotherapy showed an increased probability of survival (0.29 [95% CI 0.17-0.51], < 0.001). Based on these factors, an algorithm (AlgSurv) was developed to predict survival for elderly patients. The metabolic flux analysis showed that 12 metabolic pathways including phenylalanine (odds ratio: 28.27 [95% CI 10.56-75.72], < 0.001), fatty acid (15.61 [95% CI 6.66-36.6], < 0.001), and pyruvate (12.86 [95% CI 5.85-28.28], < 0.001) showed a consistently lower flux in the survivors vs. the deceased subgroup. This may reflect a key pathogenic mechanism of COVID-19 infection. Several factors such as interferon atmotherapy and recreased activity of specific metabolic pathways were found to be associated with survival of elderly patients. Based on these findings, a survival algorithm (AlgSurv) was developed to assist the clinical stratification for elderly patients. Dysregulation of the metabolic pathways revealed in this study may aid in the drug and vaccine development against COVID-19.
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http://dx.doi.org/10.3389/fmed.2020.595503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873923PMC
January 2021

Vascular pathologies in chronic kidney disease: pathophysiological mechanisms and novel therapeutic approaches.

J Mol Med (Berl) 2021 Mar 22;99(3):335-348. Epub 2021 Jan 22.

Heart Center, Department of Medicine II, University Hospital Bonn, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.

Cardiovascular disease (CVD) is a major cause of death in patients with chronic kidney disease (CKD). Both conditions are rising in incidence as well as prevalence, creating poor outcomes for patients and high healthcare costs. Recent data suggests CKD to be an independent risk factor for CVD. Accumulation of uremic toxins, chronic inflammation, and oxidative stress have been identified to act as CKD-specific alterations that increase cardiovascular risk. The association between CKD and cardiovascular mortality is markedly influenced through vascular alterations, in particular atherosclerosis and vascular calcification (VC). While numerous risk factors promote atherosclerosis by inducing endothelial dysfunction and its progress to vascular structural damage, CKD affects the medial layer of blood vessels primarily through VC. Ongoing research has identified VC to be a multifactorial, cell-mediated process in which numerous abnormalities like mineral dysregulation and especially hyperphosphatemia induce a phenotype switch of vascular smooth muscle cells to osteoblast-like cells. A combination of pro-calcifying stimuli and an impairment of inhibiting mechanisms like fetuin A and vitamin K-dependent proteins like matrix Gla protein and Gla-rich protein leads to mineralization of the extracellular matrix. In view of recent studies, intercellular communication pathways via extracellular vesicles and microRNAs represent key mechanisms in VC and thereby a promising field to a deeper understanding of the involved pathomechanisms. In this review, we provide an overview about pathophysiological mechanisms connecting CKD and CVD. Special emphasis is laid on vascular alterations and more recently discovered molecular pathways which present possible new therapeutic targets.
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http://dx.doi.org/10.1007/s00109-021-02037-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900031PMC
March 2021

CX3CR1 is a prerequisite for the development of cardiac hypertrophy and left ventricular dysfunction in mice upon transverse aortic constriction.

PLoS One 2021 7;16(1):e0243788. Epub 2021 Jan 7.

Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Bonn, Germany.

The CX3CL1/CX3CR1 axis mediates recruitment and extravasation of CX3CR1-expressing subsets of leukocytes and plays a pivotal role in the inflammation-driven pathology of cardiovascular disease. The cardiac immune response differs depending on the underlying causes. This suggests that for the development of successful immunomodulatory therapy in heart failure due to chronic pressure overload induced left ventricular (LV) hypertrophy, the underlying immune patterns must be examined. Here, the authors demonstrate that Fraktalkine-receptor CX3CR1 is a prerequisite for the development of cardiac hypertrophy and left ventricular dysfunction in a mouse model of transverse aortic constriction (TAC). The comparison of C57BL/6 mice with CX3CR1 deficient mice displayed reduced LV hypertrophy and preserved cardiac function in response to pressure overload in mice lacking CX3CR1. Moreover, the normal immune response following TAC induced pressure overload which is dominated by Ly6Clow macrophages changed to an early pro-inflammatory immune response driven by neutrophils, Ly6Chigh macrophages and altered cytokine expression pattern in CX3CR1 deficient mice. In this early inflammatory phase of LV hypertrophy Ly6Chigh monocytes infiltrated the heart in response to a C-C chemokine ligand 2 burst. CX3CR1 expression impacts the immune response in the development of LV hypertrophy and its absence has clear cardioprotective effects. Hence, suppression of CX3CR1 may be an important immunomodulatory therapeutic target to ameliorate pressure-overload induced heart failure.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243788PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790399PMC
January 2021

Development and validation of prognostic model for predicting mortality of COVID-19 patients in Wuhan, China.

Sci Rep 2020 12 31;10(1):22451. Epub 2020 Dec 31.

Institute of Experimental Immunology, University Clinic of Rheinische Friedrich-Wilhelms-University, Bonn, Germany.

Novel coronavirus 2019 (COVID-19) infection is a global public health issue, that has now affected more than 200 countries worldwide and caused a second wave of pandemic. Severe adult respiratory syndrome-CoV-2 (SARS-CoV-2) pneumonia is associated with a high risk of mortality. However, prognostic factors predicting poor clinical outcomes of individual patients with SARS-CoV-2 pneumonia remain under intensive investigation. We conducted a retrospective, multicenter study of patients with SARS-CoV-2 who were admitted to four hospitals in Wuhan, China from December 2019 to February 2020. Mortality at the end of the follow up period was the primary outcome. Factors predicting mortality were also assessed and a prognostic model was developed, calibrated and validated. The study included 492 patients with SARS-CoV-2 who were divided into three cohorts: the training cohort (n = 237), the validation cohort 1 (n = 120), and the validation cohort 2 (n = 135). Multivariate analysis showed that five clinical parameters were predictive of mortality at the end of follow up period, including advanced age [odds ratio (OR), 1.1/years increase (p < 0.001)], increased neutrophil-to-lymphocyte ratio [(NLR) OR, 1.14/increase (p < 0.001)], elevated body temperature on admission [OR, 1.53/°C increase (p = 0.005)], increased aspartate transaminase [OR, 2.47 (p = 0.019)], and decreased total protein [OR, 1.69 (p = 0.018)]. Furthermore, the prognostic model drawn from the training cohort was validated with validation cohorts 1 and 2 with comparable area under curves (AUC) at 0.912, 0.928, and 0.883, respectively. While individual survival probabilities were assessed, the model yielded a Harrell's C index of 0.758 for the training cohort, 0.762 for the validation cohort 1, and 0.711 for the validation cohort 2, which were comparable among each other. A validated prognostic model was developed to assist in determining the clinical prognosis for SARS-CoV-2 pneumonia. Using this established model, individual patients categorized in the high risk group were associated with an increased risk of mortality, whereas patients predicted to be in the low risk group had a higher probability of survival.
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http://dx.doi.org/10.1038/s41598-020-78870-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775455PMC
December 2020

CD8 T-Lymphocyte-Driven Limbic Encephalitis Results in Temporal Lobe Epilepsy.

Ann Neurol 2021 Apr 15;89(4):666-685. Epub 2021 Jan 15.

Section for Translational Epilepsy Research, Department of Neuropathology, University Hospital Bonn, Bonn, Germany.

Objective: Limbic encephalitis (LE) comprises a spectrum of inflammatory changes in affected brain structures including the presence of autoantibodies and lymphoid cells. However, the potential of distinct lymphocyte subsets alone to elicit key clinicopathological sequelae of LE potentially inducing temporal lobe epilepsy (TLE) with chronic spontaneous seizures and hippocampal sclerosis (HS) is unresolved.

Methods: Here, we scrutinized pathogenic consequences emerging from CD8 T cells targeting hippocampal neurons by recombinant adeno-associated virus-mediated expression of the model-autoantigen ovalbumin (OVA) in CA1 neurons of OT-I/RAG1 mice (termed "OVA-CD8 LE model").

Results: Viral-mediated antigen transfer caused dense CD8 T cell infiltrates confined to the hippocampal formation starting on day 5 after virus transduction. Flow cytometry indicated priming of CD8 T cells in brain-draining lymph nodes preceding hippocampal invasion. At the acute model stage, the inflammatory process was accompanied by frequent seizure activity and impairment of hippocampal memory skills. Magnetic resonance imaging scans at day 7 of the OVA-CD8 LE model revealed hippocampal edema and blood-brain barrier disruption that converted into atrophy until day 40. CD8 T cells specifically targeted OVA-expressing, SIINFEKL-H-2K -positive CA1 neurons and caused segmental apoptotic neurodegeneration, astrogliosis, and microglial activation. At the chronic model stage, mice exhibited spontaneous recurrent seizures and persisting memory deficits, and the sclerotic hippocampus was populated with CD8 T cells escorted by NK cells.

Interpretation: These data indicate that a CD8 T-cell-initiated attack of distinct hippocampal neurons is sufficient to induce LE converting into TLE-HS. Intriguingly, the role of CD8 T cells exceeds neurotoxic effects and points to their major pathogenic role in TLE following LE. ANN NEUROL 2021;89:666-685.
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http://dx.doi.org/10.1002/ana.26000DOI Listing
April 2021

Pathogen-induced tissue-resident memory T17 (T17) cells amplify autoimmune kidney disease.

Sci Immunol 2020 08;5(50)

Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Although it is well established that microbial infections predispose to autoimmune diseases, the underlying mechanisms remain poorly understood. After infection, tissue-resident memory T (T) cells persist in peripheral organs and provide immune protection against reinfection. However, whether T cells participate in responses unrelated to the primary infection, such as autoimmune inflammation, is unknown. By using high-dimensional single-cell analysis, we identified CD4 T cells with a T17 signature (termed T17 cells) in kidneys of patients with ANCA-associated glomerulonephritis. Experimental models demonstrated that renal T17 cells were induced by pathogens infecting the kidney, such as , , and uropathogenic , and persisted after the clearance of infections. Upon induction of experimental glomerulonephritis, these kidney T17 cells rapidly responded to local proinflammatory cytokines by producing IL-17A and thereby exacerbate renal pathology. Thus, our data show that pathogen-induced T17 cells have a previously unrecognized function in aggravating autoimmune disease.
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http://dx.doi.org/10.1126/sciimmunol.aba4163DOI Listing
August 2020

NCX1 represents an ionic Na+ sensing mechanism in macrophages.

PLoS Biol 2020 06 22;18(6):e3000722. Epub 2020 Jun 22.

Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg, Regensburg, Germany.

Inflammation and infection can trigger local tissue Na+ accumulation. This Na+-rich environment boosts proinflammatory activation of monocyte/macrophage-like cells (MΦs) and their antimicrobial activity. Enhanced Na+-driven MΦ function requires the osmoprotective transcription factor nuclear factor of activated T cells 5 (NFAT5), which augments nitric oxide (NO) production and contributes to increased autophagy. However, the mechanism of Na+ sensing in MΦs remained unclear. High extracellular Na+ levels (high salt [HS]) trigger a substantial Na+ influx and Ca2+ loss. Here, we show that the Na+/Ca2+ exchanger 1 (NCX1, also known as solute carrier family 8 member A1 [SLC8A1]) plays a critical role in HS-triggered Na+ influx, concomitant Ca2+ efflux, and subsequent augmented NFAT5 accumulation. Moreover, interfering with NCX1 activity impairs HS-boosted inflammatory signaling, infection-triggered autolysosome formation, and subsequent antibacterial activity. Taken together, this demonstrates that NCX1 is able to sense Na+ and is required for amplifying inflammatory and antimicrobial MΦ responses upon HS exposure. Manipulating NCX1 offers a new strategy to regulate MΦ function.
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http://dx.doi.org/10.1371/journal.pbio.3000722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307728PMC
June 2020

Kidney dendritic cells: fundamental biology and functional roles in health and disease.

Nat Rev Nephrol 2020 07 5;16(7):391-407. Epub 2020 May 5.

Division of Translational Immunology, III Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

Dendritic cells (DCs) are chief inducers of adaptive immunity and regulate local inflammatory responses across the body. Together with macrophages, the other main type of mononuclear phagocyte, DCs constitute the most abundant component of the intrarenal immune system. This network of functionally specialized immune cells constantly surveys its microenvironment for signs of injury or infection, which trigger the initiation of an immune response. In the healthy kidney, DCs coordinate effective immune responses, for example, by recruiting neutrophils for bacterial clearance in pyelonephritis. The pro-inflammatory actions of DCs can, however, also contribute to tissue damage in various types of acute kidney injury and chronic glomerulonephritis, as DCs recruit and activate effector T cells, which release toxic mediators and maintain tubulointerstitial immune infiltrates. These actions are counterbalanced by DC subsets that promote the activation and maintenance of regulatory T cells to support resolution of the immune response and allow kidney repair. Several studies have investigated the multiple roles for DCs in kidney homeostasis and disease, but it has become clear that current tools and subset markers are not sufficient to accurately distinguish DCs from macrophages. Multidimensional transcriptomic analysis studies promise to improve mononuclear phagocyte classification and provide a clearer view of DC ontogeny and subsets.
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http://dx.doi.org/10.1038/s41581-020-0272-yDOI Listing
July 2020

Drawing a single-cell landscape of the human kidney in (pseudo)-space and time.

Kidney Int 2020 05;97(5):842-844

Institute of Experimental Immunology, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2020.01.011DOI Listing
May 2020

A high-salt diet compromises antibacterial neutrophil responses through hormonal perturbation.

Sci Transl Med 2020 03;12(536)

Institute of Experimental Immunology, University Hospital of Bonn, Rheinische Friedrich Wilhelm University, 53127 Bonn, Germany.

The Western diet is rich in salt, which poses various health risks. A high-salt diet (HSD) can stimulate immunity through the nuclear factor of activated T cells 5 (Nfat5)-signaling pathway, especially in the skin, where sodium is stored. The kidney medulla also accumulates sodium to build an osmotic gradient for water conservation. Here, we studied the effect of an HSD on the immune defense against uropathogenic -induced pyelonephritis, the most common kidney infection. Unexpectedly, pyelonephritis was aggravated in mice on an HSD by two mechanisms. First, on an HSD, sodium must be excreted; therefore, the kidney used urea instead to build the osmotic gradient. However, in contrast to sodium, urea suppressed the antibacterial functionality of neutrophils, the principal immune effectors against pyelonephritis. Second, the body excretes sodium by lowering mineralocorticoid production via suppressing aldosterone synthase. This caused an accumulation of aldosterone precursors with glucocorticoid functionality, which abolished the diurnal adrenocorticotropic hormone-driven glucocorticoid rhythm and compromised neutrophil development and antibacterial functionality systemically. Consistently, under an HSD, systemic infection was also aggravated in a glucocorticoid-dependent manner. Glucocorticoids directly induced Nfat5 expression, but pharmacological normalization of renal Nfat5 expression failed to restore the antibacterial defense. Last, healthy humans consuming an HSD for 1 week showed hyperglucocorticoidism and impaired antibacterial neutrophil function. In summary, an HSD suppresses intrarenal neutrophils Nfat5-independently by altering the local microenvironment and systemically by glucocorticoid-mediated immunosuppression. These findings argue against high-salt consumption during bacterial infections.
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http://dx.doi.org/10.1126/scitranslmed.aay3850DOI Listing
March 2020

Unraveling the Complexity of the Renal Mononuclear Phagocyte System by Genetic Cell Lineage Tracing.

J Am Soc Nephrol 2020 02 13;31(2):233-235. Epub 2020 Jan 13.

Institute of Experimental Immunology, University Hospital Bonn, Bonn, Germany

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http://dx.doi.org/10.1681/ASN.2019121295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003312PMC
February 2020

Butyrophilin 2A1 is essential for phosphoantigen reactivity by γδ T cells.

Science 2020 02 9;367(6478). Epub 2020 Jan 9.

Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria 3010, Australia.

Gamma delta (γδ) T cells are essential to protective immunity. In humans, most γδ T cells express Vγ9Vδ2 T cell receptors (TCRs) that respond to phosphoantigens (pAgs) produced by cellular pathogens and overexpressed by cancers. However, the molecular targets recognized by these γδTCRs are unknown. Here, we identify butyrophilin 2A1 (BTN2A1) as a key ligand that binds to the Vγ9 TCR γ chain. BTN2A1 associates with another butyrophilin, BTN3A1, and these act together to initiate responses to pAg. Furthermore, binding of a second ligand, possibly BTN3A1, to a separate TCR domain incorporating Vδ2 is also required. This distinctive mode of Ag-dependent T cell activation advances our understanding of diseases involving pAg recognition and creates opportunities for the development of γδ T cell-based immunotherapies.
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http://dx.doi.org/10.1126/science.aay5516DOI Listing
February 2020

Splenic Red Pulp Macrophages Cross-Prime Early Effector CTL That Provide Rapid Defense against Viral Infections.

J Immunol 2020 01 27;204(1):87-100. Epub 2019 Nov 27.

Institut für Experimentelle Immunologie, Rheinische Friedrich-Wilhelms-Universität, 53127 Bonn, Germany; and

Cross-presentation allows dendritic cells (DCs) to present peptides derived from endocytosed Ags on MHC class I molecules, which is important for activating CTL against viral infections and tumors. Type 1 classical DCs (cDC1), which depend on the transcription factor Batf3, are considered the main cross-presenting cells. In this study, we report that soluble Ags are efficiently cross-presented also by transcription factor SpiC-dependent red pulp macrophages (RPM) of the spleen. In contrast to cDC1, RPM used the mannose receptor for Ag uptake and employed the proteasome- and TAP-dependent cytosolic cross-presentation pathway, previously shown to be used in vitro by bone marrow-derived DCs. In an in vivo vaccination model, both cDC1 and RPM cross-primed CTL efficiently but with distinct kinetics. Within a few days, RPM induced very early effector CTL of a distinct phenotype (Ly6A/E Ly6C KLRG1 CD127 CXCR1 Grz-B). In an adenoviral infection model, such CTL contained the early viral spread, whereas cDC1 induced short-lived effector CTL that eventually cleared the virus. RPM-induced early effector CTL also contributed to the endogenous antiviral response but not to CTL memory generation. In conclusion, RPM can contribute to antiviral immunity by generating a rapid CTL defense force that contains the virus until cDC1-induced CTL are available to eliminate it. This function can be harnessed for improving vaccination strategies aimed at inducing CTL.
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http://dx.doi.org/10.4049/jimmunol.1900021DOI Listing
January 2020

Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition).

Authors:
Andrea Cossarizza Hyun-Dong Chang Andreas Radbruch Andreas Acs Dieter Adam Sabine Adam-Klages William W Agace Nima Aghaeepour Mübeccel Akdis Matthieu Allez Larissa Nogueira Almeida Giorgia Alvisi Graham Anderson Immanuel Andrä Francesco Annunziato Achille Anselmo Petra Bacher Cosima T Baldari Sudipto Bari Vincenzo Barnaba Joana Barros-Martins Luca Battistini Wolfgang Bauer Sabine Baumgart Nicole Baumgarth Dirk Baumjohann Bianka Baying Mary Bebawy Burkhard Becher Wolfgang Beisker Vladimir Benes Rudi Beyaert Alfonso Blanco Dominic A Boardman Christian Bogdan Jessica G Borger Giovanna Borsellino Philip E Boulais Jolene A Bradford Dirk Brenner Ryan R Brinkman Anna E S Brooks Dirk H Busch Martin Büscher Timothy P Bushnell Federica Calzetti Garth Cameron Ilenia Cammarata Xuetao Cao Susanna L Cardell Stefano Casola Marco A Cassatella Andrea Cavani Antonio Celada Lucienne Chatenoud Pratip K Chattopadhyay Sue Chow Eleni Christakou Luka Čičin-Šain Mario Clerici Federico S Colombo Laura Cook Anne Cooke Andrea M Cooper Alexandra J Corbett Antonio Cosma Lorenzo Cosmi Pierre G Coulie Ana Cumano Ljiljana Cvetkovic Van Duc Dang Chantip Dang-Heine Martin S Davey Derek Davies Sara De Biasi Genny Del Zotto Gelo Victoriano Dela Cruz Michael Delacher Silvia Della Bella Paolo Dellabona Günnur Deniz Mark Dessing James P Di Santo Andreas Diefenbach Francesco Dieli Andreas Dolf Thomas Dörner Regine J Dress Diana Dudziak Michael Dustin Charles-Antoine Dutertre Friederike Ebner Sidonia B G Eckle Matthias Edinger Pascale Eede Götz R A Ehrhardt Marcus Eich Pablo Engel Britta Engelhardt Anna Erdei Charlotte Esser Bart Everts Maximilien Evrard Christine S Falk Todd A Fehniger Mar Felipo-Benavent Helen Ferry Markus Feuerer Andrew Filby Kata Filkor Simon Fillatreau Marie Follo Irmgard Förster John Foster Gemma A Foulds Britta Frehse Paul S Frenette Stefan Frischbutter Wolfgang Fritzsche David W Galbraith Anastasia Gangaev Natalio Garbi Brice Gaudilliere Ricardo T Gazzinelli Jens Geginat Wilhelm Gerner Nicholas A Gherardin Kamran Ghoreschi Lara Gibellini Florent Ginhoux Keisuke Goda Dale I Godfrey Christoph Goettlinger Jose M González-Navajas Carl S Goodyear Andrea Gori Jane L Grogan Daryl Grummitt Andreas Grützkau Claudia Haftmann Jonas Hahn Hamida Hammad Günter Hämmerling Leo Hansmann Goran Hansson Christopher M Harpur Susanne Hartmann Andrea Hauser Anja E Hauser David L Haviland David Hedley Daniela C Hernández Guadalupe Herrera Martin Herrmann Christoph Hess Thomas Höfer Petra Hoffmann Kristin Hogquist Tristan Holland Thomas Höllt Rikard Holmdahl Pleun Hombrink Jessica P Houston Bimba F Hoyer Bo Huang Fang-Ping Huang Johanna E Huber Jochen Huehn Michael Hundemer Christopher A Hunter William Y K Hwang Anna Iannone Florian Ingelfinger Sabine M Ivison Hans-Martin Jäck Peter K Jani Beatriz Jávega Stipan Jonjic Toralf Kaiser Tomas Kalina Thomas Kamradt Stefan H E Kaufmann Baerbel Keller Steven L C Ketelaars Ahad Khalilnezhad Srijit Khan Jan Kisielow Paul Klenerman Jasmin Knopf Hui-Fern Koay Katja Kobow Jay K Kolls Wan Ting Kong Manfred Kopf Thomas Korn Katharina Kriegsmann Hendy Kristyanto Thomas Kroneis Andreas Krueger Jenny Kühne Christian Kukat Désirée Kunkel Heike Kunze-Schumacher Tomohiro Kurosaki Christian Kurts Pia Kvistborg Immanuel Kwok Jonathan Landry Olivier Lantz Paola Lanuti Francesca LaRosa Agnès Lehuen Salomé LeibundGut-Landmann Michael D Leipold Leslie Y T Leung Megan K Levings Andreia C Lino Francesco Liotta Virginia Litwin Yanling Liu Hans-Gustaf Ljunggren Michael Lohoff Giovanna Lombardi Lilly Lopez Miguel López-Botet Amy E Lovett-Racke Erik Lubberts Herve Luche Burkhard Ludewig Enrico Lugli Sebastian Lunemann Holden T Maecker Laura Maggi Orla Maguire Florian Mair Kerstin H Mair Alberto Mantovani Rudolf A Manz Aaron J Marshall Alicia Martínez-Romero Glòria Martrus Ivana Marventano Wlodzimierz Maslinski Giuseppe Matarese Anna Vittoria Mattioli Christian Maueröder Alessio Mazzoni James McCluskey Mairi McGrath Helen M McGuire Iain B McInnes Henrik E Mei Fritz Melchers Susanne Melzer Dirk Mielenz Stephen D Miller Kingston H G Mills Hans Minderman Jenny Mjösberg Jonni Moore Barry Moran Lorenzo Moretta Tim R Mosmann Susann Müller Gabriele Multhoff Luis Enrique Muñoz Christian Münz Toshinori Nakayama Milena Nasi Katrin Neumann Lai Guan Ng Antonia Niedobitek Sussan Nourshargh Gabriel Núñez José-Enrique O'Connor Aaron Ochel Anna Oja Diana Ordonez Alberto Orfao Eva Orlowski-Oliver Wenjun Ouyang Annette Oxenius Raghavendra Palankar Isabel Panse Kovit Pattanapanyasat Malte Paulsen Dinko Pavlinic Livius Penter Pärt Peterson Christian Peth Jordi Petriz Federica Piancone Winfried F Pickl Silvia Piconese Marcello Pinti A Graham Pockley Malgorzata Justyna Podolska Zhiyong Poon Katharina Pracht Immo Prinz Carlo E M Pucillo Sally A Quataert Linda Quatrini Kylie M Quinn Helena Radbruch Tim R D J Radstake Susann Rahmig Hans-Peter Rahn Bartek Rajwa Gevitha Ravichandran Yotam Raz Jonathan A Rebhahn Diether Recktenwald Dorothea Reimer Caetano Reis e Sousa Ester B M Remmerswaal Lisa Richter Laura G Rico Andy Riddell Aja M Rieger J Paul Robinson Chiara Romagnani Anna Rubartelli Jürgen Ruland Armin Saalmüller Yvan Saeys Takashi Saito Shimon Sakaguchi Francisco Sala-de-Oyanguren Yvonne Samstag Sharon Sanderson Inga Sandrock Angela Santoni Ramon Bellmàs Sanz Marina Saresella Catherine Sautes-Fridman Birgit Sawitzki Linda Schadt Alexander Scheffold Hans U Scherer Matthias Schiemann Frank A Schildberg Esther Schimisky Andreas Schlitzer Josephine Schlosser Stephan Schmid Steffen Schmitt Kilian Schober Daniel Schraivogel Wolfgang Schuh Thomas Schüler Reiner Schulte Axel Ronald Schulz Sebastian R Schulz Cristiano Scottá Daniel Scott-Algara David P Sester T Vincent Shankey Bruno Silva-Santos Anna Katharina Simon Katarzyna M Sitnik Silvano Sozzani Daniel E Speiser Josef Spidlen Anders Stahlberg Alan M Stall Natalie Stanley Regina Stark Christina Stehle Tobit Steinmetz Hannes Stockinger Yousuke Takahama Kiyoshi Takeda Leonard Tan Attila Tárnok Gisa Tiegs Gergely Toldi Julia Tornack Elisabetta Traggiai Mohamed Trebak Timothy I M Tree Joe Trotter John Trowsdale Maria Tsoumakidou Henning Ulrich Sophia Urbanczyk Willem van de Veen Maries van den Broek Edwin van der Pol Sofie Van Gassen Gert Van Isterdael René A W van Lier Marc Veldhoen Salvador Vento-Asturias Paulo Vieira David Voehringer Hans-Dieter Volk Anouk von Borstel Konrad von Volkmann Ari Waisman Rachael V Walker Paul K Wallace Sa A Wang Xin M Wang Michael D Ward Kirsten A Ward-Hartstonge Klaus Warnatz Gary Warnes Sarah Warth Claudia Waskow James V Watson Carsten Watzl Leonie Wegener Thomas Weisenburger Annika Wiedemann Jürgen Wienands Anneke Wilharm Robert John Wilkinson Gerald Willimsky James B Wing Rieke Winkelmann Thomas H Winkler Oliver F Wirz Alicia Wong Peter Wurst Jennie H M Yang Juhao Yang Maria Yazdanbakhsh Liping Yu Alice Yue Hanlin Zhang Yi Zhao Susanne Maria Ziegler Christina Zielinski Jakob Zimmermann Arturo Zychlinsky

Eur J Immunol 2019 Oct;49(10):1457-1973

Max Planck Institute for Infection Biology, Berlin, Germany.

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 examples 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.
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http://dx.doi.org/10.1002/eji.201970107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350392PMC
October 2019

Deubiquitinating Enzyme UCH-L1 Promotes Dendritic Cell Antigen Cross-Presentation by Favoring Recycling of MHC Class I Molecules.

J Immunol 2019 10 6;203(7):1730-1742. Epub 2019 Sep 6.

Institute for Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;

The deubiquitinating enzyme ubiquitin C-terminal hydrolase-L1 (UCH-L1) is required for the maintenance of axonal integrity in neurons and is thought to regulate the intracellular pool of ubiquitin in the brain. In this study, we show that UCH-L1 has an immunological function in dendritic cell (DC) Ag cross-presentation. UCH-L1 is expressed in mouse kidney, spleen, and bone marrow-derived DCs, and its expression and activity are regulated by the immune stimuli LPS and IFN-γ. UCH-L1-deficient mice have significantly reduced ability to cross-prime CD8 T cells in vivo and in vitro because of a reduced ability of DCs to generate MHC class I (MHC I) peptide complexes for cross-presented Ags. Mechanistically, Ag uptake by phagocytosis and receptor-mediated endocytosis as well as phagosome maturation are unaffected by loss of UCH-L1 in DCs. Rather, MHC I recycling is reduced by loss of UCH-L1, which affects the colocalization of intracellular MHC I with late endosomal/lysosomal compartments necessary for cross-presentation of Ag. These results demonstrate a hitherto unrecognized role of the deubiquitinating enzyme UCH-L1 in DC Ag processing.
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http://dx.doi.org/10.4049/jimmunol.1801133DOI Listing
October 2019

Chronically stimulated human MAIT cells are unexpectedly potent IL-13 producers.

Immunol Cell Biol 2019 09 19;97(8):689-699. Epub 2019 Jul 19.

Fiona Elsey Cancer Research Institute, Ballarat, VIC, Australia.

Mucosal-associated invariant T (MAIT) cells are unconventional T cells that recognize antigens derived from riboflavin biosynthesis. In addition to anti-microbial functions, human MAIT cells are associated with cancers, autoimmunity, allergies and inflammatory disorders, although their role is poorly understood. Activated MAIT cells are well known for their rapid release of Th1 and Th17 cytokines, but we have discovered that chronic stimulation can also lead to potent interleukin (IL)-13 expression. We used RNA-seq and qRT-PCR to demonstrate high expression of the IL-13 gene in chronically stimulated MAIT cells, and directly identify IL-13 using intracellular flow cytometry and multiplex bead analysis of MAIT cell cultures. This unexpected finding has important implications for IL-13-dependent diseases, such as colorectal cancer (CRC), that occur in mucosal areas where MAIT cells are abundant. We identify MAIT cells near CRC tumors and show that these areas and precancerous polyps express high levels of the IL-13 receptor, which promotes tumor progression and metastasis. Our data suggest that MAIT cells have a more complicated role in CRC than currently realized and that they represent a promising new target for immunotherapies where IL-13 can be a critical factor.
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http://dx.doi.org/10.1111/imcb.12281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790710PMC
September 2019

Novel 3D analysis using optical tissue clearing documents the evolution of murine rapidly progressive glomerulonephritis.

Kidney Int 2019 08 15;96(2):505-516. Epub 2019 Mar 15.

Department of Nephrology and Clinical Immunology, RWTH Aachen University Clinic, Aachen, Germany; Interdisciplinary Centre for Clinical Research (IZKF Aachen), RWTH Aachen University Hospital, Aachen, Germany; Heisenberg Chair for Preventive and Translational Nephrology, Division of Nephrology, RWTH Aachen University, Aachen, Germany. Electronic address:

Recent developments in optical tissue clearing have been difficult to apply for the morphometric analysis of organs with high cellular content and small functional structures, such as the kidney. Here, we establish combinations of genetic and immuno-labelling for single cell identification, tissue clearing and subsequent de-clarification for histoimmunopathology and transmission electron microscopy. Using advanced light microscopy and computational analyses, we investigated a murine model of crescentic nephritis, an inflammatory kidney disease typified by immune-mediated damage to glomeruli leading to the formation of hypercellular lesions and the rapid loss of kidney function induced by nephrotoxic serum. Results show a graded susceptibility of the glomeruli, significant podocyte loss and capillary injury. These effects are associated with activation of parietal epithelial cells and formation of glomerular lesions that may evolve and obstruct the kidney tubule, thereby explaining the loss of kidney function. Thus, our work provides new high-throughput endpoints for the analysis of complex tissues with single-cell resolution.
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http://dx.doi.org/10.1016/j.kint.2019.02.034DOI Listing
August 2019

Bcl10-controlled Malt1 paracaspase activity is key for the immune suppressive function of regulatory T cells.

Nat Commun 2019 05 28;10(1):2352. Epub 2019 May 28.

Institute of Clinical Chemistry and Pathobiochemistry, TUM School of Medicine, Technical University of Munich, 81675, Munich, Germany.

Regulatory T cells (Tregs) have crucial functions in the inhibition of immune responses. Their development and suppressive functions are controlled by the T cell receptor (TCR), but the TCR signaling mechanisms that mediate these effects remain ill-defined. Here we show that CARD11-BCL10-MALT1 (CBM) signaling mediates TCR-induced NF-κB activation in Tregs and controls the conversion of resting Tregs to effector Tregs under homeostatic conditions. However, in inflammatory milieus, cytokines can bypass the CBM requirement for this differentiation step. By contrast, CBM signaling, in a MALT1 protease-dependent manner, is essential for mediating the suppressive function of Tregs. In malignant melanoma models, acute genetic blockade of BCL10 signaling selectively in Tregs or pharmacological MALT1 inhibition enhances anti-tumor immune responses. Together, our data uncover a segregation of Treg differentiation and suppressive function at the CBM complex level, and provide a rationale to explore MALT1 inhibitors for cancer immunotherapy.
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http://dx.doi.org/10.1038/s41467-019-10203-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538646PMC
May 2019

HIF1A and NFAT5 coordinate Na-boosted antibacterial defense via enhanced autophagy and autolysosomal targeting.

Autophagy 2019 11 14;15(11):1899-1916. Epub 2019 Apr 14.

Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg , Regensburg , Germany.

Infection and inflammation are able to induce diet-independent Na-accumulation without commensurate water retention in afflicted tissues, which favors the pro-inflammatory activation of mouse macrophages and augments their antibacterial and antiparasitic activity. While Na-boosted host defense against the protozoan parasite is mediated by increased expression of the leishmanicidal NOS2 (nitric oxide synthase 2, inducible), the molecular mechanisms underpinning this enhanced antibacterial defense of mouse macrophages with high Na (HS) exposure are unknown. Here, we provide evidence that HS-increased antibacterial activity against was neither dependent on NOS2 nor on the phagocyte oxidase. In contrast, HS-augmented antibacterial defense hinged on HIF1A (hypoxia inducible factor 1, alpha subunit)-dependent increased autophagy, and NFAT5 (nuclear factor of activated T cells 5)-dependent targeting of intracellular to acidic autolysosomal compartments. Overall, these findings suggest that the autolysosomal compartment is a novel target of Na-modulated cell autonomous innate immunity. : ACT: actins; AKT: AKT serine/threonine kinase 1; ATG2A: autophagy related 2A; ATG4C: autophagy related 4C, cysteine peptidase; ATG7: autophagy related 7; ATG12: autophagy related 12; BECN1: beclin 1; BMDM: bone marrow-derived macrophages; BNIP3: BCL2/adenovirus E1B interacting protein 3; CFU: colony forming units; CM-HDCFDA: 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester; CTSB: cathepsin B; CYBB: cytochrome b-245 beta chain; DAPI: 4,6-diamidino-2-phenylindole; DMOG: dimethyloxallyl glycine; DPI: diphenyleneiodonium chloride; ; FDR: false discovery rate; GFP: green fluorescent protein; GSEA: gene set enrichment analysis; GO: gene ontology; HIF1A: hypoxia inducible factor 1, alpha subunit; HUGO: human genome organization; HS: high salt (+ 40 mM of NaCl to standard cell culture conditions); HSP90: heat shock 90 kDa proteins; LDH: lactate dehydrogenase; LPS: lipopolysaccharide; Lyz2/LysM: lysozyme 2; NFAT5/TonEBP: nuclear factor of activated T cells 5; MΦ: macrophages; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MFI: mean fluorescence intensity; MIC: minimum inhibitory concentration; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; NaCl: sodium chloride; NES: normalized enrichment score; n.s.: not significant; NO: nitric oxide; NOS2/iNOS: nitric oxide synthase 2, inducible; NS: normal salt; PCR: polymerase chain reaction; PGK1: phosphoglycerate kinase 1; PHOX: phagocyte oxidase; RFP: red fluorescent protein; RNA: ribonucleic acid; ROS: reactive oxygen species; sCFP3A: super cyan fluorescent protein 3A; SBFI: sodium-binding benzofuran isophthalate; SLC2A1/GLUT1: solute carrier family 2 (facilitated glucose transporter), member 1; SQSTM1/p62: sequestosome 1; ULK1: unc-51 like kinase 1; v-ATPase: vacuolar-type H-ATPase; WT: wild type.
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http://dx.doi.org/10.1080/15548627.2019.1596483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844503PMC
November 2019

DAMPening sterile inflammation of the kidney.

Kidney Int 2019 03;95(3):489-491

Institute of Experimental Immunology, University Clinic of Bonn, Rheinische Friedrich Wilhelm University, Bonn, Germany. Electronic address:

Renal ischemia reperfusion injury (IRI) is a serious cause of acute kidney injury (AKI). Danger-associated-molecular pattern molecules (DAMPs) are thought to promote IRI by initiating immune cell infiltration and driving disease progression, but the underlying pathophysiological mechanisms are mainly unclear. Poluzzi et al. demonstrate that soluble biglycan is a bimodal DAMP that both recruits proinflammatory macrophages and initiates resolution of inflammation and tissue remodeling in IRI, identifying a potential therapeutic target.
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http://dx.doi.org/10.1016/j.kint.2018.12.007DOI Listing
March 2019

Protecting the kidney against autoimmunity and inflammation.

Nat Rev Nephrol 2019 02;15(2):66-68

Institute of Cellular and Integrative Physiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany.

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http://dx.doi.org/10.1038/s41581-018-0097-0DOI Listing
February 2019

The chemokine receptor CXCR1 reduces renal injury in mice with angiotensin II-induced hypertension.

Am J Physiol Renal Physiol 2018 12 12;315(6):F1526-F1535. Epub 2018 Sep 12.

III. Department of Medicine, University Hospital Hamburg-Eppendorf , Hamburg , Germany.

The role of CXCR1, also known as fractalkine receptor, in hypertension is unknown. The present study determined the role of the fractalkine receptor CXCR1 in hypertensive renal and cardiac injury. Expression of CXCR1 was determined using CXCR1 mice that express a green fluorescent protein (GFP) reporter in CXCR1 cells. FACS analysis of leukocytes isolated from the kidney showed that 34% of CD45 cells expressed CXCR1. Dendritic cells were the majority of positive cells (67%) followed by macrophages (10%), NK cells (6%), and T cells (10%). With the use of confocal microscopy, the receptor was detected in the kidney only on infiltrating cells but not on resident renal cells. To evaluate the role of CXCR1 in hypertensive end-organ injury, an aggravated model of hypertension was used. Unilateral nephrectomy was performed followed by infusion of angiotensin II (ANG II, 1.5 ng·g·min) and a high-salt diet in wild-type ( n = 15) and CXCR1-deficient mice ( n = 18). CXCR1 deficiency reduced the number of renal dendritic cells and increased the numbers of renal CD11b/F4/80 macrophages and CD11b/Ly6G neutrophils in ANG II-infused mice. Surprisingly, CXCR1-deficient mice exhibited increased albuminuria, glomerular injury, and reduced podocyte density in spite of similar levels of arterial hypertension. In contrast, cardiac damage as assessed by increased heart weight, cardiac fibrosis, and expression of fetal genes, and matrix components were not different between both genotypes. Our findings suggest that CXCR1 exerts protective properties by modulating the invasion of inflammatory cells in hypertensive renal injury. CXCR1 inhibition should be avoided in hypertension because it may promote hypertensive renal injury.
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http://dx.doi.org/10.1152/ajprenal.00149.2018DOI Listing
December 2018

Targeting kidney inflammation as a new therapy for primary hyperoxaluria?

Nephrol Dial Transplant 2019 06;34(6):908-914

Institute of Experimental Immunology, University Hospital of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany.

The primary hyperoxalurias (PHs) are inborn errors of glyoxylate metabolism characterized by endogenous oxalate overproduction in the liver, and thus elevated urinary oxalate excretion. The urinary calcium-oxalate (CaOx) supersaturation and the continuous renal accumulation of insoluble CaOx crystals yield a progressive decline in renal function that often ends with renal failure. In PH Type 1 (AGXT mutated), the most frequent and severe condition, patients typically progress to end-stage renal disease (ESRD); in PH Type 2 (GRHPR mutated), 20% of patients develop ESRD, while only one patient with PH Type 3 (HOGA1 mutated) has been reported with ESRD so far. Patients with ESRD undergo frequent maintenance (haemo)dialysis treatment, and finally must receive a combined liver-kidney transplantation as the only curative treatment option available in PH Type 1. In experimental models using oxalate-enriched chow, CaOx crystals were bound to renal tubular cells, promoting a pro-inflammatory environment that led to fibrogenesis in the renal parenchyma by activation of a NACHT, LRR and PYD domains-containing protein 3 (NALP3)-dependent inflammasome in renal dendritic cells and macrophages. Chronic fibrogenesis progressively impaired renal function. Targeting the inflammatory response has recently been suggested as a therapeutic strategy to treat not only oxalate-induced crystalline nephropathies, but also those characterized by accumulation of cystine and urate in other organs. Herein, we summarize the pathogenesis of PH, revising the current knowledge of the CaOx-mediated inflammatory response in animal models of endogenous oxalate overproduction. Furthermore, we highlight the possibility of modifying the NLRP3-dependent inflammasome as a new and complementary therapeutic strategy to treat this severe and devastating kidney disease.
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http://dx.doi.org/10.1093/ndt/gfy239DOI Listing
June 2019

Salt, inflammation, IL-17 and hypertension.

Br J Pharmacol 2019 06 15;176(12):1853-1863. Epub 2018 Jun 15.

Department of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Traditionally, arterial hypertension and subsequent end-organ damage have been attributed to haemodynamic factors, but increasing evidence indicates that inflammation also contributes to the deleterious consequences of this disease. The immune system has evolved to prevent invasion of foreign microorganisms and to promote tissue healing after injury. However, this beneficial activity comes at a cost of collateral damage when the immune system overreacts to internal injury, such as prehypertension. Over the past few years, important findings have revolutionized hypertension research. Firstly, in 2007, a seminal paper showed that adaptive immunity is involved in the pathogenesis of hypertension. Secondly, salt storage in the skin and its consequences for cardiovascular physiology were discovered. Thirdly, after the discovery that salt promotes the differentiation of CD4 T cells into T 17 cells, it was demonstrated that salt directly changes several cells of the innate and adaptive immune system and aggravates autoimmune disease but may improve antimicrobial defence. Herein, we will review pathways of activation of immune cells by salt in hypertension as the framework for understanding the multiple roles of salt and immunity in arterial hypertension and autoimmune disease. LINKED ARTICLES: This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc.
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http://dx.doi.org/10.1111/bph.14359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534785PMC
June 2019

The multifaceted role of the renal mononuclear phagocyte system.

Cell Immunol 2018 08 22;330:97-104. Epub 2018 Apr 22.

Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany. Electronic address:

The kidney contains a large and complex network of mononuclear phagocytes, which includes dendritic cells (DCs) and macrophages (MØs). The distinction between these cell types is traditionally based on the expression of molecular markers and morphology. However, several classification systems are used in parallel to identify DCs and MØs, leading to considerable uncertainty about their identity and functional roles. The discovery that a substantial proportion of macrophages in tissues like the kidney are embryonically derived further complicates the situation. Recent studies have used newly identified transcription factors such as ZBTB46 and lineage tracing techniques for classifying mononuclear phagocytes. These approaches have shed new light on the functional specialization of these cells in health and disease, uncovered an influence of the renal microenvironment and revealed considerable cellular plasticity, especially in inflammatory situations. In this review, the current knowledge about the developmental origins and versatile functional roles of DCs and MØs in kidney homeostasis and disease is discussed.
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http://dx.doi.org/10.1016/j.cellimm.2018.04.009DOI Listing
August 2018

Antigen-specific Helios , Neuropilin-1 Tregs induce apoptosis of autoreactive B cells via PD-L1.

Immunol Cell Biol 2018 09 2;96(8):852-862. Epub 2018 May 2.

Institute of Experimental Immunology, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany.

Regulatory T cells (Tregs) maintain self-tolerance and prevent autoimmunity by controlling autoreactive T cells. We recently demonstrated in vivo that Tregs can directly suppress auto-reactive B cells via programmed death ligand 1 (PD-L1) that ligated PD-1 on B cells and caused them to undergo apoptosis. Here, we asked whether this mechanism is utilized by thymus-derived natural Tregs and/or by peripheral lymphoid tissue-induced Tregs. We first demonstrated that antigen-specific PD-L1-expressing Tregs were induced in the draining lymph node of autoantigen-expressing tissue and characterized them by their lack of the transcription factor Helios and of the surface marker Neuropilin-1 (Nrp-1). Next, we established an in vitro co-culture system to study the interaction between B cells and Treg subsets under controlled conditions. We found that Nrp Treg, but not Nrp Treg suppressed autoreactive B cells, whereas both were able to suppress T-helper cells. Such suppression was antigen-specific and was facilitated by PD-L1/PD-1-induced apoptosis. Furthermore, it required physical cell contact and was MHC II-restricted, providing an explanation for the antigen-specificity of peripherally-induced Tregs. These findings identify a role for peripherally induced Helios Nrp-1 inducible Treg in controlling peripheral B-cell tolerance against tissue auto-antigens.
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http://dx.doi.org/10.1111/imcb.12053DOI Listing
September 2018

In Vivo Labeling by CD73 Marks Multipotent Stromal Cells and Highlights Endothelial Heterogeneity in the Bone Marrow Niche.

Cell Stem Cell 2018 02;22(2):262-276.e7

Institute of Physiology I, Life&Brain Center, Medical Faculty, University of Bonn, 53105 Bonn, Germany. Electronic address:

Despite much work studying ex vivo multipotent stromal cells (MSCs), the identity and characteristics of MSCs in vivo are not well defined. Here, we generated a CD73-EGFP reporter mouse to address these questions and found EGFP MSCs in various organs. In vivo, EGFP mesenchymal cells were observed in fetal and adult bones at proliferative ossification sites, while in solid organs EGFP cells exhibited a perivascular distribution pattern. EGFP cells from the bone compartment could be clonally expanded ex vivo from single cells and displayed trilineage differentiation potential. Moreover, in the central bone marrow CD73-EGFP specifically labeled sinusoidal endothelial cells, thought to be a critical component of the hematopoietic stem cell niche. Purification and molecular characterization of this CD73-EGFP population revealed an endothelial subtype that also displays a mesenchymal signature, highlighting endothelial cell heterogeneity in the marrow. Thus, the CD73-EGFP mouse is a powerful tool for studying MSCs and sinusoidal endothelium.
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http://dx.doi.org/10.1016/j.stem.2018.01.008DOI Listing
February 2018

Plasmacytoid dendritic cells: important players in human kidney allograft rejection.

Kidney Int 2018 02;93(2):301-303

Rheinische Friedrich-Wilhelms-Universität, Institute of Experimental Immunology, Bonn, NRW, Germany. Electronic address:

Plasmacytoid dendritic cells are a unique dendritic cell subset that bridges innate and adaptive immune responses. They release high amounts of type I interferons in response to viral and bacterial infection. Plasmacytoid dendritic cells are thought to act as key players in renal allograft rejection, but the underlying mechanisms are unclear. Ruben et al. now demonstrate that granulocyte/macrophage colony-stimulating factor produced by renal epithelial cells is important to induce plasmacytoid dendritic cell maturation and indirect antigen presentation triggering allogeneic immune responses.
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http://dx.doi.org/10.1016/j.kint.2017.10.025DOI Listing
February 2018

Role of immune cells in crystal-induced kidney fibrosis.

Matrix Biol 2018 08 6;68-69:280-292. Epub 2017 Dec 6.

Institute of Experimental Immunology, University Bonn, Bonn, Germany. Electronic address:

Chronic kidney diseases can lead to kidney fibrosis, which can be considered a futile attempt of tissue healing to replaces functional kidney tissue with connective tissue, basically forming a scar. Chronic inflammation is a frequent cause of kidney fibrosis. Classical as well as recently discovered immune cell subsets and their molecular mediators have been intensively investigated for their contribution to kidney fibrosis and their potential as therapeutic targets. Here we review the current knowledge about the role of immune cells in crystal-induced renal fibrosis.
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http://dx.doi.org/10.1016/j.matbio.2017.11.013DOI Listing
August 2018