Publications by authors named "Felix Luessi"

60 Publications

The relationship between BAFF serum levels, anti-NMDAR autoantibodies and fatigue in patients with systemic lupus erythematosus and multiple sclerosis.

Autoimmun Rev 2021 May 14;20(5):102802. Epub 2021 Mar 14.

Division of Rheumatology and Clinical Immunology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; Acura Rheumatology Center Rhineland Palatinate, Bad Kreuznach, Germany; University Center of Autoimmunity, Johannes Gutenberg-University, Mainz, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.autrev.2021.102802DOI Listing
May 2021

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity.

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

Department of Neurology with Institute of Translational Neurology, University of Muenster, 48149 Muenster, 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

Laquinimod dampens IL-1β signaling and Th17-polarizing capacity of monocytes in patients with MS.

Neurol Neuroimmunol Neuroinflamm 2021 01 17;8(1). Epub 2020 Nov 17.

From the Department of Neurology (S.E., V.J., S.H.-P.K., K.R., F.L.), Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg University of Mainz, Germany; Biopathology of Myelin (V.J.), Neuroprotection and Therapeutic Strategy, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), University of Strasbourg, France; Institute for Molecular Medicine (M.Z., F.C.K., A.W.), University Medical Centre of the Johannes Gutenberg University of Mainz, Germany; Sheba Cancer Research Center (M.Z.), Chaim Sheba Academic Medical Center, Ramat Gan, Israel; Department of Neurology (H.T.), University of Ulm, Germany and Specialty Clinic of Neurology Dietenbronn, Schwendi, Germany; Clinical Neuroimmunology Unit (R.F.), San Raffaele Scientific Institute, Milan, Italy; and Department of Dermatology (F.C.K.), Heidelberg University Hospital, Heidelberg, Germany.

Objective: To assess the impact of laquinimod treatment on monocytes and to investigate the underlying immunomodulatory mechanisms in MS.

Methods: In this cross-sectional study, we performed in vivo and in vitro analyses of cluster of differentiation (CD14) monocytes isolated from healthy donors (n = 15), untreated (n = 13), and laquinimod-treated patients with MS (n = 14). Their frequency and the expression of surface activation markers were assessed by flow cytometry and the viability by calcein staining. Cytokine concentrations in the supernatants of lipopolysaccharide (LPS)-stimulated monocytes were determined by flow cytometry. The messenger ribonucleic acid (mRNA) expression level of genes involved in cytokine expression was measured by quantitative PCR. The LPS-mediated nuclear factor kappa-light-chain-enhancer of activated B-cell (NF-κB) activation was determined by the quantification of the phosphorylation level of the p65 subunit. Laquinimod-treated monocytes were cocultured with CD4 T cells, and the resulting cytokine production was analyzed by flow cytometry after intracellular cytokine staining. The interleukin (IL)-17A concentration of the supernatant was assessed by ELISA.

Results: Laquinimod did not alter the frequency or viability of circulating monocytes, but led to an upregulation of CD86 expression. LPS-stimulated monocytes of laquinimod-treated patients with MS secreted less IL-1β following a downregulation of IL-1β gene expression. Phosphorylation levels of the NF-κB p65 subunit were reduced after laquinimod treatment, indicating a laquinimod-associated inhibition of the NF-κB pathway. T cells primed with laquinimod-treated monocytes differentiated significantly less into IL-17A-producing T helper (Th)-17 cells.

Conclusions: Our findings suggest that inhibited NF-κB signaling and downregulation of IL-1β expression in monocytes contributes to the immunomodulatory effects of laquinimod and that the impairment of Th17 polarization might mediate its disease-modifying activity in MS.
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http://dx.doi.org/10.1212/NXI.0000000000000908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676421PMC
January 2021

High anti-JCPyV serum titers coincide with high CSF cell counts in RRMS patients.

Mult Scler 2020 Nov 5:1352458520970103. Epub 2020 Nov 5.

Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.

Background: Progressive multifocal leukoencephalopathy (PML) can in rare cases occur in natalizumab-treated patients with high serum anti-JCPyV antibodies, hypothetically due to excessive blockade of immune cell migration.

Objective: Immune cell recruitment to the central nervous system (CNS) was assessed in relapsing-remitting multiple sclerosis (RRMS) patients stratified by low versus high anti-JCPyV antibody titers as indicator for PML risk.

Methods: Cerebrospinal fluid (CSF) cell counts of 145 RRMS patients were quantified by flow cytometry. Generalized linear models were employed to assess influence of age, sex, disease duration, Expanded Disability Status Scale (EDSS), clinical/radiological activity, current steroid or natalizumab treatment, as well as anti-JCPyV serology on CSF cell subset counts.

Results: While clinical/radiological activity was associated with increased CD4, natural killer (NK), B and plasma cell counts, natalizumab therapy reduced all subpopulations except monocytes. With and without natalizumab therapy, patients with high anti-JCPyV serum titers presented with increased CSF T-cell counts compared to patients with low anti-JCPyV serum titers. In contrast, PML patients assessed before ( = 2) or at diagnosis ( = 5) presented with comparably low CD8 and B-cell counts, which increased after plasma exchange ( = 4).

Conclusion: High anti-JCPyV indices, which could be indicative of increased viral activity, are associated with elevated immune cell recruitment to the CNS. Its excessive impairment in conjunction with viral activity could predispose for PML development.
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http://dx.doi.org/10.1177/1352458520970103DOI Listing
November 2020

Clinical implications of serum neurofilament in newly diagnosed MS patients: A longitudinal multicentre cohort study.

EBioMedicine 2020 Jun 24;56:102807. Epub 2020 May 24.

Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn(2)), University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, Mainz 55131, Germany. Electronic address:

Background: We aim to evaluate serum neurofilament light chain (sNfL), indicating neuroaxonal damage, as a biomarker at diagnosis in a large cohort of early multiple sclerosis (MS) patients.

Methods: In a multicentre prospective longitudinal observational cohort, patients with newly diagnosed relapsing-remitting MS (RRMS) or clinically isolated syndrome (CIS) were recruited between August 2010 and November 2015 in 22 centers. Clinical parameters, MRI, and sNfL levels (measured by single molecule array) were assessed at baseline and up to four-year follow-up.

Findings: Of 814 patients, 54.7% (445) were diagnosed with RRMS and 45.3% (369) with CIS when applying 2010 McDonald criteria (RRMS[2010] and CIS[2010]). After reclassification of CIS[2010] patients with existing CSF analysis, according to 2017 criteria, sNfL levels were lower in CIS[2017] than RRMS[2017] patients (9.1 pg/ml, IQR 6.2-13.7 pg/ml, n = 45; 10.8 pg/ml, IQR 7.4-20.1 pg/ml, n = 213; p = 0.036). sNfL levels correlated with number of T2 and Gd+ lesions at baseline and future clinical relapses. Patients receiving disease-modifying therapy (DMT) during the first four years had higher baseline sNfL levels than DMT-naïve patients (11.8 pg/ml, IQR 7.5-20.7 pg/ml, n = 726; 9.7 pg/ml, IQR 6.4-15.3 pg/ml, n = 88). Therapy escalation decisions within this period were reflected by longitudinal changes in sNfL levels.

Interpretation: Assessment of sNfL increases diagnostic accuracy, is associated with disease course prognosis and may, particularly when measured longitudinally, facilitate therapeutic decisions.

Funding: Supported the German Federal Ministry for Education and Research, the German Research Council, and Hertie-Stiftung.
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http://dx.doi.org/10.1016/j.ebiom.2020.102807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251380PMC
June 2020

Complete Epstein-Barr virus seropositivity in a large cohort of patients with early multiple sclerosis.

J Neurol Neurosurg Psychiatry 2020 07 5;91(7):681-686. Epub 2020 May 5.

Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany

Objective: To determine the prevalence of antibodies to Epstein-Barr virus (EBV) in a large cohort of patients with early multiple sclerosis (MS).

Methods: Serum samples were collected from 901 patients with a clinically isolated syndrome (CIS) or early relapsing-remitting multiple sclerosis (RRMS) participating in the German National MS cohort, a prospective cohort of patients with early MS with stringent inclusion criteria. Epstein-Barr nuclear antigen (EBNA)-1 and viral capsid antigen (VCA) antibodies were measured in diluted sera by chemiluminescence immunoassays (CLIAs). Sera of EBNA-1 and VCA antibody-negative patients were retested undiluted by an EBV IgG immunoblot. For comparison, we retrospectively analysed the EBV seroprevalence across different age cohorts, ranging from 0 to >80 years, in a large hospital population (N=16 163) from Berlin/Northern Germany.

Results: EBNA-1 antibodies were detected by CLIA in 839 of 901 patients with CIS/RRMS. Of the 62 patients without EBNA-1 antibodies, 45 had antibodies to VCA as detected by CLIA. In all of the remaining 17 patients, antibodies to EBV were detected by immunoblot. Altogether, 901 of 901 (100%) patients with CIS/RRMS were EBV-seropositive. EBV seropositivity increased with age in the hospital population but did not reach 100% in any of the investigated age cohorts.

Conclusion: The complete EBV seropositivity in this large cohort of patients with early MS strengthens the evidence for a role of EBV in MS. It also suggests that a negative EBV serology in patients with suspected inflammatory central nervous system disease should alert clinicians to consider diagnoses other than MS.
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http://dx.doi.org/10.1136/jnnp-2020-322941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361012PMC
July 2020

Is ε4 associated with cognitive performance in early MS?

Neurol Neuroimmunol Neuroinflamm 2020 07 1;7(4). Epub 2020 May 1.

From the Department of Neurology and Focus Program Translational Neuroscience (FTN) (S.E., C.G., M.M., S.B., S.G., F.Z., C.M.L., F.L.), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Germany; Department of Neurology (A.S.), Inselspital, Bern University Hospital, University of Bern, Switzerland; Department of Neurology (A.S., B.A., R.G.), St. Josef-Hospital, Ruhr-University Bochum; Institute of Medical Biostatistics (G.T.), Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg University Mainz; Department of Neurology (A. Bayas), Klinikum Augsburg; Department of Neurology (A. Berthele, B.H.), Klinikum rechts der Isar, Technical University of Munich; Institut für Neuroimmunologie und Multiple Sklerose (C.H.), Universitätsklinikum Hamburg-Eppendorf; Clinic of Neurology (L.K., S.G.M., H.W.), University Hospital Münster, Westphalian-Wilhelms-University Münster; Institute of Clinical Neuroimmunology (T.K.), Ludwig Maximilian University of Munich; Department of Neurology (R.A.L.), University Hospital Erlangen; NeuroCure Clinical Research Center and Experimental and Clinical Research Center (F.P.), Charité - Universitätsmedizin Berlin and Max Delbrueck Center for Molecular Medicine; Department of Neurology (M.S.), Hannover Medical School; Department of Neurology (B.T.), Philipps-University Marburg; Department of Neurology (F.T.B.), University of Leipzig; Department of Neurology (H.T.), University of Ulm; Clinic of Neurology Dietenbronn (H.T.), Schwendi; Neurology (F.W.), Max-Planck-Institute of Psychiatry, Munich; Neurological Clinic (F.W.), Sana Kliniken des Landkreises Cham; Department of Neurology (B.W.), University of Heidelberg; Department. of Neurology (U.K.Z.), University of Rostock; Central Information Office (CIO) (G.A.), Philipps-University Marburg; and Genetic and Molecular Epidemiology Group (C.M.L.), Lübeck Interdisciplinary Platform for Genome Analytics, Institutes of Neurogenetics and Cardiogenetics, University of Lübeck, Germany.

Objective: To assess the impact of polymorphisms on cognitive performance in patients newly diagnosed with clinically isolated syndrome (CIS) or relapsing-remitting MS (RRMS).

Methods: This multicenter cohort study included 552 untreated patients recently diagnosed with CIS or RRMS according to the 2005 revised McDonald criteria. The single nucleotide polymorphisms rs429358 (ε4) and rs7412 (ε2) of the haplotype were assessed by allelic discrimination assays Cognitive performance was evaluated using the 3-second paced auditory serial addition test and the Multiple Sclerosis Inventory Cognition (MUSIC). Sum scores were calculated to approximate the overall cognitive performance and memory-centered cognitive functions. The impact of the carrier status on cognitive performance was assessed using multiple linear regression models, also including demographic, clinical, MRI, and lifestyle factors.

Results: ε4 homozygosity was associated with lower overall cognitive performance, whereas no relevant association was observed for ε4 heterozygosity or ε2 carrier status. Furthermore, higher disability levels, MRI lesion load, and depressive symptoms were associated with lower cognitive performance. Patients consuming alcohol had higher test scores than patients not consuming alcohol. Female sex, lower disability, and alcohol consumption were associated with better performance in the memory-centered subtests of MUSIC, whereas no relevant association was observed for carrier status.

Conclusion: Along with parameters of a higher disease burden, ε4 homozygosity was identified as a potential predictor of cognitive performance in this large cohort of patients with CIS and early RRMS.
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http://dx.doi.org/10.1212/NXI.0000000000000728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217661PMC
July 2020

Longitudinal prevalence and determinants of pain in multiple sclerosis: results from the German National Multiple Sclerosis Cohort study.

Pain 2020 04;161(4):787-796

Department of Neurology, Technical University of Munich (TUM), School of Medicine, Munich, Germany.

Pain is frequent in multiple sclerosis (MS) and includes different types, with neuropathic pain (NP) being most closely related to MS pathology. However, prevalence estimates vary largely, and causal relationships between pain and biopsychosocial factors in MS are largely unknown. Longitudinal studies might help to clarify the prevalence and determinants of pain in MS. To this end, we analyzed data from 410 patients with newly diagnosed clinically isolated syndrome or relapsing-remitting MS participating in the prospective multicenter German National MS Cohort Study (NationMS) at baseline and after 4 years. Pain was assessed by self-report using the PainDETECT Questionnaire. Neuropsychiatric assessment included tests for fatigue, depression, and cognition. In addition, sociodemographic and clinical data were obtained. Prevalence of pain of any type was 40% and 36% at baseline and after 4 years, respectively, whereas prevalence of NP was 2% and 5%. Pain of any type and NP were both strongly linked to fatigue, depression, and disability. This link was even stronger after 4 years than at baseline. Moreover, changes in pain, depression, and fatigue were highly correlated without any of these symptoms preceding the others. Taken together, pain of any type seems to be much more frequent than NP in early nonprogressive MS. Moreover, the close relationship between pain, fatigue, and depression in MS should be considered for treatment decisions and future research on a possible common pathophysiology.
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http://dx.doi.org/10.1097/j.pain.0000000000001767DOI Listing
April 2020

MOG encephalomyelitis: distinct clinical, MRI and CSF features in patients with longitudinal extensive transverse myelitis as first clinical presentation.

J Neurol 2020 Jun 13;267(6):1632-1642. Epub 2020 Feb 13.

Department of Neurology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany.

Background: Based on clinical, immunological and histopathological evidence, MOG-IgG-associated encephalomyelitis (MOG-EM) has emerged as a distinct disease entity different from multiple sclerosis (MS) and aquaporin-4-antibody-positive neuromyelitis optica spectrum disorder (NMOSD). MOG-EM is associated with a broader clinical phenotype including optic neuritis, myelitis, brainstem lesions and acute disseminated encephalomyelitis with a substantial clinical and radiological overlap to other demyelinating CNS disorders.

Objective: To evaluate common clinical, MRI and CSF findings, as well as therapy responses in patients with longitudinal extensive transverse myelitis (LETM) as initial clinical presentation of MOG-EM.

Methods: After excluding patients with a known diagnosis of MS, we identified 153 patients with myelitis of which 7 fulfilled the inclusion criteria and were investigated for MRI, CSF and clinical parameters.

Results: Patients with LETM as first clinical presentation of MOG-EM display similar characteristics, namely a lack of gadolinium-enhancement in spinal cord MRI, marked pleocytosis, negative oligoclonal bands, a previous history of infections/vaccinations and response to antibody-depleting treatments for acute attacks and long-term treatment.

Conclusions: We identify common pathological findings in patients with LETM as first clinical presentation of MOG-EM which distinguishes it from other forms of LETM and should lead to testing for MOG-IgG in these cases.
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http://dx.doi.org/10.1007/s00415-020-09755-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293681PMC
June 2020

Association of intrathecal pleocytosis and IgG synthesis with axonal damage in early MS.

Neurol Neuroimmunol Neuroinflamm 2020 05 4;7(3). Epub 2020 Feb 4.

From the Department of Neurology (S.E., F.S., T.U., F.Z., S.B., F.L.), Focus Program Translational Neuroscience (FTN), and Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn), University Medical Center of the Johannes Gutenberg University; and Institute of Medical Biostatistics (P.S.-K.), Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

Objective: To investigate the association of serum neurofilament light chain (sNfL) levels with CSF parameters in clinically isolated syndrome (CIS) and early relapsing-remitting MS (RRMS), taking into account radiologic and clinical parameters of disease activity.

Methods: Simultaneously collected serum and CSF samples of 112 untreated patients newly diagnosed with CIS or RRMS were included in this cross-sectional study. CSF parameters were obtained as part of routine diagnostic tests. sNfL levels of patients and of 62 healthy donors were measured by highly sensitive single molecule array (SiMoA) immunoassay.

Results: Patients with RRMS (n = 91, median 10.13 pg/mL, interquartile range [IQR] 6.67-17.77 pg/mL) had higher sNfL levels than healthy donors (n = 62, median 5.25 pg/mL, IQR 4.05-6.81 pg/mL, < 0.001) and patients with CIS (n = 21, median 5.69 pg/mL, IQR 4.73-9.07 pg/mL, < 0.001). Patients positive for oligoclonal bands (OCBs) (n = 101, median 9.19 pg/mL, IQR 6.34-16.38 pg/mL) had higher sNfL levels than OCB-negative patients (n = 11, median 5.93 pg/mL, IQR 2.93-8.56 pg/mL, = 0.001). sNfL levels correlated with CSF immunoglobulin G (IgG) levels ( = 0.317, = 0.002), IgG ratio (QIgG) ( = 0.344, < 0.001), and CSF leukocyte count ( = 0.288, = 0.002). In linear regression modeling, the CSF leukocyte count combined with the number of contrast-enhancing lesions in MRI predicted sNfL levels best.

Conclusions: In active MS, sNfL levels correlate with intrathecal pleocytosis and IgG synthesis, indicating that axonal damage is associated with both acute and chronic CNS-intrinsic inflammation.
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http://dx.doi.org/10.1212/NXI.0000000000000679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051198PMC
May 2020

DeepWAS: Multivariate genotype-phenotype associations by directly integrating regulatory information using deep learning.

PLoS Comput Biol 2020 02 3;16(2):e1007616. Epub 2020 Feb 3.

Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany.

Genome-wide association studies (GWAS) identify genetic variants associated with traits or diseases. GWAS never directly link variants to regulatory mechanisms. Instead, the functional annotation of variants is typically inferred by post hoc analyses. A specific class of deep learning-based methods allows for the prediction of regulatory effects per variant on several cell type-specific chromatin features. We here describe "DeepWAS", a new approach that integrates these regulatory effect predictions of single variants into a multivariate GWAS setting. Thereby, single variants associated with a trait or disease are directly coupled to their impact on a chromatin feature in a cell type. Up to 61 regulatory SNPs, called dSNPs, were associated with multiple sclerosis (MS, 4,888 cases and 10,395 controls), major depressive disorder (MDD, 1,475 cases and 2,144 controls), and height (5,974 individuals). These variants were mainly non-coding and reached at least nominal significance in classical GWAS. The prediction accuracy was higher for DeepWAS than for classical GWAS models for 91% of the genome-wide significant, MS-specific dSNPs. DSNPs were enriched in public or cohort-matched expression and methylation quantitative trait loci and we demonstrated the potential of DeepWAS to generate testable functional hypotheses based on genotype data alone. DeepWAS is available at https://github.com/cellmapslab/DeepWAS.
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http://dx.doi.org/10.1371/journal.pcbi.1007616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043350PMC
February 2020

Continuous reorganization of cortical information flow in multiple sclerosis: A longitudinal fMRI effective connectivity study.

Sci Rep 2020 01 21;10(1):806. Epub 2020 Jan 21.

Department of Neurology, Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

Effective connectivity (EC) is able to explore causal effects between brain areas and can depict mechanisms that underlie repair and adaptation in chronic brain diseases. Thus, the application of EC techniques in multiple sclerosis (MS) has the potential to determine directionality of neuronal interactions and may provide an imaging biomarker for disease progression. Here, serial longitudinal structural and resting-state fMRI was performed at 12-week intervals over one year in twelve MS patients. Twelve healthy subjects served as controls (HC). Two approaches for EC quantification were used: Causal Bayesian Network (CBN) and Time-resolved Partial Directed Coherence (TPDC). The EC strength was correlated with the Expanded Disability Status Scale (EDSS) and Fatigue Scale for Motor and Cognitive functions (FSMC). Our findings demonstrated a longitudinal increase in EC between specific brain regions, detected in both the CBN and TPDC analysis in MS patients. In particular, EC from the deep grey matter, frontal, prefrontal and temporal regions showed a continuous increase over the study period. No longitudinal changes in EC were attested in HC during the study. Furthermore, we observed an association between clinical performance and EC strength. In particular, the EC increase in fronto-cerebellar connections showed an inverse correlation with the EDSS and FSMC. Our data depict continuous functional reorganization between specific brain regions indicated by increasing EC over time in MS, which is not detectable in HC. In particular, fronto-cerebellar connections, which were closely related to clinical performance, may provide a marker of brain plasticity and functional reserve in MS.
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http://dx.doi.org/10.1038/s41598-020-57895-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972853PMC
January 2020

The Rare Signal Peptide Coding Variant rs28385692 Decreases Secretion of IL-22BP Isoform-1, -2 and -3 and Is Associated with Risk for Multiple Sclerosis.

Cells 2020 01 10;9(1). Epub 2020 Jan 10.

Neurogenomiks Laboratory, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain.

The locus is associated with risk for multiple sclerosis (MS) but causative variants are yet to be determined. In a single nucleotide polymorphism (SNP) screen of this locus in a Basque population, rs28385692, a rare coding variant substituting Leu for Pro at position 16 emerged significantly ( = 0.02). This variant is located in the signal peptide (SP) shared by the three secreted protein isoforms produced by (IL-22 binding protein-1(IL-22BPi1), IL-22BPi2 and IL-22BPi3). Genotyping was extended to a Europe-wide case-control dataset and yielded high significance in the full dataset ( = 3.17 × 10). Importantly, logistic regression analyses conditioning on the main known MS-associated SNP at this locus, rs17066096, revealed that this association was independent from the primary association signal in the full case-control dataset. In silico analysis predicted both disruption of the alpha helix of the H-region of the SP and decreased hydrophobicity of this region, ultimately affecting the SP cleavage site. We tested the effect of the p.Leu16Pro variant on the secretion of IL-22BPi1, IL-22BPi2 and IL-22BPi3 and observed that the Pro16 risk allele significantly lowers secretion levels of each of the isoforms to around 50%-60% in comparison to the Leu16 reference allele. Thus, our study suggests that genetically coded decreased levels of IL-22BP isoforms are associated with augmented risk for MS.
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http://dx.doi.org/10.3390/cells9010175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017210PMC
January 2020

PPMS onset upon adalimumab treatment extends the spectrum of anti-TNF-α therapy-associated demyelinating disorders.

Ther Adv Neurol Disord 2020 2;13:1756286419895155. Epub 2020 Jan 2.

Department of Neurology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn²), University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstrasse 1, Mainz 55131, Germany.

Since their introduction in 1999, anti-tumour necrosis factor-α (anti-TNF-α) therapies have been suspected repeatedly to be associated with the occurrence of central nervous system (CNS) demyelinating disorders, including multiple sclerosis (MS). However, recent publications were restricted to descriptions of monophasic demyelinating events or cases of relapsing-remitting MS (RRMS). We here provide the first case report of primary progressive MS (PPMS) onset upon anti-TNF-α therapy as well as a literature review of previously published cases of anti-TNF-α therapy-associated MS onset. The 51-year old male patient was treated with adalimumab due to psoriasis arthritis. About 18 months after treatment initiation, he developed slowly progressing neurological deficits including gait impairment, paraesthesia of the lower limbs, strangury and visual impairment, which led to the discontinuation of adalimumab therapy. Magnetic resonance imaging of the brain and the spinal cord revealed multiple inflammatory lesions and cerebrospinal fluid examination showed slight pleocytosis and positive oligoclonal bands. Thus, PPMS was diagnosed according to the 2017 revision of the McDonald criteria. As PPMS often causes only subtle symptoms in the beginning and early treatment discontinuation of anti-TNF-α therapy seems essential to improve the patient's outcome, we think that it is important to increase the awareness of slowly progressing neurological deficits as a potential adverse event of anti-TNF-α therapy among all clinicians involved in the initiation and monitoring of these drugs. In addition, the occurrence of both RRMS and progressive MS upon anti-TNF-α therapy might suggest a shared TNF-α-mediated pathophysiological mechanism in the evolution of all MS subtypes.
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http://dx.doi.org/10.1177/1756286419895155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940603PMC
January 2020

Intrathecal B-cell accumulation and axonal damage distinguish MRI-based benign from aggressive onset in MS.

Neurol Neuroimmunol Neuroinflamm 2019 09 19;6(5). Epub 2019 Jul 19.

From the Department of Neurology (S.E., M.F., M.M., F.S., S.G., S.B., F.Z., F.L.), Focus Program Translational Neuroscience (FTN), and Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn), University Medical Center of the Johannes Gutenberg University, Mainz; and Institute of Medical Biostatistics (A.P.), Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

Objective: We explored the incremental value of adding multiple disease activity biomarkers in CSF and serum for distinguishing MRI-based benign from aggressive MS in early disease course.

Methods: Ninety-three patients diagnosed with clinically isolated syndrome (CIS) or early MS were divided into 3 nonoverlapping severity groups defined by objective MRI criteria. Ninety-seven patients with noninflammatory neurologic disorders and 48 patients with other inflammatory neurologic diseases served as controls. Leukocyte subsets in the CSF were analyzed by flow cytometry. CSF neurofilament light chain (NfL) and chitinase-3-like protein 1 (CHI3L1) levels were measured by ELISA. Serum NfL levels were examined using single molecule array technology.

Results: CSF CD20+/CD14+ ratios and NfL levels in CSF and serum were significantly different between high and low MRI severity groups, whereas no difference was found for CSF CHI3L1 levels. NfL levels in CSF and serum highly correlated. Receiver operating characteristic analysis demonstrated that the cumulative sums combining CSF CD20+/CD14+ ratios and NfL levels in serum or CSF considerably improved diagnostic accuracy. A composite score built from these 2 cumulative sums best distinguished MRI severity. These findings were validated by support vector machine analysis, which confirmed that the accuracy of the cumulative sums and composite score outperforms single biomarkers.

Conclusion: Patients with extreme manifestations of CIS or early MS defined by strict MRI parameters can be best distinguished by combining markers of intrathecal B-cell accumulation and axonal damage. This could stratify individual treatment decisions toward a more personalized immunotherapy.
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http://dx.doi.org/10.1212/NXI.0000000000000595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705631PMC
September 2019

Selective Brain Network and Cellular Responses Upon Dimethyl Fumarate Immunomodulation in Multiple Sclerosis.

Front Immunol 2019 30;10:1779. Epub 2019 Jul 30.

Department of Neurology, Focus Program Translational Neuroscience (FTN), Rhine-Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

Efficient personalized therapy paradigms are needed to modify the disease course and halt gray (GM) and white matter (WM) damage in patients with multiple sclerosis (MS). Presently, promising disease-modifying drugs show impressive efficiency, however, tailored markers of therapy responses are required. Here, we aimed to detect in a real-world setting patients with a more favorable brain network response and immune cell dynamics upon dimethyl fumarate (DMF) treatment. In a cohort of 78 MS patients we identified two thoroughly matched groups, based on age, disease duration, disability status and lesion volume, receiving DMF ( = 42) and NAT ( = 36) and followed them over 16 months. The rate of cortical atrophy and deep GM volumes were quantified. GM and WM network responses were characterized by brain modularization as a marker of regional and global structural alterations. In the DMF group, lymphocyte subsets were analyzed by flow cytometry and related to clinical and MRI parameters. Sixty percent (25 patients) of the DMF and 36% (13 patients) of the NAT group had disease activity during the study period. The rate of cortical atrophy was higher in the DMF group (-2.4%) compared to NAT (-2.1%, < 0.05) group. GM and WM network dynamics presented increased modularization in both groups. When dividing the DMF-treated cohort into patients free of disease activity ( = 17, DMF) and patients with disease activity ( = 25, DMF) these groups differed significantly in CD8+ cell depletion counts (DMF: 197.7 ± 97.1/μl; DMF: 298.4 ± 190.6/μl, = 0.03) and also in cortical atrophy (DMF: -1.7%; DMF: -3.2%, = 0.01). DMF presented reduced longitudinal GM and WM modularization and less atrophy as markers of preserved structural global network integrity in comparison to DMF and even NAT patients. NAT treatment contributes to a reduced rate of cortical atrophy compared to DMF therapy. However, patients under DMF treatment with a stronger CD8+ T cell depletion present a more favorable response in terms of cortical integrity and GM and WM network responses. Our findings may serve as basis for the development of personalized treatment paradigms.
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http://dx.doi.org/10.3389/fimmu.2019.01779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682686PMC
October 2020

[Diagnostics and treatment of tuberculosis under immunotherapy for multiple sclerosis : Current status and recommendations in Germany].

Nervenarzt 2019 Dec;90(12):1245-1253

Klinik für Neurologie, Forschungszentrum Translationale Neurowissenschaften (FTN), Forschungszentrum für Immuntherapie (FZI), Rhine Main Neuroscience Network (rmn2), Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Langenbeckstr. 1, 55131, Mainz, Deutschland.

After years of low incidence, a large increase of new tuberculosis (TB) cases has been reported in Germany since 2015. New immunotherapies for the treatment of multiple sclerosis (MS) are associated with a reduced immune competence and a potential increased risk for infections. Most neurologists lack specific experiences with TB infections. This article summarizes specific recommendations for the diagnostics and treatment of TB under MS immunotherapies with a focus on the situation in Germany. Due to low case numbers and little experience with the risk of TB under the new immunotherapies, the clinical competence network for MS (KKNMS) consensus recommendations have a low grade of evidence.
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http://dx.doi.org/10.1007/s00115-019-0760-0DOI Listing
December 2019

Fatigue in SLE: diagnostic and pathogenic impact of anti-N-methyl-D-aspartate receptor (NMDAR) autoantibodies.

Ann Rheum Dis 2019 09 11;78(9):1226-1234. Epub 2019 Jun 11.

Division of Rheumatology and Clinical Immunology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

Objectives: We explored the impact of circulating anti-N-methyl-D-aspartate receptor (NMDAR) antibodies on the severity of fatigue in patients with systemic lupus erythematosus (SLE).

Methods: Serum samples of 426 patients with SLE were analysed for the presence of antibodies to the NR2 subunit of the NMDAR. In parallel, the severity of fatigue was determined according to the Fatigue Scale for Motor and Cognitive functions questionnaire. In a subgroup of patients with SLE, the hippocampal volume was correlated with the levels of anti-NR2 antibodies. Isolated immunoglobulin G from patients with anti-NR2 antibodies were used for murine immunohistochemical experiments and functional assays on neuronal cell lines. Treatment effects were studied in 86 patients with lupus under belimumab therapy.

Results: We found a close correlation between the titre of anti-NR2 antibodies, the severity of fatigue, the clinical disease activity index (Systemic Lupus Erythematosus Disease Activity Index 2000) and anti-double stranded DNA antibodies-independently of the presence of neuropsychiatric lupus manifestations. Pathogenic effects could be demonstrated by (1) detection of anti-NR2 antibodies in the cerebrospinal fluid, (2) in situ binding of anti-NR2 antibodies to NMDAR of the hippocampus area and (3) distinct functional effects in vitro: downregulating the energy metabolism of neuronal cells without enhanced cytotoxicity. Treatment with belimumab for at least 6 months affected both the severity of fatigue and the levels of anti-NR2 antibodies.

Conclusion: The presence of anti-NR2 antibodies in patients with SLE with fatigue is a helpful diagnostic tool and may offer a major approach in the therapeutic management of this important disabling symptom in patients with SLE.
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http://dx.doi.org/10.1136/annrheumdis-2019-215098DOI Listing
September 2019

Can we predict cognitive decline after initial diagnosis of multiple sclerosis? Results from the German National early MS cohort (KKNMS).

J Neurol 2019 Feb 4;266(2):386-397. Epub 2018 Dec 4.

Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.

Background: Cognitive impairment (CI) affects approximately one-third of the patients with early multiple sclerosis (MS) and clinically isolated syndrome (CIS). Little is known about factors predicting CI and progression after initial diagnosis.

Methods: Neuropsychological screening data from baseline and 1-year follow-up of a prospective multicenter cohort study (NationMS) involving 1123 patients with newly diagnosed MS or CIS were analyzed. Employing linear multilevel models, we investigated whether demographic, clinical and conventional MRI markers at baseline were predictive for CI and longitudinal cognitive changes.

Results: At baseline, 22% of patients had CI (impairment in ≥2 cognitive domains) with highest frequencies and severity in processing speed and executive functions. Demographics (fewer years of academic education, higher age, male sex), clinical (EDSS, depressive symptoms) but no conventional MRI characteristics were linked to baseline CI. At follow-up, only 14% of patients showed CI suggesting effects of retesting. Neither baseline characteristics nor initiation of treatment between baseline and follow-up was able to predict cognitive changes within the follow-up period of 1 year.

Conclusions: Identification of risk factors for short-term cognitive change in newly diagnosed MS or CIS is insufficient using only demographic, clinical and conventional MRI data. Change-sensitive, re-test reliable cognitive tests and more sophisticated predictors need to be employed in future clinical trials and cohort studies of early-stage MS to improve prediction.
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http://dx.doi.org/10.1007/s00415-018-9142-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373354PMC
February 2019

GFAPα IgG-associated encephalitis upon daclizumab treatment of MS.

Neurol Neuroimmunol Neuroinflamm 2018 Sep 13;5(5):e481. Epub 2018 Jul 13.

Department of Neurology and Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Germany.

Objective: To describe a case of glial fibrillary acidic protein (GFAP)α immunoglobulin G (IgG)-associated encephalitis in a patient referred to us with MS on daclizumab treatment and to summarize characteristics of 5 additional recent German MS cases of serious encephalitis along with a previously published American case of CNS vasculitis associated with daclizumab.

Methods: Evaluation of cause, clinical symptoms, and treatment response.

Results: The 6 patients included 4 women and 2 men. The median age at onset was 38 years (range 32-51 years). Clinical presentation was marked by progressing neuropsychologic and/or neurologic deficits. Additional drug rash with eosinophilia was seen in 3 patients, whereas 2 patients showed a highly active demyelinating process. Examination of CSF samples detected pleocytosis, elevated total protein levels, and GFAPα IgG antibodies, which were not found in serum. In our case, we discovered autoimmune GFAP astrocytopathy associated with encephalitis as secondary autoimmunity, which was steroid responsive. Clinical outcome of other cases was marked by partial recovery in 4 patients and persistent foster care in 1 patient.

Conclusions: Our case of GFAPα IgG-associated encephalitis along with 12 other cases of serious inflammatory brain disorders following daclizumab treatment so far indicates that interfering with NK cells and Tregs by anti-CD25 antibody therapy can result in severe secondary CNS autoimmunity in man.
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http://dx.doi.org/10.1212/NXI.0000000000000481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047833PMC
September 2018

Regulation of IL-22BP in psoriasis.

Sci Rep 2018 03 23;8(1):5085. Epub 2018 Mar 23.

Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

IL-22 is a potent pro-inflammatory cytokine upregulated in psoriasis and in other inflammatory diseases. The function of IL-22 is regulated by the soluble scavenging receptor, IL-22 binding protein (IL-22BP or IL-22RA2). However, the role and regulation of IL-22BP itself in the pathogenesis of inflammatory disease remain unclear. We used the TLR7 agonist Imiquimod (IMQ) to induce a psoriasis-like skin disease in mice and found a strong downregulation of IL-22BP in the affected skin as well as in the lymph nodes of animals treated with IMQ. We also analysed psoriatic skin of patients and compared this to skin of healthy donors. Interestingly, IL-22BP expression was similarly downregulated in skin biopsies of psoriasis patients compared to the skin of healthy donors. Since IL-22BP is expressed foremost in dendritic cells, we characterized its expression in monocyte-derived dendritic cells (MoDC) during maturation. In this way, we found Prostaglandin E2 (PGE) to be a potent suppressor of IL-22BP expression in vitro. We conclude that regulation of IL-22BP by inflammatory mediators is an important step for the progression of inflammation in the skin and possibly also in other autoimmune diseases.
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http://dx.doi.org/10.1038/s41598-018-23510-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865214PMC
March 2018

Association of smoking but not HLA-DRB1*15:01, APOE or body mass index with brain atrophy in early multiple sclerosis.

Mult Scler 2019 04 13;25(5):661-668. Epub 2018 Mar 13.

Department of Neurology and Neuroimaging Center (NIC), Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

Background: The course of multiple sclerosis (MS) shows substantial inter-individual variability. The underlying determinants of disease severity likely involve genetic and environmental factors.

Objective: The aim of this study was to assess the impact of APOE and HLA polymorphisms as well as smoking and body mass index (BMI) in the very early MS course.

Methods: Untreated patients ( n = 263) with a recent diagnosis of relapsing-remitting (RR) MS or clinically isolated syndrome underwent standardized magnetic resonance imaging (MRI). Genotyping was performed for single-nucleotide polymorphisms (SNPs) rs3135388 tagging the HLA-DRB1*15:01 haplotype and rs7412 (Ɛ2) and rs429358 (Ɛ4) in APOE. Linear regression analyses were applied based on the three SNPs, smoking and BMI as exposures and MRI surrogate markers for disease severity as outcomes.

Results: Current smoking was associated with reduced gray matter fraction, lower brain parenchymal fraction and increased cerebrospinal fluid fraction in comparison to non-smoking, whereas no effect was observed on white matter fraction. BMI and the SNPs in HLA and APOE were not associated with structural MRI parameters.

Conclusions: Smoking may have an unfavorable effect on the gray matter fraction as a potential measure of MS severity already in early MS. These findings may impact patients' counseling upon initial diagnosis of MS.
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http://dx.doi.org/10.1177/1352458518763541DOI Listing
April 2019

Treatment choices and neuropsychological symptoms of a large cohort of early MS.

Neurol Neuroimmunol Neuroinflamm 2018 May 1;5(3):e446. Epub 2018 Mar 1.

Department of Neurology (O.v.B., B.A., R.G., A.S.), St. Josef-Hospital, Ruhr-University Bochum; Institute of Medical Biometry and Statistics (T.D., N.H., A.Z.), University of Lübeck, University Hospital Schleswig-Holstein, Campus Lübeck; Central Information Office (CIO) (G.A.), Philipps-University Marburg, Germany; School of Mathematics (A.Z.), Statistics and Computer Science, University of KwaZulu-Natal, Pietermaritzburg, South Africa; Department of Neurology (M.-M.H., L.A., B.H.), Klinikum rechts der Isar, Technical University of Munich; Munich Cluster for Systems Neurology (SyNergy) (L.A., B.H.); Department of Neurology (F.L., S.G., F.Z.), University Medicine Mainz, Johannes Gutenberg University Mainz; Department of Neurology (L.K., S.G.M., H.W.), University Hospital Münster; Department of Neurology (B.T.), Philipps-University Marburg; Department of Neurology (M.Stoppe, F.T.B.), University of Leipzig; Department of Neurology (H.T.), University of Ulm; Clinic of Neurology Dietenbronn (H.T.), Schwendi; Institute of Clinical Neuroimmunology (T.K.), Ludwig Maximilian University of Munich; Department of Neurology (M.Stangel), Hannover Medical School; Institut für Neuroimmunologie und Multiple Sklerose (C.H.), Universitätsklinikum Hamburg-Eppendorf; Department of Neurology (B.W.), University of Heidelberg; NeuroCure Clinical Research Center and Experimental and Clinical Research Center (F.P.), Charité-University Medicine Berlin and Max Delbrueck Center for Molecular Medicine; Department of Neurology (A.B.), Klinikum Augsburg; Department of Neurology (C.W.), Heinrich-Heine-University, Düsseldorf; Department of Neurology (C.W.), University Hospital Köln; Neurology (F.W.), Max-Planck-Institute of Psychiatry, Munich; Neurological Clinic (F.W.), MATERNUS Kliniken AG, Bad Oeynhausen; Department of Neurology (R.A.L.), University Hospital Erlangen; Department of Neurology & Stroke (U.Z.), Hertie Institute for Clinical Brain Research, Eberhard-Karls-University Tübingen; Department of Neurology (U.K.Z.), University of Rostock, Germany; and Department of Neurology (A.S.), Inselspital Bern, University Hospital and University of Bern, Switzerland.

Objective: To assess clinical characteristics, distribution of disease-modifying treatments (DMTs), and neuropsychological symptoms in a large cohort of patients with early-stage MS.

Methods: The German National MS Cohort is a multicenter prospective longitudinal cohort study that has recruited DMT-naive patients with clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS) since 2010. We evaluated their baseline characteristics and the prevalence of neuropsychological symptoms.

Results: Of 1,124 patients, with a 2.2:1 female-to-male ratio and median age at onset of 31.71 years (interquartile range [IQR]: 26.06-40.33), 44.6% and 55.3% had CIS and RRMS, respectively. The median Expanded Disability Status Scale (EDSS) score at baseline was 1.5 (IQR: 1.0-2.0). A proportion of 67.8% of patients started DMT after a median time of 167.0 days (IQR 90.0-377.5) since the first manifestation. A total of 64.7% and 70.4% of the 762 patients receiving early DMT were classified as CIS and RRMS, respectively. Fatigue, depressive symptoms, and cognitive dysfunction were detected in 36.5%, 33.5%, and 14.7% of patients, respectively.

Conclusion: Baseline characteristics of this large cohort of patients with early, untreated MS corroborated with other cohorts. Most patients received early DMT within the first year after disease onset, irrespective of a CIS or RRMS diagnosis. Despite the low EDSS score, neuropsychological symptoms affected a relevant proportion of patients.
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http://dx.doi.org/10.1212/NXI.0000000000000446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833336PMC
May 2018

Increased cerebrospinal fluid albumin and immunoglobulin A fractions forecast cortical atrophy and longitudinal functional deterioration in relapsing-remitting multiple sclerosis.

Mult Scler 2019 03 11;25(3):338-343. Epub 2017 Dec 11.

Department of Neurology, Focus Program Translational Neuroscience (FTN), Research Center for Immunology (FZI), Rhine-Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

Background: Currently, no unequivocal predictors of disease evolution exist in patients with multiple sclerosis (MS). Cortical atrophy measurements are, however, closely associated with cumulative disability.

Objective: Here, we aim to forecast longitudinal magnetic resonance imaging (MRI)-driven cortical atrophy and clinical disability from cerebrospinal fluid (CSF) markers.

Methods: We analyzed CSF fractions of albumin and immunoglobulins (Ig) A, G, and M and their CSF to serum quotients.

Results: Widespread atrophy was highly associated with increased baseline CSF concentrations and quotients of albumin and IgA. Patients with increased CSF and CSF showed higher functional disability at follow-up.

Conclusion: CSF markers of blood-brain barrier integrity and specific immune response forecast emerging gray matter pathology and disease progression in MS.
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http://dx.doi.org/10.1177/1352458517748474DOI Listing
March 2019

Treatment response to dimethyl fumarate is characterized by disproportionate CD8+ T cell reduction in MS.

Mult Scler 2018 04 24;24(5):632-641. Epub 2017 Apr 24.

Department of Neurology, Focus Program Translational Neuroscience (FTN), and Immunology (FZI), Rhine-Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

Background: The effect of dimethyl fumarate (DMF) on circulating lymphocyte subsets and their contribution as predictors of clinical efficacy have not yet been investigated in multiple sclerosis (MS).

Objective: To evaluate lymphocytes and lymphocyte subsets (analyzed 6 months after DMF start) in MS patients with and without disease activity after 1 year of treatment in a retrospective study.

Methods: Peripheral blood lymphocyte subsets were analyzed by flow cytometry. Untreated MS patients ( n = 40) were compared to those 6 months after onset of DMF treatment ( n = 51). Clinical and magnetic resonance imaging (MRI) disease activity of DMF-treated patients were assessed in the first year under treatment.

Results: Stable patients showed significantly lower lymphocytes, CD4+ and CD8+ T cells as well as CD19+ B cells compared to active patients under DMF treatment. Furthermore, an increased CD4/CD8 ratio ( p < 0.025) in stable patients indicated a disproportionate reduction of CD8+ T cells relative to CD4+ T cells. Reduced lymphocytes, CD8+ T cells, and CD19+ B cells 6 months after DMF start allowed prediction of the treatment response in the first year.

Conclusion: DMF treatment response is reflected by lower circulating lymphocytes and specific lymphocyte subsets. Changes in the cellular immune profiles under DMF treatment are clinically relevant and might serve as a surrogate marker of treatment response.
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http://dx.doi.org/10.1177/1352458517703799DOI Listing
April 2018

Dimethyl fumarate-induced lymphopenia in MS due to differential T-cell subset apoptosis.

Neurol Neuroimmunol Neuroinflamm 2017 May 23;4(3):e340. Epub 2017 Mar 23.

Montreal Neurological Institute (M.G., A.R., R.L., P.S.G., J.A., A.B.-O.), McGill University, Montreal, QC, Canada; Brain and Mind Centre (M.G.), University of Sydney, NSW, Australia; Institute of Actuaries of Australia (A.E.); Department of Neurology (F.L., F.Z.), University Medical Center Mainz, Germany; and Department of Neurology (A.R., R.L., A.B.-O.), Perelman School of Medicine, University of Pennsylvania, Philadelphia.

Objective: To examine the mechanism underlying the preferential CD8 vs CD4 T-cell lymphopenia induced by dimethyl fumarate (DMF) treatment of MS.

Methods: Total lymphocyte counts and comprehensive T-cell subset analyses were performed in high-quality samples obtained from patients with MS prior to and serially following DMF treatment initiation. Random coefficient mixed-effects analysis was used to model the trajectory of T-cell subset losses in vivo. Survival and apoptosis of distinct T-cell subsets were assessed following in vitro exposure to DMF.

Results: Best-fit modeling indicated that the DMF-induced preferential reductions in CD8 vs CD4 T-cell counts nonetheless followed similar depletion kinetics, suggesting a similar rather than distinct mechanism involved in losses of both the CD8 and CD4 T cells. In vitro, DMF exposure resulted in dose-dependent reductions in T-cell survival, which were found to reflect apoptotic cell death. This DMF-induced apoptosis was greater for CD8 vs CD4, as well as for memory vs naive, and conventional vs regulatory T-cell subsets, a pattern which mirrored preferential T-cell subset losses that we observed during in vivo treatment of patients.

Conclusions: Differential apoptosis mediated by DMF may underlie the preferential lymphopenia of distinct T-cell subsets, including CD8 and memory T-cell subsets, seen in treated patients with MS. This differential susceptibility of distinct T-cell subsets to DMF-induced apoptosis may contribute to both the safety and efficacy profiles of DMF in patients with MS.
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http://dx.doi.org/10.1212/NXI.0000000000000340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5365096PMC
May 2017

Dimethyl Fumarate Therapy Significantly Improves the Responsiveness of T Cells in Multiple Sclerosis Patients for Immunoregulation by Regulatory T Cells.

Int J Mol Sci 2017 Jan 28;18(2). Epub 2017 Jan 28.

Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Langenbeckstr. 1, 55131 Mainz, Germany.

Multiple sclerosis (MS) is a chronic autoimmune disease caused by an insufficient suppression of autoreactive T lymphocytes. One reason for the lack of immunological control is the reduced responsiveness of T effector cells (Teff) for the suppressive properties of regulatory T cells (Treg), a process termed Treg resistance. Here we investigated whether the disease-modifying therapy of relapsing-remitting MS (RRMS) with dimethyl fumarate (DMF) influences the sensitivity of T cells in the peripheral blood of patients towards Treg-mediated suppression. We demonstrated that DMF restores responsiveness of Teff to the suppressive function of Treg in vitro, presumably by down-regulation of interleukin-6R (IL-6R) expression on T cells. Transfer of human immune cells into immunodeficient mice resulted in a lethal graft-versus-host reaction triggered by human CD4⁺ Teff. This systemic inflammation can be prevented by activated Treg after transfer of immune cells from DMF-treated MS patients, but not after injection of Treg-resistant Teff from therapy-naïve MS patients. Furthermore, after DMF therapy, proliferation and expansion of T cells and the immigration into the spleen of the animals is reduced and modulated by activated Treg. In summary, our data reveals that DMF therapy significantly improves the responsiveness of Teff in MS patients to immunoregulation.
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http://dx.doi.org/10.3390/ijms18020271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5343807PMC
January 2017

Dimethyl Fumarate Treatment Mediates an Anti-Inflammatory Shift in B Cell Subsets of Patients with Multiple Sclerosis.

J Immunol 2017 01 14;198(2):691-698. Epub 2016 Dec 14.

Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada;

The therapeutic mode of action of dimethyl fumarate (DMF), approved for treating patients with relapsing-remitting multiple sclerosis, is not fully understood. Recently, we and others demonstrated that Ab-independent functions of distinct B cell subsets are important in mediating multiple sclerosis (MS) relapsing disease activity. Our objective was to test whether and how DMF influences both the phenotype and functional responses of disease-implicated B cell subsets in patients with MS. High-quality PBMC were obtained from relapsing-remitting MS patients prior to and serially after initiation of DMF treatment. Multiparametric flow cytometry was used to monitor the phenotype and functional response-profiles of distinct B cell subsets. Total B cell counts decreased following DMF treatment, largely reflecting losses of circulating mature/differentiated (but not of immature transitional) B cells. Within the mature B cell pool, DMF had a greater impact on memory than naive B cells. In keeping with these in vivo effects, DMF treatment in vitro remarkably diminished mature (but not transitional B cell) survival, mediated by inducing apoptotic cell death. Although DMF treatment (both in vivo and in vitro) minimally impacted B cell IL-10 expression, it strongly reduced B cell expression of GM-CSF, IL-6, and TNF-α, resulting in a significant anti-inflammatory shift of B cell response profiles. The DMF-mediated decrease in B cell proinflammatory cytokine responses was further associated with reduced phosphorylation of STAT5/6 and NF-κB in surviving B cells. Together, these data implicate novel mechanisms by which DMF may modulate MS disease activity through shifting the balance between pro- and anti-inflammatory B cell responses.
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http://dx.doi.org/10.4049/jimmunol.1601649DOI Listing
January 2017

Protein kinase CK2 governs the molecular decision between encephalitogenic TH17 cell and Treg cell development.

Proc Natl Acad Sci U S A 2016 09 23;113(36):10145-50. Epub 2016 Aug 23.

Institute for Immunology, University Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany;

T helper 17 (TH17) cells represent a discrete TH cell subset instrumental in the immune response to extracellular bacteria and fungi. However, TH17 cells are considered to be detrimentally involved in autoimmune diseases like multiple sclerosis (MS). In contrast to TH17 cells, regulatory T (Treg) cells were shown to be pivotal in the maintenance of peripheral tolerance. Thus, the balance between Treg cells and TH17 cells determines the severity of a TH17 cell-driven disease and therefore is a promising target for treating autoimmune diseases. However, the molecular mechanisms controlling this balance are still unclear. Here, we report that pharmacological inhibition as well as genetic ablation of the protein kinase CK2 (CK2) ameliorates experimental autoimmune encephalomyelitis (EAE) severity and relapse incidence. Furthermore, CK2 inhibition or genetic ablation prevents TH17 cell development and promotes the generation of Treg cells. Molecularly, inhibition of CK2 leads to reduced STAT3 phosphorylation and strongly attenuated expression of the IL-23 receptor, IL-17, and GM-CSF. Thus, these results identify CK2 as a nodal point in TH17 cell development and suggest this kinase as a potential therapeutic target to treat TH17 cell-driven autoimmune responses.
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http://dx.doi.org/10.1073/pnas.1523869113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5018788PMC
September 2016