Publications by authors named "Manuel A Friese"

85 Publications

CSF Findings in Acute NMDAR and LGI1 Antibody-Associated Autoimmune Encephalitis.

Neurol Neuroimmunol Neuroinflamm 2021 Nov 25;8(6). Epub 2021 Oct 25.

From the Department of Neurology (M.D., M.S., J.D., H.T., J.L.), Ulm University; Department of Neurosurgery (M.D.), University Hospital Tübingen; Neuroimmunology (G.N., K.-P.W., F.L.), Institute of Clinical Chemistry, University Hospital Schleswig-Holstein Kiel/Lübeck; Department of Neurology (K.-W.S., P.S.), Hannover Medical School; Department of Neurology (C.G.), University Hospital Jena; Department of Neurology (M.R., H.-P.H., N.M.), Medical Faculty, Heinrich Heine University Düsseldorf; Department of Neurology (M.R.), Center for Neurology and Neuropsychiatry, LVR-Klinikum Düsseldorf, Düsseldorf; Institute of Neuroimmunology and Multiple Sclerosis (M.A.F., M.K.), University Medical Center Hamburg-Eppendorf; Department of Neurology (M.P.M., M.M.), University of Cologne, Faculty of Medicine and University Hospital; Institute of Clinical Neuroimmunology (F.S.T., T.K.), University Hospital and Biomedical Center, Ludwig-Maximilians University Munich; Department of Pediatrics (M.G.H.), University Hospital RWTH Aachen; Technische Universität Dresden (H.S.), and Department of Neurology, University Hospital Augsburg; Department of Neurology (F.T.B.), University Hospital Leipzig; Department of Neurology (C.K.), Klinikum Osnabrück; Department of Neurology (U.K.Z.), Section for Neuroimmunology, University Hospital Rostock; Department of Neurology with Institute of Translational Neurology (N.M., C.C.G.), University Hospital Münster; Department of Neurology (P.L.), University Hospital Göttingen; Institute of Epidemiology and Medical Biometry, Ulm University; and Department of Neurology (F.L.), University Hospital Schleswig-Holstein and Kiel University, Germany.

Background And Objectives: CSF in antibody-defined autoimmune encephalitis (AE) subtypes shows subtype-dependent degrees of inflammation ranging from rare and often mild to frequent and often robust. AEs with NMDA receptor antibodies (NMDAR-E) and leucine-rich glioma-inactivated protein 1 antibodies (LGI1-E) represent opposite ends of this spectrum: NMDAR-E with typically frequent/robust and LGI1-E with rare/mild CSF inflammation. For a more in-depth analysis, we characterized CSF findings in acute, therapy-naive NMDAR-E and LGI1-E in a multicentric, retrospective, cross-sectional setting.

Methods: Eighty-two patients with NMDAR-E and 36 patients with LGI1-E from the GErman NEtwork for Research of AuToimmune Encephalitis (GENERATE) with lumbar puncture within 90 days of onset and before immunotherapy were included. CSF parameters comprised leukocytes, oligoclonal bands (OCBs), and CSF/serum ratios for albumin, immunoglobulin G (IgG), A (IgA), and M (IgM), the latter 3 converted to Z scores according to Reiber formulas. The MRZ reaction was tested in 14 patients with NMDAR-E and 6 patients with LGI1-E, respectively.

Results: CSF was abnormal in 94% of NMDAR-E but only in 36% of LGI1-E patients. Robust quantitative intrathecal immunoglobulin synthesis (IIS, IgG > IgM >> IgA) was characteristic for NMDAR-E, but absent in LGI-E. In NMDAR-E, CSF leukocytes were higher when IIS was present or more pronounced. In addition, in NMDAR-E, CSF leukocytes were lower and IIS occurred less often and if so to a lesser degree at older age. Patients with NMDAR-E with severe functional impairment more often had positive OCBs. In CSF obtained later than 3 weeks of onset, leukocytes were lower. In parallel, the correlation of leukocytes with IIS disappeared as IIS was partially independent of disease duration. The MRZ reaction was positive in 5 (36%) patients with NMDAR-E. All these associations were completely absent in LGI1-E. Here, younger patients showed more blood-CSF barrier dysfunction. In LGI1-E, but not in NMDAR-E, the blood-CSF barrier was more dysfunctional when CSF leukocytes were higher.

Discussion: NMDAR-E and LGI-E differ in their typical extent of CSF inflammation. In addition, the patterns formed by the different inflammatory CSF parameters and their relationship with disease severity, age, and disease duration are subtype-characteristic. Moreover, signs for multiple sclerosis-like chronic inflammation are present in a subgroup of patients with NMDAR-E. These CSF patterns might be markers for the different immunopathogeneses of LGI1-E and NMDAR-E.
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http://dx.doi.org/10.1212/NXI.0000000000001086DOI Listing
November 2021

Upregulation of Phosphodiesterase 2A Augments T Cell Activation by Changing cGMP/cAMP Cross-Talk.

Front Pharmacol 2021 5;12:748798. Epub 2021 Oct 5.

Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

3',5'-cyclic adenosine monophosphate (cAMP) is well-known for its diverse immunomodulatory properties, primarily inhibitory effects during T cell activation, proliferation, and production of pro-inflammatory cytokines. A decrease in cAMP levels, due to the hydrolyzing activity of phosphodiesterases (PDE), is favoring inflammatory responses. This can be prevented by selective PDE inhibitors, which makes PDEs important therapeutic targets for autoimmune disorders. In this study, we investigated the specific roles of PDE2A and PDE3B in the regulation of intracellular cAMP levels in different mouse T cell subsets. Unexpectedly, T cell receptor (TCR) activation led to a selective upregulation of PDE2A at the protein level in conventional T cells (Tcon), whereas no changes were detected in regulatory T cells (Treg). In contrast, protein expression of PDE3B was significantly higher in both non-activated and activated Tcon subsets as compared to Treg, with no changes upon TCR engagement. Live-cell imaging of T cells expressing a highly sensitive Förster resonance energy transfer (FRET)-based biosensor, Epac1-camps, has enabled cAMP measurements in real time and revealed stronger responses to the PDE2A inhibitors in activated vs non-activated Tcon. Importantly, stimulation of intracellular cGMP levels with natriuretic peptides led to an increase of cAMP in non-activated and a decrease of cAMP in activated Tcon, suggesting that TCR activation changes the PDE3B-dependent positive to PDE2A-dependent negative cGMP/cAMP cross-talk. Functionally, this switch induced higher expression of early activation markers CD25 and CD69. This constitutes a potentially interesting feed-forward mechanism during autoimmune and inflammatory responses that may be exploited therapeutically.
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http://dx.doi.org/10.3389/fphar.2021.748798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523859PMC
October 2021

Identification of the factor XII contact activation site enables sensitive coagulation diagnostics.

Nat Commun 2021 09 22;12(1):5596. Epub 2021 Sep 22.

Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Contact activation refers to the process of surface-induced activation of factor XII (FXII), which initiates blood coagulation and is captured by the activated partial thromboplastin time (aPTT) assay. Here, we show the mechanism and diagnostic implications of FXII contact activation. Screening of recombinant FXII mutants identified a continuous stretch of residues Gln317-Ser339 that was essential for FXII surface binding and activation, thrombin generation and coagulation. Peptides spanning these 23 residues competed with surface-induced FXII activation. Although FXII mutants lacking residues Gln317-Ser339 were susceptible to activation by plasmin and plasma kallikrein, they were ineffective in supporting arterial and venous thrombus formation in mice. Antibodies raised against the Gln317-Ser339 region induced FXII activation and triggered controllable contact activation in solution leading to thrombin generation by the intrinsic pathway of coagulation. The antibody-activated aPTT allows for standardization of particulate aPTT reagents and for sensitive monitoring of coagulation factors VIII, IX, XI.
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http://dx.doi.org/10.1038/s41467-021-25888-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458485PMC
September 2021

Intrathecal Antibody Production Against Epstein-Barr, Herpes Simplex, and Other Neurotropic Viruses in Autoimmune Encephalitis.

Neurol Neuroimmunol Neuroinflamm 2021 Nov 24;8(6). Epub 2021 Aug 24.

From the Department of Neurology (P.S., T.S., F.F.K., Nora Möhn, M.S., K.-W.S.), Hannover Medical School; Department of Neurology (P.L.), Georg August University Göttingen; Department of Neurology (M.D., J.L.), Ulm University; Department of Neurology (M.R.), Medical Faculty, Heinrich-Heine-University Düsseldorf; Department of Neurology (M.R., T.M.), Centre for Neurology and Neuropsychiatry, LVR-Klinikum, Heinrich-Heine-University Düsseldorf; Institute of Neuroimmunology and Multiple Sclerosis (M.A.F.), University Medical Center Hamburg-Eppendorf; Department of Neurology with Institute of Translational Neurology (Nico Melzer), University Hospital Muenster; Department of Neurology (M.P.M.), University Hospital Cologne; Division of Neuropediatrics and Social Pediatrics (M.H.), Department of Pediatrics, Medical Faculty, RWTH Aachen University; and Institute of Clinical Neuroimmunology (F.S.T.), University Hospital and Biomedical Center, Ludwig-Maximilians University Munich, Germany.

Background And Objectives: Neurotropic viruses are suspected to play a role in the pathogenesis of autoimmune diseases of the CNS such as the association between the Epstein-Barr virus (EBV) and multiple sclerosis (MS). A group of autoimmune encephalitis (AE) is linked to antibodies against neuronal cell surface proteins. Because CNS infection with the herpes simplex virus can trigger anti-NMDA receptor (NMDAR) encephalitis, a similar mechanism for EBV and other neurotropic viruses could be postulated. To investigate for previous viral infections of the CNS, intrathecally produced virus-specific antibody synthesis was determined in patients with AE.

Methods: Antibody-specific indices (AIs) against EBV and measles, rubella, varicella zoster, herpes simplex virus, and cytomegalovirus were determined in 27 patients having AE (anti-NMDAR encephalitis, n = 21, and LGI1 encephalitis, n = 6) and in 2 control groups comprising of 30 patients with MS and 21 patients with noninflammatory CNS diseases (NIND), which were sex and age matched.

Results: An intrathecal synthesis of antibodies against EBV was found in 5/27 (19%) patients with AE and 2/30 (7%) of the patients with MS. All these patients had also at least 1 additional elevated virus-specific AI. In contrast, in none of the patients with NIND, an elevated virus-specific AI was detected.

Discussion: Intrathecally produced antibodies against EBV can be found in patients with AE and MS but only together with antibodies against different neurotropic viruses. Evidence of these antibodies is the result of a polyspecific immune response similar yet distinct from MS response rather than an elapsed infection of the CNS.
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http://dx.doi.org/10.1212/NXI.0000000000001062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387013PMC
November 2021

Multi-dimensional and longitudinal systems profiling reveals predictive pattern of severe COVID-19.

iScience 2021 Jul 19;24(7):102752. Epub 2021 Jun 19.

I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.

COVID-19 is a respiratory tract infection that can affect multiple organ systems. Predicting the severity and clinical outcome of individual patients is a major unmet clinical need that remains challenging due to intra- and inter-patient variability. Here, we longitudinally profiled and integrated more than 150 clinical, laboratory, and immunological parameters of 173 patients with mild to fatal COVID-19. Using systems biology, we detected progressive dysregulation of multiple parameters indicative of organ damage that correlated with disease severity, particularly affecting kidneys, hepatobiliary system, and immune landscape. By performing unsupervised clustering and trajectory analysis, we identified T and B cell depletion as early indicators of a complicated disease course. In addition, markers of hepatobiliary damage emerged as robust predictor of lethal outcome in critically ill patients. This allowed us to propose a novel clinical VID-19 everiy (COST) score that distinguishes complicated disease trajectories and predicts lethal outcome in critically ill patients.
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http://dx.doi.org/10.1016/j.isci.2021.102752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213514PMC
July 2021

Activity-regulated cytoskeleton-associated protein/activity-regulated gene 3.1 (Arc/Arg3.1) enhances dendritic cell vaccination in experimental melanoma.

Oncoimmunology 2021 05 14;10(1):1920739. Epub 2021 May 14.

Department of Neurology, Mannheim Medical Center, University of Heidelberg, Mannheim, Germany.

Dendritic cell (DC) vaccination has proven to be an effective and safe adjuvant for cancer immunotherapies. As the presence of DCs within the tumor microenvironment promotes adaptive antitumor immunity, enhancement of DC migration toward the tumor microenvironment following DC vaccination might represent one possible approach to increase its therapeutic efficacy. While recent findings suggest the activity-regulated cytoskeleton-associated protein/activity-regulated gene 3.1 (Arc/Arg3.1) as critical regulator of DC migration in the context of autoimmune diseases, we aimed to investigate the impact of Arc/Arg3.1 expression for DC-based cancer vaccines. To this end, DC migration capacity as well as the induction of T cell-mediated antitumor immunity was assessed in an experimental B16 melanoma model with and -expressing BMDCs applied as a subcutaneous vaccine. While antigen presentation on DCs was critical for unleashing effective T cell mediated antitumor immune responses, Arc/Arg3.1 expression enhanced DC migration toward the tumor and secondary lymphoid organs. Moreover, Arc/Arg3.1-expressing BMDCs shape the tumor immune microenvironment by facilitating tumor recruitment of antigen-specific effector T cells. Thus, Arc/Arg3.1 may represent a novel therapeutic target in DCs in order to increase the therapeutic efficacy of DC vaccination.
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http://dx.doi.org/10.1080/2162402X.2021.1920739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128181PMC
May 2021

SnapShot: Neuronal dysfunction in inflammation.

Neuron 2021 05;109(10):1754-1754.e1

Institute of Neuroimmunology and Multiple Sclerosis (INIMS), Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.

Neuronal function relies on tightly controlled cytoskeleton transport with adaptive cargo trafficking as prerequisite for synaptic transmission. During inflammation in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), axonal transport efficiency declines, followed by neurodegeneration. Furthermore, neuroinflammation causes an imbalance between excitatory and inhibitory transmission, triggering synaptic dysfunction and loss. Recent data suggest that neuronal transport and synaptic deficits during neuroinflammation are functionally interconnected. To view this SnapShot, open or download the PDF.
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http://dx.doi.org/10.1016/j.neuron.2021.03.005DOI Listing
May 2021

aHSCT is superior to alemtuzumab in maintaining NEDA and improving cognition in multiple sclerosis.

Ann Clin Transl Neurol 2021 06 5;8(6):1269-1278. Epub 2021 May 5.

Institute of Neuroimmunology and Multiple Sclerosis, University Medical Centre Hamburg-Eppendorf, Falkenried 94, Hamburg, 20251, Germany.

Objective: Autologous hematopoietic stem cell transplantation (aHSCT) is increasingly recognized as a potential therapy for patients with highly active multiple sclerosis (MS). This study aims to assess outcome differences in disease activity in MS patients treated either with aHSCT or alemtuzumab.

Methods: We conducted a monocentric registry-based cohort study by recording the clinical course (EDSS and relapses), MRI parameters (new T2 lesions), and neuropsychological assessment in all 19 MS patients receiving aHSCT, and all 21 patients receiving alemtuzumab between 2007 and 2018. We used survival analyses of no evidence of disease activity (NEDA) as the primary objective which was defined by no EDSS progression, no relapse, and no new T2 lesion on MRI. Secondary objectives were EDSS improvement and neurocognitive performance.

Results: Both treatment groups were similar in respect of age, gender, disability, and neurocognitive performance except for significantly longer disease duration in the alemtuzumab group. Mean follow-up was 58.8 [range 29-140] months in the aHSCT group compared to 27.6 [range 11-52] months in the alemtuzumab-treated group. We observed significantly more patients maintaining NEDA in the aHSCT group (p = 0.048) compared to the alemtuzumab-treated patients. Furthermore, 37% of the aHSCT patients showed an improvement of EDSS compared to none in the alemtuzumab-treated group (p = 0.033). It is of note that cognitive function was significantly improved in the aHSCT-treated patients.

Interpretation: aHSCT suppresses inflammatory activity more effectively than alemtuzumab and might enable improvement of overall disability and cognition in MS.
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http://dx.doi.org/10.1002/acn3.51366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164852PMC
June 2021

Single-cell atlas of hepatic T cells reveals expansion of liver-resident naive-like CD4 T cells in primary sclerosing cholangitis.

J Hepatol 2021 08 24;75(2):414-423. Epub 2021 Mar 24.

I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany; Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany; Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany. Electronic address:

Background & Aims: Little is known about the composition of intrahepatic immune cells and their contribution to the pathogenesis of primary sclerosing cholangitis (PSC). Herein, we aimed to create an atlas of intrahepatic T cells and thereby perform an in-depth characterization of T cells in inflamed human liver.

Methods: Different single-cell RNA sequencing methods were combined with in silico analyses on intrahepatic and peripheral T cells from patients with PSC (n = 11) and healthy donors (HDs, n = 4). Multi-parameter flow cytometry and functional in vitro experiments were conducted on samples from patients with PSC (n = 24), controls with other liver diseases and HDs.

Results: We identified a population of intrahepatic naive-like CD4 T cells, which was present in all liver diseases tested, but particularly expanded in PSC. This population had a transcriptome and T cell receptor repertoire similar to circulating naive T cells but expressed a set of genes associated with tissue residency. Their periductal location supported the concept of tissue-resident naive-like T cells in livers of patients with PSC. Trajectory inference suggested that these cells had the developmental propensity to acquire a T helper 17 (T17) polarization state. Functional and chromatin accessibility experiments revealed that circulating naive T cells in patients with PSC were predisposed to polarize towards T17 cells.

Conclusion: We report the first atlas of intrahepatic T cells in PSC, which led to the identification of a previously unrecognized population of tissue-resident naive-like T cells in the inflamed human liver and to the finding that naive CD4 T cells in PSC harbour the propensity to develop into T17 cells.

Lay Summary: The composition of intrahepatic immune cells in primary sclerosing cholangitis (PSC) and their contribution to disease pathogenesis is widely unknown. We analysed intrahepatic T cells and identified a previously uncharacterized population of liver-resident CD4 T cells which are expanded in the livers of patients with PSC compared to healthy liver tissue and other liver diseases. These cells are likely to contribute to the pathogenesis of PSC and could be targeted in novel therapeutic approaches.
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http://dx.doi.org/10.1016/j.jhep.2021.03.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310924PMC
August 2021

Identifying CNS-colonizing T cells as potential therapeutic targets to prevent progression of multiple sclerosis.

Med (N Y) 2021 Mar;2(3):296-312.e8

Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

Background: Multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS), can be suppressed in its early stages but eventually becomes clinically progressive and unresponsive to therapy. Here, we investigate whether the therapeutic resistance of progressive MS can be attributed to chronic immune cell accumulation behind the blood-brain barrier (BBB).

Methods: We systematically track CNS-homing immune cells in the peripheral blood of 31 MS patients and 31 matched healthy individuals in an integrated analysis of 497,705 single-cell transcriptomes and 355,433 surface protein profiles from 71 samples. Through spatial RNA sequencing, we localize these cells in brain tissue of 6 progressive MS patients contrasted against 4 control brains (20 samples, 85,000 spot transcriptomes).

Findings: We identify a specific pathogenic CD161+/lymphotoxin beta (LTB)+ T cell population that resides in brains of progressive MS patients. Intriguingly, our data suggest that the colonization of the CNS by these T cells may begin earlier in the disease course, as they can be mobilized to the blood by usage of the integrin-blocking antibody natalizumab in relapsing-remitting MS patients.

Conclusions: As a consequence, we lay the groundwork for a therapeutic strategy to deplete CNS-homing T cells before they can fuel treatment-resistant progression.

Funding: This study was supported by funding from the University Medical Center Hamburg-Eppendorf, the Stifterverband für die Deutsche Wissenschaft, the OAK Foundation, Medical Research Council UK, and Wellcome.
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http://dx.doi.org/10.1016/j.medj.2021.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966680PMC
March 2021

Neuronal metabotropic glutamate receptor 8 protects against neurodegeneration in CNS inflammation.

J Exp Med 2021 05;218(5)

Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with continuous neuronal loss. Treatment of clinical progression remains challenging due to lack of insights into inflammation-induced neurodegenerative pathways. Here, we show that an imbalance in the neuronal receptor interactome is driving glutamate excitotoxicity in neurons of MS patients and identify the MS risk-associated metabotropic glutamate receptor 8 (GRM8) as a decisive modulator. Mechanistically, GRM8 activation counteracted neuronal cAMP accumulation, thereby directly desensitizing the inositol 1,4,5-trisphosphate receptor (IP3R). This profoundly limited glutamate-induced calcium release from the endoplasmic reticulum and subsequent cell death. Notably, we found Grm8-deficient neurons to be more prone to glutamate excitotoxicity, whereas pharmacological activation of GRM8 augmented neuroprotection in mouse and human neurons as well as in a preclinical mouse model of MS. Thus, we demonstrate that GRM8 conveys neuronal resilience to CNS inflammation and is a promising neuroprotective target with broad therapeutic implications.
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http://dx.doi.org/10.1084/jem.20201290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938362PMC
May 2021

Clinical Presentation and Disease Course of 37 Consecutive Cases of Progressive Multifocal Leukoencephalopathy (PML) at a German Tertiary-Care Hospital: A Retrospective Observational Study.

Front Neurol 2021 4;12:632535. Epub 2021 Feb 4.

Division of Infectious Disease, I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Progressive multifocal leukoencephalopathy (PML) caused by JCV is a rare but frequently fatal disease of the central nervous system, usually affecting immunocompromised individuals. Our study aims to expand the data on patient characteristics, diagnosis, clinical course, possible PML-directed treatment, and outcome of patients with PML at a German tertiary-care hospital. In this single-center observational cohort study, 37 consecutive patients with a confirmed diagnosis of PML seen at the University Medical Center Hamburg-Eppendorf from 2013 until 2019 were retrospectively analyzed by chart review with a special focus on demographics, risk factors, and clinical aspects as well as PML-directed treatment and survival. We identified 37 patients with definite, probable, and possible PML diagnosis. 36 patients (97%) had underlying immunosuppressive disorders such as HIV/AIDS ( = 17; 46%), previous treatment with monoclonal antibodies ( = 6; 16%), hematological or oncological malignancies ( = 6; 16%), sarcoidosis ( = 5; 14%), solid organ transplantation ( = 1; 3%), and diagnosis of mixed connective tissue disease ( = 1; 3%). In only one patient no evident immunocompromised condition was detected ( = 1; 3%). Treatment attempts to improve the outcome of PML were reported in 13 patients ( = 13; 35%). Twenty seven percent of patients were lost to follow-up ( = 10). Twenty four-month survival rate after diagnosis of PML was 56% ( = 15). This interdisciplinary retrospective study describes epidemiology, risk factors, clinical course, and treatment trials in patients with PML at a German tertiary-care hospital. Acquired immunosuppression due to HIV-1 constituted the leading cause of PML in this monocenter cohort.
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http://dx.doi.org/10.3389/fneur.2021.632535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890249PMC
February 2021

Enhancing mitochondrial activity in neurons protects against neurodegeneration in a mouse model of multiple sclerosis.

Elife 2021 Feb 10;10. Epub 2021 Feb 10.

Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

While transcripts of neuronal mitochondrial genes are strongly suppressed in central nervous system inflammation, it is unknown whether this results in mitochondrial dysfunction and whether an increase of mitochondrial function can rescue neurodegeneration. Here, we show that predominantly genes of the electron transport chain are suppressed in inflamed mouse neurons, resulting in impaired mitochondrial complex IV activity. This was associated with post-translational inactivation of the transcriptional co-regulator proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). In mice, neuronal overexpression of , which encodes for PGC-1α, led to increased numbers of mitochondria, complex IV activity, and maximum respiratory capacity. Moreover, -overexpressing neurons showed a higher mitochondrial membrane potential that related to an improved calcium buffering capacity. Accordingly, neuronal deletion of aggravated neurodegeneration during experimental autoimmune encephalomyelitis, while neuronal overexpression of ameliorated it. Our study provides systemic insights into mitochondrial dysfunction in neurons during inflammation and commends elevation of mitochondrial activity as a promising neuroprotective strategy.
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http://dx.doi.org/10.7554/eLife.61798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993994PMC
February 2021

Frequent neurocognitive deficits after recovery from mild COVID-19.

Brain Commun 2020 23;2(2):fcaa205. Epub 2020 Nov 23.

Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.

Neuropsychiatric complications associated with coronavirus disease 2019 caused by the Coronavirus SARS-CoV-2 (COVID-19) are increasingly appreciated. While most studies have focussed on severely affected individuals during acute infection, it remains unclear whether mild COVID-19 results in neurocognitive deficits in young patients. Here, we established a screening approach to detect cognitive deficiencies in post-COVID-19 patients. In this cross-sectional study, we recruited 18 mostly young patients 20-105 days (median, 85 days) after recovery from mild to moderate disease who visited our outpatient clinic for post-COVID-19 care. Notably, 14 (78%) patients reported sustained mild cognitive deficits and performed worse in the Modified Telephone Interview for Cognitive Status screening test for mild cognitive impairment compared to 10 age-matched healthy controls. While short-term memory, attention and concentration were particularly affected by COVID-19, screening results did not correlate with hospitalization, treatment, viremia or acute inflammation. Additionally, Modified Telephone Interview for Cognitive Status scores did not correlate with depressed mood or fatigue. In two severely affected patients, we excluded structural or other inflammatory causes by magnetic resonance imaging, serum and cerebrospinal fluid analyses. Together, our results demonstrate that sustained sub-clinical cognitive impairments might be a common complication after recovery from COVID-19 in young adults, regardless of clinical course that were unmasked by our diagnostic approach.
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http://dx.doi.org/10.1093/braincomms/fcaa205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717144PMC
November 2020

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity.

Proc Natl Acad Sci U S A 2021 01;118(1)

Department of Neurology, Neuroimmunological Section, University of Rostock, 18051 Rostock, Germany.

Multiple sclerosis (MS) disease risk is associated with reduced sun-exposure. This study assessed the relationship between measures of sun exposure (vitamin D [vitD], latitude) and MS severity in the setting of two multicenter cohort studies ( = 946, = 990). Additionally, effect-modification by medication and photosensitivity-associated variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), reduced risk for relapses, and lower disability accumulation over time. Low latitude was associated with higher vitD, lower MSSS, fewer gadolinium-enhancing lesions, and lower disability accumulation. The association of latitude with disability was lacking in IFN-β-treated patients. In carriers of :rs1805008(T), who reported increased sensitivity toward sunlight, lower latitude was associated with higher MRI activity, whereas for noncarriers there was less MRI activity at lower latitudes. In a further exploratory approach, the effect of ultraviolet (UV)-phototherapy on the transcriptome of immune cells of MS patients was assessed using samples from an earlier study. Phototherapy induced a vitD and type I IFN signature that was most apparent in monocytes but that could also be detected in B and T cells. In summary, our study suggests beneficial effects of sun exposure on established MS, as demonstrated by a correlative network between the three factors: Latitude, vitD, and disease severity. However, sun exposure might be detrimental for photosensitive patients. Furthermore, a direct induction of type I IFNs through sun exposure could be another mechanism of UV-mediated immune-modulation in MS.
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http://dx.doi.org/10.1073/pnas.2018457118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817192PMC
January 2021

A Passenger Mutation Affects the Vitality and Function of T cells in Congenic Mice.

iScience 2020 Dec 27;23(12):101870. Epub 2020 Nov 27.

Department of Neurology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg-Eppendorf, Germany.

Among laboratory mouse strains many genes are differentially expressed in the same cell population. As consequence, gene targeting in 129-derived embryonic stem cells (ESCs) and backcrossing the modified mice onto the C57BL/6 background can introduce passenger mutations in the close proximity of the targeted gene. Here, we demonstrate that several transgenic mice carry a passenger mutation that affects the function of T cells. By the example of P2rx4 we demonstrate that P2X4ko T cells express higher levels of P2X7 and are more sensitive toward the P2X7 activators ATP and NAD, rendering these cells more vulnerable toward NAD-induced cell death (NICD) compared with wild type (WT). The enhanced NICD sensitivity confounded functional assays e.g. cytokine production and cell migration. Our results need to be considered when working with P2rx4 mice or other 129-based transgenic strains that target neighboring genes.
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http://dx.doi.org/10.1016/j.isci.2020.101870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733020PMC
December 2020

Voltage-Gated Proton Channel Hv1 Controls TLR9 Activation in Plasmacytoid Dendritic Cells.

J Immunol 2020 12 30;205(11):3001-3010. Epub 2020 Oct 30.

Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, 20251 Hamburg, Germany.

The voltage-gated proton channel Hv1 regulates proton fluxes across membranes, thereby influencing pH-dependent processes. Plasmacytoid dendritic cells (pDCs) require a particularly tight regulation of endosomal pH to ensure strong type I IFN secretion exclusively during infection, avoiding autoimmunity. However, whether Hv1 is important for pH control in pDCs is presently unknown. In this study, we show that mouse pDCs require Hv1 to achieve potent type I IFN responses after the recognition of foreign DNA by endosomal TLR9. Genetic disruption of , which encodes Hv1, impaired mouse pDC activation by CpG oligonucleotides in vitro and in vivo, reducing IFN-α secretion and the induction of IFN-stimulated genes. Mechanistically, deficiency delayed endosomal acidification and enhanced intracellular reactive oxygen species production, consequently limiting protease activity and TLR9 signaling. Our study reveals a critical role of Hv1 during innate immune responses and places this channel as a key modulator of type I IFN production, the hallmark function of pDCs, commending Hv1 as an attractive target for modulating type I IFN-driven autoimmunity.
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http://dx.doi.org/10.4049/jimmunol.2000404DOI Listing
December 2020

TRPV4-Mediated Regulation of the Blood Brain Barrier Is Abolished During Inflammation.

Front Cell Dev Biol 2020 27;8:849. Epub 2020 Aug 27.

Institut für Neuroimmunologie und Multiple Sklerose, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

Blood-brain barrier (BBB) dysfunction is critically involved in determining the extent of several central nervous systems (CNS) pathologies and here in particular neuroinflammatory conditions. Inhibiting BBB breakdown could reduce the level of vasogenic edema and the number of immune cells invading the CNS, thereby counteracting neuronal injury. Transient receptor potential (TRP) channels have an important role as environmental sensors and constitute attractive therapeutic targets that are involved in calcium homeostasis during pathologies of the CNS. Transient receptor potential vanilloid 4 (TRPV4) is a calcium permeable, non-selective cation channel highly expressed in endothelial cells. As it is involved in the regulation of the blood brain barrier permeability and consequently cerebral edema formation, we anticipated a regulatory role of TRPV4 in CNS inflammation and subsequent neuronal damage. Here, we detected an increase in transendothelial resistance in mouse brain microvascular endothelial cells (MbMECs) after treatment with a selective TRPV4 inhibitor. However, this effect was abolished after the addition of IFNγ and TNFα indicating that inflammatory conditions override TRPV4-mediated permeability. Accordingly, we did not observe a protection of -deficient mice when compared to wildtype controls in a preclinical model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), and no differences in infarct sizes following transient middle cerebral artery occlusion (tMCAO), the experimental stroke model, which leads to an acute postischemic inflammatory response. Furthermore, Evans Blue injections did not show differences in alterations of the blood brain barrier (BBB) permeability between genotypes in both animal models. Together, TRPV4 does not regulate brain microvascular endothelial permeability under inflammation.
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http://dx.doi.org/10.3389/fcell.2020.00849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481434PMC
August 2020

Motor neuron translatome reveals deregulation of SYNGR4 and PLEKHB1 in mutant TDP-43 amyotrophic lateral sclerosis models.

Hum Mol Genet 2020 09;29(16):2647-2661

Neuronal Translational Control Research Group, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany.

Amyotrophic lateral sclerosis (ALS) is an incurable neurological disease with progressive loss of motor neuron (MN) function in the brain and spinal cord. Mutations in TARDBP, encoding the RNA-binding protein TDP-43, are one cause of ALS, and TDP-43 mislocalization in MNs is a key pathological feature of >95% of ALS cases. While numerous studies support altered RNA regulation by TDP-43 as a major cause of disease, specific changes within MNs that trigger disease onset remain unclear. Here, we combined translating ribosome affinity purification (TRAP) with RNA sequencing to identify molecular changes in spinal MNs of TDP-43-driven ALS at motor symptom onset. By comparing the MN translatome of hTDP-43A315T mice to littermate controls and to mice expressing wild type hTDP-43, we identified hundreds of mRNAs that were selectively up- or downregulated in MNs. We validated the deregulated candidates Tex26, Syngr4, and Plekhb1 mRNAs in an independent TRAP experiment. Moreover, by quantitative immunostaining of spinal cord MNs, we found corresponding protein level changes for SYNGR4 and PLEKHB1. We also observed these changes in spinal MNs of an independent ALS mouse model caused by a different patient mutant allele of TDP-43, suggesting that they are general features of TDP-43-driven ALS. Thus, we identified SYNGR4 and PLEKHB1 to be deregulated in MNs at motor symptom onset in TDP-43-driven ALS models. This spatial and temporal pattern suggests that these proteins could be functionally important for driving the transition to the symptomatic phase of the disease.
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http://dx.doi.org/10.1093/hmg/ddaa140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530531PMC
September 2020

Contribution of NAADP to Glutamate-Evoked Changes in Ca Homeostasis in Mouse Hippocampal Neurons.

Front Cell Dev Biol 2020 25;8:496. Epub 2020 Jun 25.

Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.

Nicotinic acid adenine dinucleotide phosphate (NAADP) is a second messenger that evokes calcium release from intracellular organelles by the engagement of calcium release channels, including members of the Transient Receptor Potential (TRP) family, such as TRPML1, the (structurally) related Two Pore Channel type 1 (TPC1) and TPC2 channels as well as Ryanodine Receptors type 1 (RYR1; Guse, 2012). NAADP evokes calcium release from acidic calcium stores of many cell types (Guse, 2012), and NAADP-sensitive Ca stores have been described in hippocampal neurons of the rat (Bak et al., 1999; McGuinness et al., 2007). Glutamate triggers Ca-mediated neuronal excitotoxicity in inflammation-induced neurodegenerative pathologies such as Multiple Sclerosis (MS; Friese et al., 2014), and when applied extracellularly to neurons glutamate can elevate NAADP levels in these cells. Accordingly, glutamate-evoked Ca signals from intracellular organelles were inhibited by preventing organelle acidification (Pandey et al., 2009). Analysis of reported RNA sequencing experiments of cultured hippocampal neurons revealed the abundance of Mcoln1 (encoding TRPML1), Tpcn1, and Tpcn2 (encoding TPC1 and TPC2, respectively) as potential NAADP target channels in these cells. Transcripts encoding Ryr1 were not found in contrast to Ryr2 and Ryr3. To study the contribution of NAADP signaling to glutamate-evoked calcium transients in murine hippocampal neurons we used the NAADP antagonists Ned-19 (Naylor et al., 2009) and BZ194 (Dammermann et al., 2009). Our results show that both NAADP antagonists significantly reduce glutamate-evoked calcium transients. In addition to extracellular glutamate application, we studied synchronized calcium oscillations in the cells of the neuronal cultures evoked by addition of the GABA receptor antagonist bicuculline. Pretreatment with Ned-19 (50 μM) or BZ194 (100 μM) led to an increase in the frequency of bicuculline-induced calcium oscillations at the cost of calcium transient amplitudes. Interestingly, Ned-19 triggered a rise in intracellular calcium concentrations 25 min after bicuculline stimulation, leading to the question whether NAADP acts as a neuroprotective messenger in hippocampal neurons. Taken together, our results are in agreement with the concept that NAADP signaling significantly contributes to glutamate evoked Ca rise in hippocampal neurons and to the amplitude and frequency of synchronized Ca oscillations triggered by spontaneous glutamate release events.
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http://dx.doi.org/10.3389/fcell.2020.00496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333232PMC
June 2020

Genetic determinants of the humoral immune response in MS.

Neurol Neuroimmunol Neuroinflamm 2020 09 16;7(5). Epub 2020 Jul 16.

From the Department of Neurology (C.G., T.F.M.A., A. Keating, B.K., A. Klein, V.P., A. Berthele, B.H.), Klinikum rechts der Isar, School of Medicine, Technical University of Munich; Institute of Human Genetics (P.L.), Helmholtz Zentrum München, Neuherberg; Department of Neurology (R.G.), St. Josef Hospital, Ruhr-University Bochum; Department of Neurology, Focus Program Translational Neurosciences (FTN) and Research Center for Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn2) (F.Z.), University Medical Center of the Johannes Gutenberg University Mainz; Department of Neurology and Translational Center for Regenerative Medicine (F.T.B.), University of Leipzig; Clinical Neuroimmunology and Neurochemistry (M.S.), Department of Neurology, Hannover Medical School, Hannover; Department of Neurology (H.T.), University of Ulm; Clinic of Neurology Dietenbronn (H.T.), Schwendi; Department of Neurology (B.W.), University Hospital Heidelberg; Department of Neurology (H.W.), University of Münster; Department of Neurology (A. Bayas), University Hospital Augsburg; Institute of Clinical Neuroimmunology (T.K.), University Hospital and Biomedical Center, Ludwig-Maximilians University Munich; Department of Neurology (U.K.Z.), Neuroimmunological Section, University of Rostock; Department of Neurology (R.A.L.), University Hospital Erlangen; Department of Neurology (R.A.L.), University of Regensburg; Department of Neurology & Stroke and Hertie-Institute for Clinical Brain Research (U.Z.), Eberhard-Karls-Universität Tübingen; Max Planck Institute of Psychiatry (M.K.), Munich; Department of Neurology (C.W.), Medical Faculty, Heinrich Heine University, Düsseldorf; Department of Neurology (C.W.), University Hospital Cologne; Institute of Neuroimmunology and Multiple Sclerosis (M.A.F), University Medical Centre Hamburg-Eppendorf, Hamburg; NeuroCure Clinical Research Center (F.P.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin; Berlin Institute of Health and Experimental and Clinical Research Center (F.P.), Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin; and Center of Neuroimmunology (B.T.), Philipps-University Marburg; and Munich Cluster for Systems Neurology (SyNergy) (B.H.), Germany.

Objective: In this observational study, we investigated the impact of genetic factors at the immunoglobulin heavy chain constant locus on chromosome 14 and the major histocompatibility complex region on intrathecal immunoglobulin G, A, and M levels as well as on B cells and plasmablasts in the CSF and blood of patients with multiple sclerosis (MS).

Methods: Using regression analyses, we tested genetic variants on chromosome 14 and imputed human leukocyte antigen (HLA) alleles for associations with intrathecal immunoglobulins in 1,279 patients with MS or clinically isolated syndrome and with blood and CSF B cells and plasmablasts in 301 and 348 patients, respectively.

Results: The minor alleles of variants on chromosome 14 were associated with higher intrathecal immunoglobulin G levels (β = 0.58 [0.47 to 0.68], lowest adjusted = 2.32 × 10), and lower intrathecal immunoglobulin M (β = -0.56 [-0.67 to -0.46], = 2.06 × 10) and A (β = -0.42 [-0.54 to -0.31], = 7.48 × 10) levels. Alleles from the HLA-B*07:02-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype were associated with higher (lowest = 2.14 × 10) and HLA-B*44:02 with lower (β = -0.35 [-0.54 to -0.17], = 1.38 × 10) immunoglobulin G levels. Of interest, different HLA alleles were associated with lower intrathecal immunoglobulin M (HLA-C*02:02, β = -0.45 [-0.61 to -0.28], = 1.01 × 10) and higher immunoglobulin A levels (HLA-DQA1*01:03-DQB1*06:03-DRB1*13:01 haplotype, β = 0.40 [0.21 to 0.60], = 4.46 × 10). The impact of HLA alleles on intrathecal immunoglobulin G and M levels could mostly be explained by associations with CSF B cells and plasmablasts.

Conclusion: Although some HLA alleles seem to primarily drive the extent of humoral immune responses in the CNS by increasing CSF B cells and plasmablasts, genetic variants at the immunoglobulin heavy chain constant locus might regulate intrathecal immunoglobulins levels via different mechanisms.
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http://dx.doi.org/10.1212/NXI.0000000000000827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371373PMC
September 2020

Control of SARS-CoV-2 infection in rituximab-treated neuroimmunological patients.

J Neurol 2021 Jan 11;268(1):5-7. Epub 2020 Jul 11.

Institute of Neuroimmunology and Multiple Sclerosis (INIMS), Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.

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http://dx.doi.org/10.1007/s00415-020-10046-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353821PMC
January 2021

An automated and high-throughput-screening compatible pluripotent stem cell-based test platform for developmental and reproductive toxicity assessment of small molecule compounds.

Cell Biol Toxicol 2021 04 20;37(2):229-243. Epub 2020 Jun 20.

Fraunhofer IME ScreeningPort, Schnackenburgallee 114, 22525, Hamburg, Germany.

The embryonic stem cell test (EST) represents the only validated and accepted in vitro system for the detection and classification of compounds according to their developmental and reproductive teratogenic potency. The widespread implementation of the EST, however, in particular for routine application in pharmaceutical development, has not been achieved so far. Several drawbacks still limit the high-throughput screening of potential drug candidates in this format: The long assay period, the use of non-homogeneous viability assays, the low throughput analysis of marker protein expression and the compatibility of the assay procedures to automation. We have therefore introduced several advancements into the EST workflow: A reduction of the assay period, an introduction of homogeneous viability assays, and a straightforward analysis of marker proteins by flow cytometry and high content imaging to assess the impact of small molecules on differentiation capacity. Most importantly, essential parts of the assay procedure have been adapted to lab automation in 96-well format, thus enabling the interrogation of several compounds in parallel. In addition, extensive investigations were performed to explore the predictive capacity of this next-generation EST, by testing a set of well-known embryotoxicants that encompasses the full range of chemical-inherent embryotoxic potencies possible. Due to these significant improvements, the augmented workflow provides a basis for a sensitive, more rapid, and reproducible high throughput screening compatible platform to predict in vivo developmental toxicity from in vitro data which paves the road towards application in an industrial setting. Graphical abstract •The embryonic stem cell test to predict teratogenicity was made automation-compatible. •Several key improvements to the assay procedure have been introduced to increase performance. •The workflow was adapted to human iPS cells and isogenic fibroblast donor cells.
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http://dx.doi.org/10.1007/s10565-020-09538-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012336PMC
April 2021

A novel neurodegenerative spectrum disorder in patients with MLKL deficiency.

Cell Death Dis 2020 05 1;11(5):303. Epub 2020 May 1.

Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DS, UK.

Mixed lineage kinase domain-like (MLKL) is the main executor of necroptosis, an inflammatory form of programmed cell death. Necroptosis is implicated in combating infections, but also in contributing to numerous other clinical conditions, including cardiovascular diseases and neurodegenerative disorders. Inhibition of necroptosis is therefore of therapeutic interest. Here we report two siblings both of whom over the course of 35 years developed a similar progressive, neurodegenerative spectrum disorder characterized by paresis, ataxia and dysarthria. Magnetic resonance imaging of their central nervous system (CNS) revealed severe global cerebral volume loss and atrophy of the cerebellum and brainstem. These brothers are homozygous for a rare haplotype identified by whole genome sequencing carrying a frameshift variant in MLKL, as well as an in-frame deletion of one amino acid in the adjacent fatty acid 2-hydroxylase (FA2H) gene. Functional studies of patient-derived primary cells demonstrated that the variant in MLKL leads to a deficiency of MLKL protein resulting in impairment of necroptosis. Conversely, shotgun lipidomic analysis of the variant in FA2H shows no impact on either the abundance or the enzymatic activity of the encoded hydroxylase. To our knowledge, this is the first report of complete necroptosis deficiency in humans. The findings may suggest that impaired necroptosis is a novel mechanism of neurodegeneration, promoting a disorder that shares some clinical features with primary progressive multiple sclerosis (PPMS) and other neurodegenerative diseases. Importantly, the necroptotic deficiency does not cause symptoms outside the nervous system, nor does it confer susceptibility to infections. Given the current interest in pharmacological inhibition of necroptosis by targeting MLKL and its associated pathways, this strategy should be developed with caution, with careful consideration of the possible development of adverse neurological effects.
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http://dx.doi.org/10.1038/s41419-020-2494-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195448PMC
May 2020

Moving exercise research in multiple sclerosis forward (the MoXFo initiative): Developing consensus statements for research.

Mult Scler 2020 10 12;26(11):1303-1308. Epub 2020 Mar 12.

Institut für Neuroimmunologie und Multiple Sklerose, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany/Klinik und Poliklinik für Neurologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

Exercise as a subset of physical activity is a cornerstone in the management of multiple sclerosis (MS) based on its pleotropic effects. There is an exponential increase in the quantity of research on exercise in MS, yet a number of barriers associated with study content and quality hamper rapid progress in the field. To address these barriers and accelerate discovery, a new international partnership of MS-related experts in exercise has emerged with the goal of advancing the research agenda. As a first step, the expert panel met in May 2018 and identified the most urgent areas for moving the field forward, and discussed the framework for such a process. This led to identification of five themes, namely "Definitions and terminology," "Study methodology," "Reporting and outcomes," "Adherence to exercise," and "Mechanisms of action." Based on the identified themes, five expert groups have been formed, that will further (a) outline the challenges per theme and (b) provide recommendations for moving forward. We aim to involve and collaborate with people with MS/MS organizations (e.g. Multiple Sclerosis International Federation (MSIF) and European Multiple Sclerosis Platform (EMSP)) in all of these five themes. The generation of this thematic framework with multi-expert perspectives can bolster the quality and scope of exercise studies in MS that may ultimately improve the daily lives of people with MS.
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http://dx.doi.org/10.1177/1352458520910360DOI Listing
October 2020

T Cell Repertoire Dynamics during Pregnancy in Multiple Sclerosis.

Cell Rep 2019 10;29(4):810-815.e4

Institut für Neuroimmunologie und Multiple Sklerose (INIMS), Universitätsklinikum Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany; Charité - Universitätsmedizin Berlin, Klinik für Psychiatrie und Medizinische Klinik m.S. Psychosomatik, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany. Electronic address:

Identifying T cell clones associated with human autoimmunity has remained challenging. Intriguingly, many autoimmune diseases, including multiple sclerosis (MS), show strongly diminished activity during pregnancy, providing a unique research paradigm to explore dynamics of immune repertoire changes during active and inactive disease. Here, we characterize immunomodulation at the single-clone level by sequencing the T cell repertoire in healthy women and female MS patients over the course of pregnancy. Clonality is significantly reduced from the first to third trimester in MS patients, indicating that the T cell repertoire becomes less dominated by expanded clones. However, only a few T cell clones are substantially modulated during pregnancy in each patient. Moreover, relapse-associated T cell clones identified in an individual patient contract during pregnancy and expand during a postpartum relapse. Our data provide evidence that profiling the T cell repertoire during pregnancy could serve as a tool to discover and track "private" T cell clones associated with disease activity in autoimmunity.
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http://dx.doi.org/10.1016/j.celrep.2019.09.025DOI Listing
October 2019

Pregnancy Enables Expansion of Disease-Specific Regulatory T Cells in an Animal Model of Multiple Sclerosis.

J Immunol 2019 10 23;203(7):1743-1752. Epub 2019 Aug 23.

Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, 20251 Hamburg, Germany;

Disease activity of autoimmune disorders such as multiple sclerosis and its mouse model experimental autoimmune encephalomyelitis (EAE) is temporarily suppressed by pregnancy. However, whether disease amelioration is due to nonspecific immunomodulation or mediated by Ag-specific regulation of disease-causing conventional T cells (Tcon) and immunosuppressive regulatory T cells (Tregs) remains elusive. In the current study, we systematically analyzed changes of the TCRβ repertoire driven by EAE and pregnancy using TCR sequencing. We demonstrate that EAE, but not pregnancy, robustly increased TCR repertoire clonality in both peripheral Tcon and Treg. Notably, pregnancy was required for the expansion of Treg harboring the dominant EAE-associated TRBV13-2 chain and increased the frequency of EAE-associated clonotypes within the Treg compartment. Our findings indicate that pregnancy supports the expansion of Treg clonotypes that are equipped to recognize EAE-associated Ags. These Treg are thereby particularly suited to control corresponding encephalitogenic Tcon responses and likely contribute to pregnancy-associated protection in autoimmunity.
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http://dx.doi.org/10.4049/jimmunol.1900611DOI Listing
October 2019

Neuronal vulnerability and multilineage diversity in multiple sclerosis.

Nature 2019 09 17;573(7772):75-82. Epub 2019 Jul 17.

Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.

Multiple sclerosis (MS) is a neuroinflammatory disease with a relapsing-remitting disease course at early stages, distinct lesion characteristics in cortical grey versus subcortical white matter and neurodegeneration at chronic stages. Here we used single-nucleus RNA sequencing to assess changes in expression in multiple cell lineages in MS lesions and validated the results using multiplex in situ hybridization. We found selective vulnerability and loss of excitatory CUX2-expressing projection neurons in upper-cortical layers underlying meningeal inflammation; such MS neuron populations exhibited upregulation of stress pathway genes and long non-coding RNAs. Signatures of stressed oligodendrocytes, reactive astrocytes and activated microglia mapped most strongly to the rim of MS plaques. Notably, single-nucleus RNA sequencing identified phagocytosing microglia and/or macrophages by their ingestion and perinuclear import of myelin transcripts, confirmed by functional mouse and human culture assays. Our findings indicate lineage- and region-specific transcriptomic changes associated with selective cortical neuron damage and glial activation contributing to progression of MS lesions.
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http://dx.doi.org/10.1038/s41586-019-1404-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731122PMC
September 2019

A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.

Acta Neuropathol 2019 08 27;138(2):237-250. Epub 2019 May 27.

Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.
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http://dx.doi.org/10.1007/s00401-019-02026-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660501PMC
August 2019
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