Momsen Reincke

All Publications

• Single-cell peripheral immunoprofiling of lewy body and Parkinson's disease in a multi-site cohort. Molecular neurodegeneration Phongpreecha, T., Mathi, K., Cholerton, B., Fox, E. J., Sigal, N., Espinosa, C., Reincke, M., Chung, P., Hwang, L. J., Gajera, C. R., Berson, E., Perna, A., Xie, F., Shu, C. H., Hazra, D., Channappa, D., Dunn, J. E., Kipp, L. B., Poston, K. L., Montine, K. S., Maecker, H. T., Aghaeepour, N., Montine, T. J. 2024; 19 (1): 59

  Abstract

  Multiple lines of evidence support peripheral organs in the initiation or progression of Lewy body disease (LBD), a spectrum of neurodegenerative diagnoses that include Parkinson's Disease (PD) without or with dementia (PDD) and dementia with Lewy bodies (DLB). However, the potential contribution of the peripheral immune response to LBD remains unclear. This study aims to characterize peripheral immune responses unique to participants with LBD at single-cell resolution to highlight potential biomarkers and increase mechanistic understanding of LBD pathogenesis in humans.In a case-control study, peripheral mononuclear cell (PBMC) samples from research participants were randomly sampled from multiple sites across the United States. The diagnosis groups comprise healthy controls (HC, n = 159), LBD (n = 110), Alzheimer's disease dementia (ADD, n = 97), other neurodegenerative disease controls (NDC, n = 19), and immune disease controls (IDC, n = 14). PBMCs were activated with three stimulants (LPS, IL-6, and IFNa) or remained at basal state, stained by 13 surface markers and 7 intracellular signal markers, and analyzed by flow cytometry, which generated 1,184 immune features after gating.The model classified LBD from HC with an AUROC of 0.87 ± 0.06 and AUPRC of 0.80 ± 0.06. Without retraining, the same model was able to distinguish LBD from ADD, NDC, and IDC. Model predictions were driven by pPLCγ2, p38, and pSTAT5 signals from specific cell populations under specific activation. The immune responses characteristic for LBD were not associated with other common medical conditions related to the risk of LBD or dementia, such as sleep disorders, hypertension, or diabetes.Quantification of PBMC immune response from multisite research participants yielded a unique pattern for LBD compared to HC, multiple related neurodegenerative diseases, and autoimmune diseases thereby highlighting potential biomarkers and mechanisms of disease.

  View details for DOI 10.1186/s13024-024-00748-2

  View details for PubMedID 39090623

  View details for PubMedCentralID 9739123

• Comprehensive overview of the anesthesiology research landscape: A machine Learning Analysis of 737 NIH-funded anesthesiology primary Investigator's publication trends. Heliyon Ghanem, M., Espinosa, C., Chung, P., Reincke, M., Harrison, N., Phongpreecha, T., Shome, S., Saarunya, G., Berson, E., James, T., Xie, F., Shu, C. H., Hazra, D., Mataraso, S., Kim, Y., Seong, D., Chakraborty, D., Studer, M., Xue, L., Marić, I., Chang, A. L., Tjoa, E., Gaudillière, B., Tawfik, V. L., Mackey, S., Aghaeepour, N. 2024; 10 (7): e29050

  Abstract

  Anesthesiology plays a crucial role in perioperative care, critical care, and pain management, impacting patient experiences and clinical outcomes. However, our understanding of the anesthesiology research landscape is limited. Accordingly, we initiated a data-driven analysis through topic modeling to uncover research trends, enabling informed decision-making and fostering progress within the field.The easyPubMed R package was used to collect 32,300 PubMed abstracts spanning from 2000 to 2022. These abstracts were authored by 737 Anesthesiology Principal Investigators (PIs) who were recipients of National Institute of Health (NIH) funding from 2010 to 2022. Abstracts were preprocessed, vectorized, and analyzed with the state-of-the-art BERTopic algorithm to identify pillar topics and trending subtopics within anesthesiology research. Temporal trends were assessed using the Mann-Kendall test.The publishing journals with most abstracts in this dataset were Anesthesia & Analgesia 1133, Anesthesiology 992, and Pain 671. Eight pillar topics were identified and categorized as basic or clinical sciences based on a hierarchical clustering analysis. Amongst the pillar topics, "Cells & Proteomics" had both the highest annual and total number of abstracts. Interestingly, there was an overall upward trend for all topics spanning the years 2000-2022. However, when focusing on the period from 2015 to 2022, topics "Cells & Proteomics" and "Pulmonology" exhibit a downward trajectory. Additionally, various subtopics were identified, with notable increasing trends in "Aneurysms", "Covid 19 Pandemic", and "Artificial intelligence & Machine Learning".Our work offers a comprehensive analysis of the anesthesiology research landscape by providing insights into pillar topics, and trending subtopics. These findings contribute to a better understanding of anesthesiology research and can guide future directions.

  View details for DOI 10.1016/j.heliyon.2024.e29050

  View details for PubMedID 38623206

  View details for PubMedCentralID PMC11016610

• Chimeric autoantibody receptor T cells deplete NMDA receptor-specific B cells. Cell Reincke, S. M., von Wardenburg, N., Homeyer, M. A., Kornau, H. C., Spagni, G., Li, L. Y., Kreye, J., Sánchez-Sendín, E., Blumenau, S., Stappert, D., Radbruch, H., Hauser, A. E., Künkele, A., Edes, I., Schmitz, D., Prüss, H. 2023

  Abstract

  Anti-NMDA receptor (NMDAR) autoantibodies cause NMDAR encephalitis, the most common autoimmune encephalitis, leading to psychosis, seizures, and autonomic dysfunction. Current treatments comprise broad immunosuppression or non-selective antibody removal. We developed NMDAR-specific chimeric autoantibody receptor (NMDAR-CAAR) T cells to selectively eliminate anti-NMDAR B cells and disease-causing autoantibodies. NMDAR-CAARs consist of an extracellular multi-subunit NMDAR autoantigen fused to intracellular 4-1BB/CD3ζ domains. NMDAR-CAAR T cells recognize a large panel of human patient-derived autoantibodies, release effector molecules, proliferate, and selectively kill antigen-specific target cell lines even in the presence of high autoantibody concentrations. In a passive transfer mouse model, NMDAR-CAAR T cells led to depletion of an anti-NMDAR B cell line and sustained reduction of autoantibody levels without notable off-target toxicity. Treatment of patients may reduce side effects, prevent relapses, and improve long-term prognosis. Our preclinical work paves the way for CAAR T cell phase I/II trials in NMDAR encephalitis and further autoantibody-mediated diseases.

  View details for DOI 10.1016/j.cell.2023.10.001

  View details for PubMedID 37918394

• Preclinical safety and efficacy of a therapeutic antibody that targets SARS-CoV-2 at the sotrovimab face but is escaped by Omicron. iScience Kreye, J., Reincke, S. M., Edelburg, S., Jeworowski, L. M., Kornau, H., Trimpert, J., Hombach, P., Halbe, S., Nolle, V., Meyer, M., Kattenbach, S., Sanchez-Sendin, E., Schmidt, M. L., Schwarz, T., Rose, R., Krumbholz, A., Merz, S., Adler, J. M., Eschke, K., Abdelgawad, A., Schmitz, D., Sander, L. E., Janssen, U., Corman, V. M., Pruss, H. 2023; 26 (4): 106323

  Abstract

  The recurrent emerging of novel viral variants of concern (VOCs) with evasion of preexisting antibody immunity upholds severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) case numbers and maintains a persistent demand for updated therapies. We selected the patient-derived antibody CV38-142 based on its potency and breadth against the VOCs Alpha, Beta, Gamma, and Delta for preclinical development into a therapeutic. CV38-142 showed invivo efficacy in a Syrian hamster VOC infection model after post-exposure and therapeutic application and revealed a favorable safety profile in a human protein library screen and tissue cross-reactivity study. Although CV38-142 targets the same viral surface as sotrovimab, which maintains activity against Omicron, CV38-142 did not neutralize the Omicron lineages BA.1 and BA.2. These results highlight the contingencies of developing antibody therapeutics in the context of antigenic drift and reinforce the need to develop broadly neutralizing variant-proof antibodies against SARS-CoV-2.

  View details for DOI 10.1016/j.isci.2023.106323

  View details for PubMedID 36925720

• Antigenic imprinting in SARS-CoV-2 CLINICAL AND TRANSLATIONAL MEDICINE Reincke, S., Pruss, H., Wilson, I. A., Kreye, J. 2022; 12 (7): e923

  View details for DOI 10.1002/ctm2.923

  View details for Web of Science ID 000822203000001

  View details for PubMedID 35808842

  View details for PubMedCentralID PMC9270639

• Intravenous immunoglobulins for treatment of severe COVID-19-related acute encephalopathy JOURNAL OF NEUROLOGY Huo, S., Ferse, C., Boesl, F., Reincke, S., Enghard, P., Hinrichs, C., Treskatsch, S., Angermair, S., Eckardt, K., Audebert, H. J., Ploner, C. J., Endres, M., Pruess, H., Franke, C., Scheibe, F. 2022; 269 (8): 4013-4020

  View details for DOI 10.1007/s00415-022-11152-5

  View details for Web of Science ID 000793065000003

  View details for PubMedID 35538168

  View details for PubMedCentralID PMC9089297

• Key benefits of dexamethasone and antibody treatment in COVID-19 hamster models revealed by single-cell transcriptomics MOLECULAR THERAPY Wyler, E., Adler, J. M., Eschke, K., Alves, G., Peidli, S., Pott, F., Kazmierski, J., Michalick, L., Kershaw, O., Bushe, J., Andreotti, S., Pennitz, P., Abdelgawad, A., Postmus, D., Goffinet, C., Kreye, J., Reincke, S., Pruess, H., Bluethgen, N., Gruber, A. D., Kuebler, W. M., Witzenrath, M., Landthaler, M., Nouailles, G., Trimpert, J. 2022; 30 (5): 1952-1965

  Abstract

  For coronavirus disease 2019 (COVID-19), effective and well-understood treatment options are still scarce. Since vaccine efficacy is challenged by novel variants, short-lasting immunity, and vaccine hesitancy, understanding and optimizing therapeutic options remains essential. We aimed at better understanding the effects of two standard-of-care drugs, dexamethasone and anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies, on infection and host responses. By using two COVID-19 hamster models, pulmonary immune responses were analyzed to characterize effects of single or combinatorial treatments. Pulmonary viral burden was reduced by anti-SARS-CoV-2 antibody treatment and unaltered or increased by dexamethasone alone. Dexamethasone exhibited strong anti-inflammatory effects and prevented fulminant disease in a severe disease model. Combination therapy showed additive benefits with both anti-viral and anti-inflammatory potency. Bulk and single-cell transcriptomic analyses confirmed dampened inflammatory cell recruitment into lungs upon dexamethasone treatment and identified a specifically responsive subpopulation of neutrophils, thereby indicating a potential mechanism of action. Our analyses confirm the anti-inflammatory properties of dexamethasone and suggest possible mechanisms, validate anti-viral effects of anti-SARS-CoV-2 antibody treatment, and reveal synergistic effects of a combination therapy, thus informing more effective COVID-19 therapies.

  View details for DOI 10.1016/j.ymthe.2022.03.014

  View details for Web of Science ID 000799823700015

  View details for PubMedID 35339689

  View details for PubMedCentralID PMC8942568

• SARS-CoV-2 Beta variant infection elicits potent lineage-specific and cross-reactive antibodies. Science (New York, N.Y.) Reincke, S. M., Yuan, M., Kornau, H. C., Corman, V. M., van Hoof, S., Sánchez-Sendin, E., Ramberger, M., Yu, W., Hua, Y., Tien, H., Schmidt, M. L., Schwarz, T., Jeworowski, L. M., Brandl, S. E., Rasmussen, H. F., Homeyer, M. A., Stöffler, L., Barner, M., Kunkel, D., Huo, S., Horler, J., von Wardenburg, N., Kroidl, I., Eser, T. M., Wieser, A., Geldmacher, C., Hoelscher, M., Gänzer, H., Weiss, G., Schmitz, D., Drosten, C., Prüss, H., Wilson, I. A., Kreye, J. 2022; 375 (6582): 782-787

  Abstract

  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Beta variant of concern (VOC) resists neutralization by major classes of antibodies from COVID-19 patients and vaccinated individuals. In this study, serum of Beta-infected patients revealed reduced cross-neutralization of wild-type virus. From these patients, we isolated Beta-specific and cross-reactive receptor-binding domain (RBD) antibodies. The Beta-specificity results from recruitment of VOC-specific clonotypes and accommodation of mutations present in Beta and Omicron into a major antibody class that is normally sensitive to these mutations. The Beta-elicited cross-reactive antibodies share genetic and structural features with wild type-elicited antibodies, including a public VH1-58 clonotype that targets the RBD ridge. These findings advance our understanding of the antibody response to SARS-CoV-2 shaped by antigenic drift, with implications for design of next-generation vaccines and therapeutics.

  View details for DOI 10.1126/science.abm5835

  View details for PubMedID 35076281

  View details for PubMedCentralID PMC8939768

• Encephalitis patient-derived monoclonal GABA(A) receptor antibodies cause epileptic seizures JOURNAL OF EXPERIMENTAL MEDICINE Kreye, J., Wright, S. K., van Casteren, A., Stoffler, L., Machule, M., Reincke, S., Nikolaus, M., van Hoof, S., Sanchez-Sendin, E., Homeyer, M. A., Gomez, C., Kornau, H., Schmitz, D., Kaindl, A. M., Boehm-Sturm, P., Mueller, S., Wilson, M. A., Upadhya, M. A., Dhangar, D. R., Greenhill, S., Woodhall, G., Turko, P., Vida, I., Garner, C. C., Wickel, J., Geis, C., Fukata, Y., Fukata, M., Pruss, H. 2021; 218 (11)

  Abstract

  Autoantibodies targeting the GABAA receptor (GABAAR) hallmark an autoimmune encephalitis presenting with frequent seizures and psychomotor abnormalities. Their pathogenic role is still not well-defined, given the common overlap with further autoantibodies and the lack of patient-derived mAbs. Five GABAAR mAbs from cerebrospinal fluid cells bound to various epitopes involving the α1 and γ2 receptor subunits, with variable binding strength and partial competition. mAbs selectively reduced GABAergic currents in neuronal cultures without causing receptor internalization. Cerebroventricular infusion of GABAAR mAbs and Fab fragments into rodents induced a severe phenotype with seizures and increased mortality, reminiscent of encephalitis patients' symptoms. Our results demonstrate direct pathogenicity of autoantibodies on GABAARs independent of Fc-mediated effector functions and provide an animal model for GABAAR encephalitis. They further provide the scientific rationale for clinical treatments using antibody depletion and can serve as tools for the development of antibody-selective immunotherapies.

  View details for DOI 10.1084/jem.20210012

  View details for Web of Science ID 000707487900001

  View details for PubMedID 34546336

  View details for PubMedCentralID PMC8480667

• A combination of cross-neutralizing antibodies synergizes to prevent SARS-CoV-2 and SARS-CoV pseudovirus infection CELL HOST & MICROBE Liu, H., Yuan, M., Huang, D., Bangaru, S., Zhao, F., Lee, C. D., Peng, L., Barman, S., Zhu, X., Nemazee, D., Burton, D. R., van Gils, M. J., Sanders, R. W., Kornau, H., Reincke, S., Pruss, H., Kreye, J., Wu, N. C., Ward, A. B., Wilson, I. A. 2021; 29 (5): 806-+

  Abstract

  Coronaviruses have caused several human epidemics and pandemics including the ongoing coronavirus disease 2019 (COVID-19). Prophylactic vaccines and therapeutic antibodies have already shown striking effectiveness against COVID-19. Nevertheless, concerns remain about antigenic drift in SARS-CoV-2 as well as threats from other sarbecoviruses. Cross-neutralizing antibodies to SARS-related viruses provide opportunities to address such concerns. Here, we report on crystal structures of a cross-neutralizing antibody, CV38-142, in complex with the receptor-binding domains from SARS-CoV-2 and SARS-CoV. Recognition of the N343 glycosylation site and water-mediated interactions facilitate cross-reactivity of CV38-142 to SARS-related viruses, allowing the antibody to accommodate antigenic variation in these viruses. CV38-142 synergizes with other cross-neutralizing antibodies, notably COVA1-16, to enhance neutralization of SARS-CoV and SARS-CoV-2, including circulating variants of concern B.1.1.7 and B.1.351. Overall, this study provides valuable information for vaccine and therapeutic design to address current and future antigenic drift in SARS-CoV-2 and to protect against zoonotic SARS-related coronaviruses.

  View details for DOI 10.1016/j.chom.2021.04.005

  View details for Web of Science ID 000653680400017

  View details for PubMedID 33894127

  View details for PubMedCentralID PMC8049401

• High frequency of cerebrospinal fluid autoantibodies in COVID-19 patients with neurological symptoms BRAIN BEHAVIOR AND IMMUNITY Franke, C., Ferse, C., Kreye, J., Reincke, S., Sanchez-Sendin, E., Rocco, A., Steinbrenner, M., Angermair, S., Treskatsch, S., Zickler, D., Eckardt, K., Dersch, R., Hosp, J., Audebert, H. J., Endres, M., Ploner, J., Pruess, H. 2021; 93: 415-419

  Abstract

  COVID-19 intensive care patients can present with neurological syndromes, usually in the absence of SARS-CoV-2 in cerebrospinal fluid (CSF). The recent finding of some virus-neutralizing antibodies cross-reacting with brain tissue suggests the possible involvement of specific autoimmunity.Blood and CSF samples from eleven critically ill COVID-19 patients presenting with unexplained neurological symptoms including myoclonus, oculomotor disturbance, delirium, dystonia and epileptic seizures, were analyzed for anti-neuronal and anti-glial autoantibodies.Using cell-based assays and indirect immunofluorescence on unfixed murine brain sections, all patients showed anti-neuronal autoantibodies in serum or CSF. Antigens included intracellular and neuronal surface proteins, such as Yo or NMDA receptor, but also various specific undetermined epitopes, reminiscent of the brain tissue binding observed with certain human monoclonal SARS-CoV-2 antibodies. These included vessel endothelium, astrocytic proteins and neuropil of basal ganglia, hippocampus or olfactory bulb.The high frequency of autoantibodies targeting the brain in the absence of other explanations suggests a causal relationship to clinical symptoms, in particular to hyperexcitability (myoclonus, seizures). Several underlying autoantigens and their potential molecular mimicry with SARS-CoV-2 still await identification. However, autoantibodies may already now explain some aspects of multi-organ disease in COVID-19 and can guide immunotherapy in selected cases.

  View details for DOI 10.1016/j.bbi.2020.12.022

  View details for Web of Science ID 000630772300001

  View details for PubMedID 33359380

  View details for PubMedCentralID PMC7834471

• A Therapeutic Non-self-reactive SARS-CoV-2 Antibody Protects from Lung Pathology in a COVID-19 Hamster Model CELL Kreye, J., Reincke, S., Kornau, H., Sanchez-Sendin, E., Corman, V., Liu, H., Yuan, M., Wu, N. C., Zhu, X., Lee, C. D., Trimpert, J., Hoeltje, M., Dietert, K., Stoeffler, L., von Wardenburg, N., van Hoof, S., Homeyer, M. A., Hoffmann, J., Abdelgawad, A., Gruber, A. D., Bertzbach, L. D., Vladimirova, D., Li, L. Y., Barthel, P., Skriner, K., Hocke, A. C., Hippenstiel, S., Witzenrath, M., Suttorp, N., Kurth, F., Franke, C., Endres, M., Schmitz, D., Jeworowski, L., Richter, A., Schmidt, M., Schwarz, T., Mueller, M., Drosten, C., Wendisch, D., Sander, L. E., Osterrieder, N., Wilson, I. A., Pruess, H. 2020; 183 (4): 1058-+

  Abstract

  The emergence of SARS-CoV-2 led to pandemic spread of coronavirus disease 2019 (COVID-19), manifesting with respiratory symptoms and multi-organ dysfunction. Detailed characterization of virus-neutralizing antibodies and target epitopes is needed to understand COVID-19 pathophysiology and guide immunization strategies. Among 598 human monoclonal antibodies (mAbs) from 10 COVID-19 patients, we identified 40 strongly neutralizing mAbs. The most potent mAb, CV07-209, neutralized authentic SARS-CoV-2 with an IC50 value of 3.1 ng/mL. Crystal structures of two mAbs in complex with the SARS-CoV-2 receptor-binding domain at 2.55 and 2.70 Å revealed a direct block of ACE2 attachment. Interestingly, some of the near-germline SARS-CoV-2-neutralizing mAbs reacted with mammalian self-antigens. Prophylactic and therapeutic application of CV07-209 protected hamsters from SARS-CoV-2 infection, weight loss, and lung pathology. Our results show that non-self-reactive virus-neutralizing mAbs elicited during SARS-CoV-2 infection are a promising therapeutic strategy.

  View details for DOI 10.1016/j.cell.2020.09.049

  View details for Web of Science ID 000588640900019

  View details for PubMedID 33058755

  View details for PubMedCentralID PMC7510528

• Brain antibody sequence evaluation (BASE): an easy-to-use software for complete data analysis in single cell immunoglobulin cloning BMC BIOINFORMATICS Reincke, S., Pruess, H., Kreye, J. 2020; 21 (1): 446

  Abstract

  Repertoire analysis of patient-derived recombinant monoclonal antibodies is an important tool to study the role of B cells in autoimmune diseases of the human brain and beyond. Current protocols for generation of patient-derived recombinant monoclonal antibody libraries are time-consuming and contain repetitive steps, some of which can be assisted with the help of software automation.We developed BASE, an easy-to-use software for complete data analysis in single cell immunoglobulin cloning. BASE consists of two modules: aBASE for immunological annotations and cloning primer lookup, and cBASE for plasmid sequence identity confirmation before expression. Comparing automated BASE analysis with manual analysis we confirmed the validity of BASE output: identity between manual and automated aBASE analysis was 100% for all outputs, except for immunoglobulin isotype determination. In this case, aBASE yielded correct results in 96% of cases, whereas 4% of cases required manual confirmation. cBASE automatically concluded expression recommendations in 89.8% of cases, 91.8% of which were identical to manually derived results and none of them were false-positive.BASE offers an easy-to-use software solution suitable for complete Ig sequence data analysis and tracking during recombinant mAb cloning from single cells. Plasmid sequence identity confirmation by cBASE offers functionality not provided by existing software solutions in the field and will help to reduce time-consuming steps of the monoclonal antibody generation workflow. BASE can be installed locally or accessed online at Code Ocean.

  View details for DOI 10.1186/s12859-020-03741-w

  View details for Web of Science ID 000576178500001

  View details for PubMedID 33032524

  View details for PubMedCentralID PMC7542697

• Do cross-reactive antibodies cause neuropathology in COVID-19? NATURE REVIEWS IMMUNOLOGY Kreye, J., Reincke, S., Pruess, H. 2020; 20 (11): 645-646

  Abstract

  Neurological symptoms are seen in patients with COVID-19 and can persist or re-emerge after clearance of SARS-CoV-2. Recent findings suggest that antibodies to SARS-CoV-2 can cross-react with mammalian proteins. Focusing on neurological symptoms, we discuss whether these cross-reactive antibodies could contribute to COVID-19 disease pathology and to the persistence of symptoms in patients who have cleared the initial viral infection.

  View details for DOI 10.1038/s41577-020-00458-y

  View details for Web of Science ID 000575750000004

  View details for PubMedID 33024283

  View details for PubMedCentralID PMC7537977

• Daratumumab treatment for therapy-refractory anti-CASPR2 encephalitis JOURNAL OF NEUROLOGY Scheibe, F., Ostendorf, L., Reincke, S., Pruess, H., Von Bruenneck, A., Koehnlein, M., Alexander, T., Meisel, C., Meisel, A. 2020; 267 (2): 317-323

  Abstract

  The anti-CD38 antibody daratumumab is approved for treatment of refractory multiple myeloma and acts by depletion of plasma cells and modification of various T-cell functions. Its safety, immunological effects and therapeutic potential was evaluated in a 60-year old patient with life-threatening and treatment-refractory anti-CASPR2 encephalitis requiring medical care and artificial ventilation in an intensive care unit. His autoimmune dysfunction was driven by exceptional high anti-CASPR2 autoantibody titers combined with an abnormally increased T-cell activation. As he remained unresponsive to standard and escalation immunotherapies (methylprednisolone, plasma exchange, immunoadsorption, immunoglobulins, rituximab and bortezomib), therapy was escalated to 13 cycles of 16 mg/kg daratumumab. During the treatment period, clinical, radiological, histological and laboratory findings, including quantification of autoreactive and protective antibody levels and FACS-based immune phenotyping, were analyzed. Daratumumab treatment was associated with significant clinical improvement, substantial reduction of anti-CASPR2 antibody titers, especially in CSF, decrease of immunoglobulin levels and protective vaccine titers, as well as normalization of initially increased T-cell activation markers. However, the patient died of Gram-negative septicemia in a neurorehabilitation center. In conclusion, our findings suggest that daratumumab induces not only depletion of autoreactive long-lived plasma cells associated with improvements of neurological sequelae, but also severe side effects requiring clinical studies investigating efficacy and safety of anti-CD38 therapy in antibody-driven autoimmune encephalitis.

  View details for DOI 10.1007/s00415-019-09585-6

  View details for Web of Science ID 000491642400002

  View details for PubMedID 31630242

• N-methyl-D-aspartate receptor dysfunction by unmutated human antibodies against the NR1 subunit ANNALS OF NEUROLOGY Wenke, N., Kreye, J., Andrzejak, E., van Casteren, A., Leubner, J., Murgueitio, M. S., Reincke, S., Secker, C., Schmidl, L., Geis, C., Ackermann, F., Nikolaus, M., Garner, C. C., Wardemann, H., Wolber, G., Pruess, H. 2019; 85 (5): 771-776

  Abstract

  Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common autoimmune encephalitis related to autoantibody-mediated synaptic dysfunction. Cerebrospinal fluid-derived human monoclonal NR1 autoantibodies showed low numbers of somatic hypermutations or were unmutated. These unexpected germline-configured antibodies showed weaker binding to the NMDAR than matured antibodies from the same patient. In primary hippocampal neurons, germline NR1 autoantibodies strongly and specifically reduced total and synaptic NMDAR currents in a dose- and time-dependent manner. The findings suggest that functional NMDAR antibodies are part of the human naïve B cell repertoire. Given their effects on synaptic function, they might contribute to a broad spectrum of neuropsychiatric symptoms. Ann Neurol 2019;85:771-776.

  View details for DOI 10.1002/ana.25460

  View details for Web of Science ID 000466492700015

  View details for PubMedID 30843274

  View details for PubMedCentralID PMC6593665

• Affinities of human NMDA receptor autoantibodies: implications for disease mechanisms and clinical diagnostics JOURNAL OF NEUROLOGY Lam-Thanh Ly, Kreye, J., Jurek, B., Leubner, J., Scheibe, F., Lemcke, J., Wenke, N., Reincke, S., Pruess, H. 2018; 265 (11): 2625-2632

  Abstract

  Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a common autoimmune encephalitis presenting with psychosis, dyskinesias, autonomic dysfunction and seizures. The underlying autoantibodies against the NR1 subunit are directly pathogenic by disrupting synaptic NMDAR currents. However, antibody titers correlate only partially with the clinical outcome, suggesting the relevance of other factors such as antibody affinity. We thus determined the binding curves of human monoclonal autoantibodies and patients' cerebrospinal fluid (CSF) against NR1-expressing HEK293 cells using flow cytometry. Antibody affinity was highly variable with binding constants (half-maximal concentration, c50) ranging from 1 to 74 µg/ml for monoclonal antibodies. Comparing values of individual monoclonal antibodies with human CSF samples suggested that the CSF signal is predominantly represented by higher-affinity antibodies, potentially in a concentration range of NR1 antibodies between 0.1 and 5 µg/ml, roughly reflecting 1-10% of total CSF IgG in NMDAR encephalitis. Binding curves further depended on the CSF composition which must be considered when interpreting established clinical routine assays. Normalization of measurements using reference samples allowed high reproducibility. Accurate and reproducible measurement of NR1 antibody binding suggested that biophysical properties of the antibody might contribute to disease severity. Normalization of the data can be an elegant way to allow comparable inter-laboratory quantification of CSF NR1 antibody titers in autoimmune encephalitis patients, a prerequisite for use as surrogate markers in clinical trials. Based on our calculations, low-affinity antibodies can easily remain undetected in routine cell-based assays, indicating that their relation to clinical symptoms should be analyzed in future studies.

  View details for DOI 10.1007/s00415-018-9042-1

  View details for Web of Science ID 000448450200014

  View details for PubMedID 30187160

  View details for PubMedCentralID PMC6182686

• Spectra of the Dirac Operator of Pseudo-Riemannian Spin Manifolds ADVANCES IN APPLIED CLIFFORD ALGEBRAS Reincke, M. 2017; 27 (2): 1675-1713

  View details for DOI 10.1007/s00006-016-0725-3

  View details for Web of Science ID 000401669000047

• Inactivation and Anion Selectivity of Volume-regulated Anion Channels (VRACs) Depend on C-terminal Residues of the First Extracellular Loop JOURNAL OF BIOLOGICAL CHEMISTRY Ullrich, F., Reincke, S., Voss, F. K., Stauber, T., Jentsch, T. J. 2016; 291 (33): 17040-17048

  Abstract

  Canonical volume-regulated anion channels (VRACs) are crucial for cell volume regulation and have many other important roles, including tumor drug resistance and release of neurotransmitters. Although VRAC-mediated swelling-activated chloride currents (ICl,vol) have been studied for decades, exploration of the structure-function relationship of VRAC has become possible only after the recent discovery that VRACs are formed by differently composed heteromers of LRRC8 proteins. Inactivation of ICl,vol at positive potentials, a typical hallmark of VRACs, strongly varies between native cell types. Exploiting the large differences in inactivation between different LRRC8 heteromers, we now used chimeras assembled from isoforms LRRC8C and LRRC8E to uncover a highly conserved extracellular region preceding the second LRRC8 transmembrane domain as a major determinant of ICl,vol inactivation. Point mutations identified two amino acids (Lys-98 and Asp-100 in LRRC8A and equivalent residues in LRRC8C and -E), which upon charge reversal strongly altered the kinetics and voltage dependence of inactivation. Importantly, charge reversal at the first position also reduced the iodide > chloride permeability of ICl,vol This change in selectivity was stronger when both the obligatory LRRC8A subunit and the other co-expressed isoform (LRR8C or -E) carried such mutations. Hence, the C-terminal part of the first extracellular loop not only determines VRAC inactivation but might also participate in forming its outer pore. Inactivation of VRACs may involve a closure of the extracellular mouth of the permeation pathway.

  View details for DOI 10.1074/jbc.M116.739342

  View details for Web of Science ID 000382643800011

  View details for PubMedID 27325695

  View details for PubMedCentralID PMC5016109

• Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs EMBO JOURNAL Planells-Cases, R., Lutter, D., Guyader, C., Gerhards, N. M., Ullrich, F., Elger, D. A., Kucukosmanoglu, A., Xu, G., Voss, F. K., Reincke, S., Stauber, T., Blomen, V. A., Vis, D. J., Wessels, L. F., Brummelkamp, T. R., Borst, P., Rottenberg, S., Jentsch, T. J. 2015; 34 (24): 2993-3008

  Abstract

  Although platinum-based drugs are widely used chemotherapeutics for cancer treatment, the determinants of tumor cell responsiveness remain poorly understood. We show that the loss of subunits LRRC8A and LRRC8D of the heteromeric LRRC8 volume-regulated anion channels (VRACs) increased resistance to clinically relevant cisplatin/carboplatin concentrations. Under isotonic conditions, about 50% of cisplatin uptake depended on LRRC8A and LRRC8D, but neither on LRRC8C nor on LRRC8E. Cell swelling strongly enhanced LRRC8-dependent cisplatin uptake, bolstering the notion that cisplatin enters cells through VRAC. LRRC8A disruption also suppressed drug-induced apoptosis independently from drug uptake, possibly by impairing VRAC-dependent apoptotic cell volume decrease. Hence, by mediating cisplatin uptake and facilitating apoptosis, VRAC plays a dual role in the cellular drug response. Incorporation of the LRRC8D subunit into VRAC substantially increased its permeability for cisplatin and the cellular osmolyte taurine, indicating that LRRC8 proteins form the channel pore. Our work suggests that LRRC8D-containing VRACs are crucial for cell volume regulation by an important organic osmolyte and may influence cisplatin/carboplatin responsiveness of tumors.

  View details for DOI 10.15252/embj.201592409

  View details for Web of Science ID 000367918000004

  View details for PubMedID 26530471

  View details for PubMedCentralID PMC4687416