22 results on '"Räuber, Saskia"'
Search Results
2. Preventing long-term disability in CIDP: the role of timely diagnosis and treatment monitoring in a multicenter CIDP cohort.
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Quint, Paula, Schroeter, Christina B., Kohle, Felix, Öztürk, Menekse, Meisel, Andreas, Tamburrino, Giuliano, Mausberg, Anne K., Szepanowski, Fabian, Afzali, Ali Maisam, Fischer, Katinka, Nelke, Christopher, Räuber, Saskia, Voth, Jan, Masanneck, Lars, Willison, Alice, Vogelsang, Anna, Hemmer, Bernhard, Berthele, Achim, Schroeter, Michael, and Hartung, Hans-Peter
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CHRONIC inflammatory demyelinating polyradiculoneuropathy ,NERVE conduction studies ,PERIPHERAL neuropathy ,ALCOHOLISM ,TREATMENT effectiveness - Abstract
Background: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an inflammatory disease affecting the peripheral nerves and the most frequent autoimmune polyneuropathy. Given the lack of established biomarkers or risk factors for the development of CIDP and patients' treatment response, this research effort seeks to identify potential clinical factors that may influence disease progression and overall treatment efficacy. Methods: In this multicenter, retrospective analysis, we have screened 197 CIDP patients who presented to the University Hospitals in Düsseldorf, Berlin, Cologne, Essen, Magdeburg and Munich between 2018 and 2022. We utilized the respective hospital information system and examined baseline data with clinical examination, medical letters, laboratory results, antibody status, nerve conduction studies, imaging and biopsy findings. Aside from clinical baseline data, we analyzed treatment outcomes using the Standard of Care (SOC) definition, as well as a comparison of an early (within the first 12 months after manifestation) versus late (more than 12 months after manifestation) onset of therapy. Results: In terms of treatment, most patients received intravenous immunoglobulin (56%) or prednisolone (39%) as their first therapy. Patients who started their initial treatment later experienced a worsening disease course, as reflected by a significant deterioration in their Inflammatory Neuropathy Cause and Treatment (INCAT) leg disability score. SOC-refractory patients had worse clinical outcomes than SOC-responders. Associated factors for SOC-refractory status included the presence of fatigue as a symptom and alcohol dependence. Conclusion: Timely diagnosis, prompt initiation of treatment and careful monitoring of treatment response are essential for the prevention of long-term disability in CIDP and suggest a "hit hard and early" treatment paradigm. [ABSTRACT FROM AUTHOR]
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- 2024
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3. Inter-alpha-trypsin inhibitor heavy chain H3 is a potential biomarker for disease activity in myasthenia gravis.
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Schroeter, Christina B., Nelke, Christopher, Stascheit, Frauke, Huntemann, Niklas, Preusse, Corinna, Dobelmann, Vera, Theissen, Lukas, Pawlitzki, Marc, Räuber, Saskia, Willison, Alice, Vogelsang, Anna, Marina, Adela Della, Hartung, Hans-Peter, Melzer, Nico, Konen, Felix F., Skripuletz, Thomas, Hentschel, Andreas, König, Simone, Schweizer, Michaela, and Stühler, Kai
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MYASTHENIA gravis ,BIOMARKERS ,NEUROMUSCULAR transmission ,NEUROMUSCULAR diseases ,NEURAL transmission ,PROTEIN expression - Abstract
Myasthenia gravis is a chronic antibody-mediated autoimmune disease disrupting neuromuscular synaptic transmission. Informative biomarkers remain an unmet need to stratify patients with active disease requiring intensified monitoring and therapy; their identification is the primary objective of this study. We applied mass spectrometry-based proteomic serum profiling for biomarker discovery. We studied an exploration and a prospective validation cohort consisting of 114 and 140 anti-acetylcholine receptor antibody (AChR-Ab)-positive myasthenia gravis patients, respectively. For downstream analysis, we applied a machine learning approach. Protein expression levels were confirmed by ELISA and compared to other myasthenic cohorts, in addition to myositis and neuropathy patients. Anti-AChR-Ab levels were determined by a radio receptor assay. Immunohistochemistry and immunofluorescence of intercostal muscle biopsies were employed for validation in addition to interactome studies of inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3). Machine learning identified ITIH3 as potential serum biomarker reflective of disease activity. Serum levels correlated with disease activity scores in the exploration and validation cohort and were confirmed by ELISA. Lack of correlation between anti-AChR-Ab levels and clinical scores underlined the need for biomarkers. In a subgroup analysis, ITIH3 was indicative of treatment responses. Immunostaining of muscle specimens from these patients demonstrated ITIH3 localization at the neuromuscular endplates in myasthenia gravis but not in controls, thus providing a structural equivalent for our serological findings. Immunoprecipitation of ITIH3 and subsequent proteomics lead to identification of its interaction partners playing crucial roles in neuromuscular transmission. This study provides data on ITIH3 as a potential pathophysiological-relevant biomarker of disease activity in myasthenia gravis. Future studies are required to facilitate translation into clinical practice. [ABSTRACT FROM AUTHOR]
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- 2024
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4. [18F]DPA-714-PET-MRI reveals pronounced innate immunity in human anti-LGI1 and anti-CASPR2 limbic encephalitis.
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Roll, Wolfgang, Bauer, Jan, Dik, Andre, Mueller, Christoph, Backhaus, Philipp, Räuber, Saskia, Zinnhardt, Bastian, Gallus, Marco, Wimberley, Catriona, Körtvelyessy, Peter, Schindler, Philipp, Stenzel, Werner, Elger, Christian E., Becker, Albert, Lewerenz, Jan, Wiendl, Heinz, Meuth, Sven G., Schäfers, Michael, and Melzer, Nico
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EPILEPSY ,ANTI-NMDA receptor encephalitis ,NATURAL immunity ,ENCEPHALITIS ,SCIENCE education - Abstract
This document, published in the Journal of Neurology, explores the use of [18F]DPA-714-PET-MRI as a diagnostic tool for autoimmune limbic encephalitis (ALE) with specific autoantibodies. The study involved two patients with these autoantibodies, and the results showed increased tracer uptake in certain areas of the brain. The study suggests that [18F]DPA-714-PET-MRI could be a valuable tool for diagnosing ALE and assessing the immune response in the brain. However, further research is needed to fully understand its potential for clinical use in ALE. [Extracted from the article]
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- 2024
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5. Resident and recruited macrophages differentially contribute to cardiac healing after myocardial ischemia.
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Weinberger, Tobias, Denise, Messerer, Joppich, Markus, Fischer, Maximilian, Rodriguez, Clarisabel Garcia, Kumaraswami, Konda, Wimmler, Vanessa, Ablinger, Sonja, Räuber, Saskia, Jiahui Fang, Lulu Liu, Wing Han Liu, Winterhalter, Julia, Lichti, Johannes, Thomas, Lukas, Esfandyari, Dena, Percin, Guelce, Matin, Sandra, Hidalgo, Andrés, and Waskow, Claudia
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- 2024
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6. Recombinant Acetylcholine Receptor Immunization Induces a Robust Model of Experimental Autoimmune Myasthenia Gravis in Mice.
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Theissen, Lukas, Schroeter, Christina B., Huntemann, Niklas, Räuber, Saskia, Dobelmann, Vera, Cengiz, Derya, Herrmann, Alexander, Koch-Hölsken, Kathrin, Gerdes, Norbert, Hu, Hao, Mourikis, Philipp, Polzin, Amin, Kelm, Malte, Hartung, Hans-Peter, Meuth, Sven G., Nelke, Christopher, and Ruck, Tobias
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MYASTHENIA gravis ,CHOLINERGIC receptors ,T helper cells ,MUSCLE weakness ,NEUROMUSCULAR diseases ,RECOMBINANT proteins ,MYONEURAL junction - Abstract
Myasthenia gravis (MG) is a prototypical autoimmune disease of the neuromuscular junction (NMJ). The study of the underlying pathophysiology has provided novel insights into the interplay of autoantibodies and complement-mediated tissue damage. Experimental autoimmune myasthenia gravis (EAMG) emerged as a valuable animal model, designed to gain further insight and to test novel therapeutic approaches for MG. However, the availability of native acetylcholine receptor (AChR) protein is limited favouring the use of recombinant proteins. To provide a simplified platform for the study of MG, we established a model of EAMG using a recombinant protein containing the immunogenic sequence of AChR in mice. This model recapitulates key features of EAMG, including fatigable muscle weakness, the presence of anti-AChR-antibodies, and engagement of the NMJ by complement and a reduced NMJ density. Further characterization of this model demonstrated a prominent B cell immunopathology supported by T follicular helper cells. Taken together, the herein-presented EAMG model may be a valuable tool for the study of MG pathophysiology and the pre-clinical testing of therapeutic applications. [ABSTRACT FROM AUTHOR]
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- 2024
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7. The Use of Nitrosative Stress Molecules as Potential Diagnostic Biomarkers in Multiple Sclerosis.
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Räuber, Saskia, Förster, Moritz, Schüller, Julia, Willison, Alice, Golombeck, Kristin S., Schroeter, Christina B., Oeztuerk, Menekse, Jansen, Robin, Huntemann, Niklas, Nelke, Christopher, Korsen, Melanie, Fischer, Katinka, Kerkhoff, Ruth, Leven, Yana, Kirschner, Patricia, Kölsche, Tristan, Nikolov, Petyo, Mehsin, Mohammed, Marae, Gelenar, and Kokott, Alma
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CEREBROSPINAL fluid examination , *NATALIZUMAB , *MULTIPLE sclerosis , *CENTRAL nervous system diseases , *NEUROLOGICAL disorders , *BIOMARKERS - Abstract
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) of still unclear etiology. In recent years, the search for biomarkers facilitating its diagnosis, prognosis, therapy response, and other parameters has gained increasing attention. In this regard, in a previous meta-analysis comprising 22 studies, we found that MS is associated with higher nitrite/nitrate (NOx) levels in the cerebrospinal fluid (CSF) compared to patients with non-inflammatory other neurological diseases (NIOND). However, many of the included studies did not distinguish between the different clinical subtypes of MS, included pre-treated patients, and inclusion criteria varied. As a follow-up to our meta-analysis, we therefore aimed to analyze the serum and CSF NOx levels in clinically well-defined cohorts of treatment-naïve MS patients compared to patients with somatic symptom disorder. To this end, we analyzed the serum and CSF levels of NOx in 117 patients (71 relapsing–remitting (RR) MS, 16 primary progressive (PP) MS, and 30 somatic symptom disorder). We found that RRMS and PPMS patients had higher serum NOx levels compared to somatic symptom disorder patients. This difference remained significant in the subgroup of MRZ-negative RRMS patients. In conclusion, the measurement of NOx in the serum might indeed be a valuable tool in supporting MS diagnosis. [ABSTRACT FROM AUTHOR]
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- 2024
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8. Senescent fibro-adipogenic progenitors are potential drivers of pathology in inclusion body myositis.
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Nelke, Christopher, Schroeter, Christina B., Theissen, Lukas, Preusse, Corinna, Pawlitzki, Marc, Räuber, Saskia, Dobelmann, Vera, Cengiz, Derya, Kleefeld, Felix, Roos, Andreas, Schoser, Benedikt, Brunn, Anna, Neuen-Jacob, Eva, Zschüntzsch, Jana, Meuth, Sven G., Stenzel, Werner, and Ruck, Tobias
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INCLUSION body myositis ,CHOLINERGIC receptors ,MYONEURAL junction ,MUSCLE cells ,CELL populations ,SKELETAL muscle ,CELLULAR aging - Abstract
Inclusion body myositis (IBM) is unique across the spectrum of idiopathic inflammatory myopathies (IIM) due to its distinct clinical presentation and refractoriness to current treatment approaches. One explanation for this resistance may be the engagement of cell-autonomous mechanisms that sustain or promote disease progression of IBM independent of inflammatory activity. In this study, we focused on senescence of tissue-resident cells as potential driver of disease. For this purpose, we compared IBM patients to non-diseased controls and immune-mediated necrotizing myopathy patients. Histopathological analysis suggested that cellular senescence is a prominent feature of IBM, primarily affecting non-myogenic cells. In-depth analysis by single nuclei RNA sequencing allowed for the deconvolution and study of muscle-resident cell populations. Among these, we identified a specific cluster of fibro-adipogenic progenitors (FAPs) that demonstrated key hallmarks of senescence, including a pro-inflammatory secretome, expression of p21, increased β-galactosidase activity, and engagement of senescence pathways. FAP function is required for muscle cell health with changes to their phenotype potentially proving detrimental. In this respect, the transcriptomic landscape of IBM was also characterized by changes to the myogenic compartment demonstrating a pronounced loss of type 2A myofibers and a rarefication of acetylcholine receptor expressing myofibers. IBM muscle cells also engaged a specific pro-inflammatory phenotype defined by intracellular complement activity and the expression of immunogenic surface molecules. Skeletal muscle cell dysfunction may be linked to FAP senescence by a change in the collagen composition of the latter. Senescent FAPs lose collagen type XV expression, which is required to support myofibers' structural integrity and neuromuscular junction formation in vitro. Taken together, this study demonstrates an altered phenotypical landscape of muscle-resident cells and that FAPs, and not myofibers, are the primary senescent cell type in IBM. [ABSTRACT FROM AUTHOR]
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- 2023
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9. Classifying flow cytometry data using Bayesian analysis helps to distinguish ALS patients from healthy controls.
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Räuber, Saskia, Nelke, Christopher, Schroeter, Christina B., Barman, Sumanta, Pawlitzki, Marc, Ingwersen, Jens, Akgün, Katja, Günther, Rene, Garza, Alejandra P., Marggraf, Michaela, Dunay, Ildiko Rita, Schreiber, Stefanie, Vielhaber, Stefan, Ziemssen, Tjalf, Melzer, Nico, Ruck, Tobias, Meuth, Sven G., and Herty, Michael
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BAYESIAN analysis ,FLOW cytometry ,AMYOTROPHIC lateral sclerosis ,CD38 antigen - Abstract
Introduction: Given its wide availability and cost-effectiveness, multidimensional flow cytometry (mFC) became a core method in the field of immunology allowing for the analysis of a broad range of individual cells providing insights into cell subset composition, cellular behavior, and cell-to-cell interactions. Formerly, the analysis of mFC data solely relied on manual gating strategies. With the advent of novel computational approaches, (semi-)automated gating strategies and analysis tools complemented manual approaches. Methods: Using Bayesian network analysis, we developed a mathematical model for the dependencies of different obtained mFC markers. The algorithm creates a Bayesian network that is a HC tree when including raw, ungated mFC data of a randomly selected healthy control cohort (HC). The HC tree is used to classify whether the observed marker distribution (either patients with amyotrophic lateral sclerosis (ALS) or HC) is predicted. The relative number of cells where the probability q is equal to zero is calculated reflecting the similarity in the marker distribution between a randomly chosen mFC file (ALS or HC) and the HC tree. Results: Including peripheral blood mFC data from 68 ALS and 35 HC, the algorithm could correctly identify 64/68 ALS cases. Tuning of parameters revealed that the combination of 7 markers, 200 bins, and 20 patients achieved the highest AUC on a significance level of p < 0.0001. The markers CD4 and CD38 showed the highest zero probability. We successfully validated our approach by including a second, independent ALS and HC cohort (55 ALS and 30 HC). In this case, all ALS were correctly identified and side scatter and CD20 yielded the highest zero probability. Finally, both datasets were analyzed by the commercially available algorithm 'Citrus', which indicated superior ability of Bayesian network analysis when including raw, ungated mFC data. Discussion: Bayesian network analysis might present a novel approach for classifying mFC data, which does not rely on reduction techniques, thus, allowing to retain information on the entire dataset. Future studies will have to assess the performance when discriminating clinically relevant differential diagnoses to evaluate the complementary diagnostic benefit of Bayesian network analysis to the clinical routine workup. [ABSTRACT FROM AUTHOR]
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- 2023
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10. Driving time-based identification of gaps in specialised care coverage: An example of neuroinflammatory diseases in Germany.
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Masanneck, Lars, Räuber, Saskia, Schroeter, Christina B, Lehnerer, Sophie, Ziemssen, Tjalf, Ruck, Tobias, Meuth, Sven G., and Pawlitzki, Marc
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- 2023
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11. Cladribine treatment improves cortical network functionality in a mouse model of autoimmune encephalomyelitis.
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Schroeter, Christina B., Rolfes, Leoni, Gothan, K. S. Sophie, Gruchot, Joel, Herrmann, Alexander M., Bock, Stefanie, Fazio, Luca, Henes, Antonia, Narayanan, Venu, Pfeuffer, Steffen, Nelke, Christopher, Räuber, Saskia, Huntemann, Niklas, Duarte-Silva, Eduardo, Dobelmann, Vera, Hundehege, Petra, Wiendl, Heinz, Raba, Katharina, Küry, Patrick, and Kremer, David
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Background: Cladribine is a synthetic purine analogue that interferes with DNA synthesis and repair next to disrupting cellular proliferation in actively dividing lymphocytes. The compound is approved for the treatment of multiple sclerosis (MS). Cladribine can cross the blood-brain barrier, suggesting a potential effect on central nervous system (CNS) resident cells. Here, we explored compartment-specific immunosuppressive as well as potential direct neuroprotective effects of oral cladribine treatment in experimental autoimmune encephalomyelitis (EAE) mice.Methods: In the current study, we compare immune cell frequencies and phenotypes in the periphery and CNS of EAE mice with distinct grey and white matter lesions (combined active and focal EAE) either orally treated with cladribine or vehicle, using flow cytometry. To evaluate potential direct neuroprotective effects, we assessed the integrity of the primary auditory cortex neuronal network by studying neuronal activity and spontaneous synaptic activity with electrophysiological techniques ex vivo.Results: Oral cladribine treatment significantly attenuated clinical deficits in EAE mice. Ex vivo flow cytometry showed that cladribine administration led to peripheral immune cell depletion in a compartment-specific manner and reduced immune cell infiltration into the CNS. Histological evaluations revealed no significant differences for inflammatory lesion load following cladribine treatment compared to vehicle control. Single cell electrophysiology in acute brain slices was performed and showed an impact of cladribine treatment on intrinsic cellular firing patterns and spontaneous synaptic transmission in neurons of the primary auditory cortex. Here, cladribine administration in vivo partially restored cortical neuronal network function, reducing action potential firing. Both, the effect on immune cells and neuronal activity were transient.Conclusions: Our results indicate that cladribine exerts a neuroprotective effect after crossing the blood-brain barrier independently of its peripheral immunosuppressant action. [ABSTRACT FROM AUTHOR]- Published
- 2022
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12. High-Dimensional Cytometry Dissects Immunological Fingerprints of Idiopathic Inflammatory Myopathies.
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Nelke, Christopher, Pawlitzki, Marc, Schroeter, Christina B., Huntemann, Niklas, Räuber, Saskia, Dobelmann, Vera, Preusse, Corinna, Roos, Andreas, Allenbach, Yves, Benveniste, Olivier, Wiendl, Heinz, Lundberg, Ingrid E., Stenzel, Werner, Meuth, Sven G., and Ruck, Tobias
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CYTOMETRY ,CYTOTOXIC T cells ,MUSCLE diseases ,B cells ,T cells ,FLOW cytometry ,T helper cells - Abstract
Chronic inflammation of skeletal muscle is the common feature of idiopathic inflammatory myopathies (IIM). Given the rarity of the disease and potential difficulty of routinely obtaining target tissue, i.e., standardized skeletal muscle, our understanding of immune signatures of the IIM spectrum remains incomplete. Further insight into the immune topography of IIM is needed to determine specific treatment targets according to clinical and immunological phenotypes. Thus, we used high-dimensional flow cytometry to investigate the immune phenotypes of anti-synthetase syndrome (ASyS), dermatomyositis (DM) and inclusion-body myositis (IBM) patients as representative entities of the IIM spectrum and compared them to healthy controls. We studied the CD8, CD4 and B cell compartments in the blood aiming to provide a contemporary overview of the immune topography of the IIM spectrum. ASyS was characterized by altered CD4 composition and expanded T follicular helper cells supporting B cell-mediated autoimmunity. For DM, unsupervised clustering identified expansion of distinct B cell subtypes highly expressing immunoglobulin G4 (IgG4) and CD38. Lastly, terminally differentiated, cytotoxic CD8 T cells distinguish IBM from other IIM. Interestingly, these terminally differentiated CD8 T cells highly expressed the integrin CD18 mediating cellular adhesion and infiltration. The distinct immune cell topography of IIM might provide the framework for targeted treatment approaches potentially improving therapeutic outcomes. [ABSTRACT FROM AUTHOR]
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- 2022
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13. Immune response to SARS-CoV-2 vaccination in relation to peripheral immune cell profiles among patients with multiple sclerosis receiving ocrelizumab.
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Räuber, Saskia, Korsen, Melanie, Huntemann, Niklas, Rolfes, Leoni, Müntefering, Thomas, Dobelmann, Vera, Hermann, Alexander M., Kölsche, Tristan, von Wnuck Lipinski, Karin, Schroeter, Christina B., Nelke, Christopher, Regner-Nelke, Liesa, Ingwersen, Jens, Pawlitzki, Marc, Teegen, Bianca, Barnett, Michael Harry, Hartung, Hans-Peter, Aktas, Orhan, Albrecht, Philipp, and Levkau, Bodo
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- 2022
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14. Activation of non-classical NMDA receptors by glycine impairs barrier function of brain endothelial cells.
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Epping, Lisa, Schroeter, Christina B., Nelke, Christopher, Bock, Stefanie, Gola, Lukas, Ritter, Nadine, Herrmann, Alexander M., Räuber, Saskia, Henes, Antonia, Wasser, Beatrice, Fernandez-Orth, Juncal, Neuhaus, Winfried, Bittner, Stefan, Budde, Thomas, Platten, Michael, Kovac, Stjepana, Seebohm, Guiscard, Ruck, Tobias, Cerina, Manuela, and Meuth, Sven G.
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Blood–brain barrier (BBB) integrity is necessary to maintain homeostasis of the central nervous system (CNS). NMDA receptor (NMDAR) function and expression have been implicated in BBB integrity. However, as evidenced in neuroinflammatory conditions, BBB disruption contributes to immune cell infiltration and propagation of inflammatory pathways. Currently, our understanding of the pathophysiological role of NMDAR signaling on endothelial cells remains incomplete. Thus, we investigated NMDAR function on primary mouse brain microvascular endothelial cells (MBMECs). We detected glycine-responsive NMDAR channels, composed of functional GluN1, GluN2A and GluN3A subunits. Importantly, application of glycine alone, but not glutamate, was sufficient to induce NMDAR-mediated currents and an increase in intracellular Ca
2+ concentrations. Functionally, glycine-mediated NMDAR activation leads to loss of BBB integrity and changes in actin distribution. Treatment of oocytes that express NMDARs composed of different subunits, with GluN1 and GluN3A binding site inhibitors, resulted in abrogation of NMDAR signaling as measured by two-electrode voltage clamp (TEVC). This effect was only detected in the presence of the GluN2A subunits, suggesting the latter as prerequisite for pharmacological modulation of NMDARs on brain endothelial cells. Taken together, our findings argue for a novel role of glycine as NMDAR ligand on endothelial cells shaping BBB integrity. [ABSTRACT FROM AUTHOR]- Published
- 2022
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15. Neuromyotonia with Central Nervous System Lesions following Quadrivalent Human Papilloma Virus Vaccination.
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Hatami, Maryam, Förster, Moritz, Weyers, Vivien, Räuber, Saskia, Meuth, Sven G., and Kremer, David
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PAPILLOMAVIRUSES ,CENTRAL nervous system ,ISAACS syndrome ,PERIPHERAL nervous system ,VACCINATION - Abstract
Neuromyotonia is a rare peripheral nerve hyperexcitability syndrome often associated with antibodies directed against contactin-associated protein-like 2 and leucine-rich, glioma inactivated 1. The quadrivalent human papilloma virus vaccine Gardasil
® , first approved in 2006, is known to be a highly effective prophylaxis against papillomavirus types 6, 11, 16, and 18. Molecularly, this non-infectious recombinant vaccine is based on purified L1 proteins from the human papilloma virus capsid. Since the approval of this vaccine, several studies have investigated its safety regarding the occurrence of autoimmune conditions following application. Here, we present the first case of neuromyotonia with active Gadolinium enhancing demyelinating central nervous system lesions following vaccination with Gardasil® . [ABSTRACT FROM AUTHOR]- Published
- 2022
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16. Modulation of Rxr α Expression in Mononuclear Phagocytes Impacts on Cardiac Remodeling after Ischemia-Reperfusion Injury.
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Räuber, Saskia, Fischer, Maximilian, Messerer, Denise, Wimmler, Vanessa, Konda, Kumaraswami, Todica, Andrei, Lorenz, Michael, Titova, Anna, Schulz, Christian, and Weinberger, Tobias
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MACROPHAGES ,REPERFUSION injury ,RETINOID X receptors ,NUCLEAR receptors (Biochemistry) ,IMMUNE response - Abstract
Retinoid X receptors (RXRs), as members of the steroid/thyroid hormone superfamily of nuclear receptors, are crucial regulators of immune response during health and disease. RXR subtype expression is dependent on tissue and cell type, RXRα being the relevant isoform in monocytes and macrophages. Previous studies have assessed different functions of RXRs and positive implications of RXR agonists on outcomes after ischemic injuries have been described. However, the impact of a reduced Rxrα expression in mononuclear phagocytes on cardiac remodeling after myocardial infarction (MI) has not been investigated to date. Here, we use a temporally controlled deletion of Rxrα in monocytes and macrophages to determine its role in ischemia-reperfusion injury. We show that reduced expression of Rxrα in mononuclear phagocytes leads to a decreased phagocytic activity and an accumulation of apoptotic cells in the myocardium, reduces angiogenesis and cardiac macrophage proliferation in the infarct border zone/infarct area, and has an impact on monocyte/macrophage subset composition. These changes are associated with a greater myocardial defect 30 days after ischemia/reperfusion injury. Overall, the reduction of Rxrα levels in monocytes and macrophages negatively impacts cardiac remodeling after myocardial infarction. Thus, RXRα might represent a therapeutic target to regulate the immune response after MI in order to improve cardiac remodeling. [ABSTRACT FROM AUTHOR]
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- 2022
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17. Neuropsychological Performance in Autoimmune Limbic Encephalitis: Evidence from an Immunotherapy-Naïve Cohort.
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Mueller, Christoph, Langenbruch, Lisa, Rau, Johanna M H, Brix, Tobias, Strippel, Christine, Dik, Andre, Golombeck, Kristin S, Mönig, Constanze, Johnen, Andreas, Räuber, Saskia, Wiendl, Heinz, Meuth, Sven G, Bölte, Jens, Kovac, Stjepana, and Melzer, Nico
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EXECUTIVE function ,RECOGNITION (Psychology) ,EMOTION recognition ,ENCEPHALITIS ,LIMBIC system ,APRAXIA ,EPISODIC memory - Abstract
Objective Autoimmune limbic encephalitis (ALE) is characterized by memory impairment, psychiatric symptoms, and epileptic seizures. Though, the neuropsychological profile of ALE is not yet well defined. However, there is some evidence that neuropsychological impairments might exceed those related to the limbic system and that different autoantibodies (AABs) are associated with distinguishable pattern of neuropsychological impairments. We provide a comprehensive presentation of neuropsychological performance of ALE in an immune therapy-naïve sample. Methods We retrospectively analyzed 69 immunotherapy-naïve ALE-patients (26 seropositive—[8 LGI1-, 4 CASPR2-, 2 GABA
B -R-, 3 Hu-, 4 GAD65-, 2 Ma2-, 2 unknown antigen, and 1 Yo-AABs] and 43 seronegative patients, mean age 56.0 years [21.9–78.2], mean disease duration 88 weeks [0–572]). Neuropsychological evaluations comprised of the domains memory, attention, praxis, executive functions, language, social cognition, and psychological symptoms. We compared these functions between seronegative −, seropositive patients with AABs against intracellular neural antigens and seropositive patients with AABs against surface membrane neural antigens. Results No effect of AAB group on neuropsychological performance could be detected. Overall, ALE predominantly presents with deficits in long-term memory and memory recognition, autobiographical-episodic memory loss, impairment of emotion recognition, and depressed mood. Furthermore, deficits in praxis of pantomimes and imitations, visuo-construction, and flexibility may occur. Conclusion ALE shows a wide spectrum of neuropsychological impairments, which might exceed the limbic system, with no evidence of differences between AAB groups. Neuropsychological assessment for diagnosing ALE should include long-term memory, memory recognition, autobiographical-episodic memory, emotion recognition, and a detailed investigation of depression. [ABSTRACT FROM AUTHOR]- Published
- 2022
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18. Impact of T cells on neurodegeneration in anti‐GAD65 limbic encephalitis.
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Dik, Andre, Widman, Guido, Schulte‐Mecklenbeck, Andreas, Witt, Juri‐Alexander, Pitsch, Julika, Golombeck, Kristin S., Wagner, Jan, Gallus, Marco, Strippel, Christine, Hansen, Niels, Mönig, Constanze, Räuber, Saskia, Wiendl, Heinz, Elger, Christian E., Surges, Rainer, Meuth, Sven G., Helmstaedter, Christoph, Gross, Catharina C., Becker, Albert J., and Melzer, Nico
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T cells ,REGULATORY T cells ,GLUTAMATE decarboxylase ,ENCEPHALITIS ,HLA histocompatibility antigens ,PERFORINS - Abstract
Objective: Direct pathogenic effects of autoantibodies to the 65 kDa isoform of glutamic acid decarboxylase (GAD65) in autoimmune limbic encephalitis (LE) have been questioned due to its intracellular localization. We therefore hypothesized a pathogenic role for T cells. Methods: We assessed magnet resonance imaging, neuropsychological and peripheral blood, and CSF flow cytometry data of 10 patients with long‐standing GAD65‐LE compared to controls in a cross‐sectional manner. These data were related to each other within the GAD65‐LE group and linked to neuropathological findings in selective hippocampectomy specimen from another two patients. In addition, full‐resolution human leukocyte antigen (HLA) genotyping of all patients was performed. Results: Compared to controls, no alteration in hippocampal volume but impaired memory function and elevated fractions of activated HLADR+ CD4+ and CD8+ T cells in peripheral blood and cerebrospinal fluid were found. Intrathecal fractions of CD8+ T cells negatively correlated with hippocampal volume and memory function, whereas the opposite was true for CD4+ T cells. Consistently, antigen‐experienced CD8+ T cells expressed increased levels of the cytotoxic effector molecule perforin in peripheral blood, and perforin‐expressing CD8+ T cells were found attached mainly to small interneurons but also to large principal neurons together with wide‐spread hippocampal neurodegeneration. 6/10 LE patients harbored the HLA‐A*02:01 allele known to present the immunodominant GAD65114–123 peptide in humans. Interpretation: Our data suggest a pathogenic effect of CD8+ T cells and a regulatory effect of CD4+ T cells in patients with long‐standing GAD65‐LE. [ABSTRACT FROM AUTHOR]
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- 2021
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19. Cerebrospinal fluid proteomics indicates immune dysregulation and neuronal dysfunction in antibody associated autoimmune encephalitis.
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Räuber, Saskia, Schroeter, Christina B., Strippel, Christine, Nelke, Christopher, Ruland, Tillmann, Dik, Andre, Golombeck, Kristin S., Regner-Nelke, Liesa, Paunovic, Manuela, Esser, Daniela, Münch, Christian, Rosenow, Felix, van Duijn, Martijn, Henes, Antonia, Ruck, Tobias, Amit, Ido, Leypoldt, Frank, Titulaer, Maarten J., Wiendl, Heinz, and Meuth, Sven G.
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ANTI-NMDA receptor encephalitis , *CEREBROSPINAL fluid , *PROTEOMICS , *GLUTAMATE decarboxylase , *HUMORAL immunity , *CENTRAL nervous system - Abstract
Autoimmune Encephalitis (AE) spans a group of non-infectious inflammatory conditions of the central nervous system due to an imbalanced immune response. Aiming to elucidate the pathophysiological mechanisms of AE, we applied an unsupervised proteomic approach to analyze the cerebrospinal fluid (CSF) protein profile of AE patients with autoantibodies against N -methyl- d -aspartate receptor (NMDAR) (n = 9), leucine-rich glioma-inactivated protein 1 (LGI1) (n = 9), or glutamate decarboxylase 65 (GAD65) (n = 8) compared to 9 patients with relapsing-remitting multiple sclerosis as inflammatory controls, and 10 patients with somatic symptom disorder as non-inflammatory controls. We found a dysregulation of the complement system, a disbalance between pro-inflammatory and anti-inflammatory proteins on the one hand, and dysregulation of proteins involved in synaptic transmission, synaptogenesis, brain connectivity, and neurodegeneration on the other hand to a different extent in all AE subtypes compared to non-inflammatory controls. Furthermore, elevated levels of several proteases and reduction in protease inhibitors could be detected in all AE subtypes compared to non-inflammatory controls. Moreover, the different AE subtypes showed distinct protein profiles compared to each other and inflammatory controls which may facilitate future identification of disease-specific biomarkers. Overall, CSF proteomics provides insights into the complex pathophysiological mechanisms of AE, including immune dysregulation, neuronal dysfunction, neurodegeneration, and altered protease function. • AE feature a dysregulation of CSF proteins involved in the cellular and humoral immune response. • Proteins associated with neuronal function and neurodegeneration are differentially regulated in AE compared to controls. • Higher levels of proteases and reduction in protease inhibitors could be detected in all AE subtypes compared to controls. • AE subtypes show distinct protein profiles, which could facilitate identification of potential disease-specific biomarkers. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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20. Nitrosative Stress Molecules in Multiple Sclerosis: A Meta-Analysis.
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Förster, Moritz, Nelke, Christopher, Räuber, Saskia, Lassmann, Hans, Ruck, Tobias, Sormani, Maria Pia, Signori, Alessio, Hartung, Hans-Peter, Küry, Patrick, Meuth, Sven G., and Kremer, David
- Subjects
MULTIPLE sclerosis ,CENTRAL nervous system diseases ,RANDOM effects model ,NEUROLOGICAL disorders - Abstract
Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system of unknown etiology. As it is still a diagnosis of exclusion, there is an urgent need for biomarkers supporting its diagnosis. Increasing evidence suggests that nitrosative stress may play a pivotal role in the pathogenesis of MS. However, previous reports supporting the role of nitrosative stress molecules as disease biomarkers are inconsistent overall. We therefore systematically analyzed the existing literature to compare the serum and cerebrospinal fluid (CSF) levels of nitrite/nitrate in MS patients with those in patients with noninflammatory other neurological diseases (NIOND) and healthy controls (HC), respectively. We searched the PubMed database and included original articles investigating nitrite/nitrate levels in MS patients and NIOND patients or HC based on predefined selection criteria. Effect sizes were estimated by the standardized mean difference using a random effects model. Our results suggest that MS is associated with higher nitrite/nitrate levels within the CSF compared with patients with NIOND (SMD of 1.51; 95% CI: 0.72, 2.30; p = 0.0008). Likewise, nitrite/nitrate in the CSF of MS patients trends towards increased levels compared with those of HC but does not reach statistical significance (SMD of 3.35; 95% CI: −0.48, 7.19; p = 0.07). Measurement of nitrite/nitrate in the CSF might be a valuable tool facilitating the differentiation of MS and NIOND. Further studies with more homogeneous study criteria are needed to corroborate this hypothesis. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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21. NK Cell Patterns in Idiopathic Inflammatory Myopathies with Pulmonary Affection.
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Pawlitzki, Marc, Nelke, Christopher, Rolfes, Leoni, Hasseli, Rebecca, Tomaras, Stylianos, Feist, Eugen, Schänzer, Anne, Räuber, Saskia, Regner, Liesa, Preuße, Corinna, Allenbach, Yves, Benveniste, Olivier, Wiendl, Heinz, Stenzel, Werner, Meuth, Sven G., and Ruck, Tobias
- Subjects
KILLER cells ,CELL aggregation ,DERMATOMYOSITIS ,THERAPEUTICS ,VITAL capacity (Respiration) ,T cells ,B cells - Abstract
Background: Pulmonary affection (PA) is associated with a substantial increase in morbidity and mortality in patients with idiopathic inflammatory myopathies (IIM). However, the underlying immune mechanisms of PA remain enigmatic and prompt deeper immunological analyses. Importantly, the Janus-faced role of natural killer (NK) cells, capable of pro-inflammatory as well as regulatory effects, might be of interest for the pathophysiologic understanding of PA in IIM. Methods: To extend our understanding of immunological alterations in IIM patients with PA, we compared the signatures of NK cells in peripheral blood using multi-color flow cytometry in IIM patients with (n = 12, of which anti-synthetase syndrome = 8 and dermatomyositis = 4) or without PA (n = 12). Results: We did not observe any significant differences for B cells, CD4, and CD8 T cells, while total NK cell numbers in IIM patients with PA were reduced compared to non-PA patients. NK cell alterations were driven by a particular decrease of CD56
dim NK cells, while CD56bright NK cells remained unchanged. Comparisons of the cell surface expression of a large panel of NK receptors revealed an increased mean fluorescence intensity of NKG2D+ on NK cells from patients with PA compared with non-PA patients, especially on the CD56dim subset. NKG2D+ and NKp46+ cell surface levels were associated with reduced vital capacity, serving as a surrogate marker for clinical severity of PA. Conclusion: Our data illustrate that PA in IIM is associated with alterations of the NK cell repertoire, suggesting a relevant contribution of NK cells in certain IIMs, which might pave the way for NK cell-targeted therapeutic approaches. [ABSTRACT FROM AUTHOR]- Published
- 2021
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22. Social interaction, psychotic disorders and inflammation: A triangle of interest.
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Faustmann, Timo Jendrik, Kamp, Daniel, Räuber, Saskia, Dukart, Juergen, Melzer, Nico, and Schilbach, Leonhard
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PSYCHOSES , *SOCIAL interaction , *SOCIAL influence , *SOCIAL processes , *SOCIAL skills , *TRIANGLES - Abstract
Social interaction difficulties are a hallmark of psychotic disorders, which in some cases can be definitely traced back to autoimmunological causes. Interestingly, systemic and intrathecal inflammation have been shown to significantly influence social processing by increasing sensitivity to threatening social stimuli, which bears some resemblance to psychosis. In this article, we review evidence for the involvement of systemic and intrathecal inflammatory processes in psychotic disorders and how this might help to explain some of the social impairments associated with this group of disorders. Vice versa, we also discuss evidence for the immunomodulatory function of social interactions and their potential role for therapeutic interventions in psychotic disorders. • Deficits in social interaction could aggravate symptoms of psychotic disorders. • Psychotic disorders are associated, in some cases, with low-grade inflammation. • Inflammation influences social interaction in multiple and contradicting ways. • Diagnostic tools integrating inflammation/psychosis/social aspects are required. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
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