Publications by authors named "Benjamin Knier"

30 Publications

  • Page 1 of 1

Skin and gut imprinted helper T cell subsets exhibit distinct functional phenotypes in central nervous system autoimmunity.

Nat Immunol 2021 Jun 7. Epub 2021 Jun 7.

Institute for Experimental Neuroimmunology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

Multidimensional single-cell analyses of T cells have fueled the debate about whether there is extensive plasticity or 'mixed' priming of helper T cell subsets in vivo. Here, we developed an experimental framework to probe the idea that the site of priming in the systemic immune compartment is a determinant of helper T cell-induced immunopathology in remote organs. By site-specific in vivo labeling of antigen-specific T cells in inguinal (i) or gut draining mesenteric (m) lymph nodes, we show that i-T cells and m-T cells isolated from the inflamed central nervous system (CNS) in a model of multiple sclerosis (MS) are distinct. i-T cells were Cxcr6, and m-T cells expressed P2rx7. Notably, m-T cells infiltrated white matter, while i-T cells were also recruited to gray matter. Therefore, we propose that the definition of helper T cell subsets by their site of priming may guide an advanced understanding of helper T cell biology in health and disease.
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http://dx.doi.org/10.1038/s41590-021-00948-8DOI Listing
June 2021

The APOSTEL 2.0 Recommendations for Reporting Quantitative Optical Coherence Tomography Studies.

Neurology 2021 Apr 28. Epub 2021 Apr 28.

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

Objective: To update the consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results, thus revising the previously published Advised Protocol for OCT Study Terminology and Elements (APOSTEL) recommendations.

Methods: To identify studies reporting quantitative OCT results, we performed a PubMed search for the terms "quantitative" and "optical coherence tomography" from 2015 to 2017. Corresponding authors of the identified publications were invited to provide feedback on the initial APOSTEL recommendations via online surveys following the principle of a modified Delphi method. The results were evaluated and discussed by a panel of experts, and changes to the initial recommendations were proposed. A final survey was recirculated among the corresponding authors to obtain a majority vote on the proposed changes.

Results: One hundred sixteen authors participated in the surveys, resulting in 15 suggestions, of which 12 were finally accepted and incorporated into an updated 9-point-checklist. We harmonized the nomenclature of the outer retinal layers, added the exact area of measurement to the description of volume scans; we suggested reporting device-specific features. We advised to address potential bias in manual segmentation or manual correction of segmentation errors. References to specific reporting guidelines and room light conditions were removed. The participants' consensus with the recommendations increased from 80% for the previous APOSTEL version to greater than 90%.

Conclusions: The modified Delphi method resulted in an expert-led guideline (evidence class III, GRADE criteria) concerning study protocol, acquisition device, acquisition settings, scanning protocol, fundoscopic imaging, post-acquisition data selection, post-acquisition analysis, nomenclature and abbreviations, and statistical approach. It will still be essential to update these recommendations to new research and practices regularly.
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http://dx.doi.org/10.1212/WNL.0000000000012125DOI Listing
April 2021

Formation and immunomodulatory function of meningeal B-cell aggregates in progressive CNS autoimmunity.

Brain 2021 Mar 9. Epub 2021 Mar 9.

Klinikum rechts der Isar, Department of Neurology, Technical University of Munich, 81675 Munich, Germany.

Meningeal B lymphocyte aggregates have been described in autopsy material of patients with chronic Multiple Sclerosis. The presence of meningeal B cell aggregates has been correlated with worse disease. However, the functional role of these meningeal B cell aggregates is not understood. Here, we use a mouse model of Multiple Sclerosis, the spontaneous opticospinal encephalomyelitis model, which is built on the double transgenic expression of myelin oligodendrocyte glycoprotein-specific T cell- and B cell-receptors, to show that the formation of meningeal B cell aggregates is dependent on the expression of α4 integrins by antigen-specific T cells. T cell-conditional genetic ablation of α4 integrins in opticospinal encephalomyelitis mice impaired the formation of meningeal B cell aggregates, and surprisingly, led to a higher disease incidence as compared to opticospinal encephalomyelitis mice with α4 integrin-sufficient T cells. B cell-conditional ablation of α4 integrins in opticospinal encephalomyelitis mice resulted in the entire abrogation of the formation of meningeal B cell aggregates, and opticospinal encephalomyelitis mice with α4 integrin-deficient B cells suffered from a higher disease burden than regular opticospinal encephalomyelitis mice. While anti-CD20 antibody-mediated systemic depletion of B cells in opticospinal encephalomyelitis mice after onset of disease failed to efficiently decrease meningeal B cell aggregates without significantly modulating disease progression, treatment with anti-CD19 chimeric antigen receptor-T cells eliminated meningeal B cell aggregates and exacerbated clinical disease in opticospinal encephalomyelitis mice. Since about 20 percent of B cells in organised meningeal B cell aggregates produced either IL-10 or IL-35, we propose that meningeal B cell aggregates might also have an immunoregulatory function as to the immunopathology in adjacent spinal cord white matter. The immunoregulatory function of meningeal B cell aggregates needs to be considered when designing highly efficient therapies directed against meningeal B cell aggregates for clinical application in Multiple Sclerosis.
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http://dx.doi.org/10.1093/brain/awab093DOI Listing
March 2021

Treatment- and population-specific genetic risk factors for anti-drug antibodies against interferon-beta: a GWAS.

BMC Med 2020 11 4;18(1):298. Epub 2020 Nov 4.

Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Ismaninger Str 22, 81675, Munich, Germany.

Background: Upon treatment with biopharmaceuticals, the immune system may produce anti-drug antibodies (ADA) that inhibit the therapy. Up to 40% of multiple sclerosis patients treated with interferon β (IFNβ) develop ADA, for which a genetic predisposition exists. Here, we present a genome-wide association study on ADA and predict the occurrence of antibodies in multiple sclerosis patients treated with different interferon β preparations.

Methods: We analyzed a large sample of 2757 genotyped and imputed patients from two cohorts (Sweden and Germany), split between a discovery and a replication dataset. Binding ADA (bADA) levels were measured by capture-ELISA, neutralizing ADA (nADA) titers using a bioassay. Genome-wide association analyses were conducted stratified by cohort and treatment preparation, followed by fixed-effects meta-analysis.

Results: Binding ADA levels and nADA titers were correlated and showed a significant heritability (47% and 50%, respectively). The risk factors differed strongly by treatment preparation: The top-associated and replicated variants for nADA presence were the HLA-associated variants rs77278603 in IFNβ-1a s.c.- (odds ratio (OR) = 3.55 (95% confidence interval = 2.81-4.48), p = 2.1 × 10) and rs28366299 in IFNβ-1b s.c.-treated patients (OR = 3.56 (2.69-4.72), p = 6.6 × 10). The rs77278603-correlated HLA haplotype DR15-DQ6 conferred risk specifically for IFNβ-1a s.c. (OR = 2.88 (2.29-3.61), p = 7.4 × 10) while DR3-DQ2 was protective (OR = 0.37 (0.27-0.52), p = 3.7 × 10). The haplotype DR4-DQ3 was the major risk haplotype for IFNβ-1b s.c. (OR = 7.35 (4.33-12.47), p = 1.5 × 10). These haplotypes exhibit large population-specific frequency differences. The best prediction models were achieved for ADA in IFNβ-1a s.c.-treated patients. Here, the prediction in the Swedish cohort showed AUC = 0.91 (0.85-0.95), sensitivity = 0.78, and specificity = 0.90; patients with the top 30% of genetic risk had, compared to patients in the bottom 30%, an OR = 73.9 (11.8-463.6, p = 4.4 × 10) of developing nADA. In the German cohort, the AUC of the same model was 0.83 (0.71-0.92), sensitivity = 0.80, specificity = 0.76, with an OR = 13.8 (3.0-63.3, p = 7.5 × 10).

Conclusions: We identified several HLA-associated genetic risk factors for ADA against interferon β, which were specific for treatment preparations and population backgrounds. Genetic prediction models could robustly identify patients at risk for developing ADA and might be used for personalized therapy recommendations and stratified ADA screening in clinical practice. These analyses serve as a roadmap for genetic characterizations of ADA against other biopharmaceutical compounds.
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http://dx.doi.org/10.1186/s12916-020-01769-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641861PMC
November 2020

Code Stroke Patient Referral by Emergency Medical Services During the Public COVID-19 Pandemic Lockdown.

J Stroke Cerebrovasc Dis 2020 Nov 21;29(11):105175. Epub 2020 Jul 21.

Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.

Background: The COVID-19 pandemic caused public lockdowns around the world. We analyzed if the public lockdown altered the referral pattern of Code Stroke patients by Emergency Medical Services (EMS) to our Comprehensive Stroke Center.

Methods: Retrospective single-center study at a Bavarian Comprehensive Stroke Center. Patients who were directly referred to our stroke unit by EMS between the 1 of January 2020 and the 19 of April 2020 were identified and number of referrals, clinical characteristics and treatment strategies were analyzed during the public lockdown and before. The public lockdown started on 21 of March and ended on 19 April 2020.

Results: In total 241 patients were referred to our center during the study period, i.e. 171 before and 70 during the lockdown. The absolute daily number of Code Stroke referrals and the portion of patients with stroke mimics remained stable. The portion of female stroke patients decreased (55% to 33%; p = 0.03), and stroke severity as measured by the National Institutes of Health Stroke Scale (median 3 (IQR 0-7) versus 6 (IQR 1-15.5) points; p = 0.04) increased during the lockdown. There was no difference of daily numbers of patients receiving thrombolysis and thrombectomy.

Conclusions: Referral of Code Stroke patients by EMS could be maintained sufficiently despite the COVID-19 pandemic lockdown. However, patients' health care utilization of the EMS may have changed within the public lockdown. EMS remains a useful tool for Code Stroke patient referral during lockdowns, but public education about stroke is required prior to further lockdowns.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373060PMC
November 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

Protective effects of 4-aminopyridine in experimental optic neuritis and multiple sclerosis.

Brain 2020 04;143(4):1127-1142

NeuroCure Clinical Research Center and Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health and Max Delbrueck Center for Molecular Medicine, Berlin, Germany.

Chronic disability in multiple sclerosis is linked to neuroaxonal degeneration. 4-aminopyridine (4-AP) is used and licensed as a symptomatic treatment to ameliorate ambulatory disability in multiple sclerosis. The presumed mode of action is via blockade of axonal voltage gated potassium channels, thereby enhancing conduction in demyelinated axons. In this study, we provide evidence that in addition to those symptomatic effects, 4-AP can prevent neuroaxonal loss in the CNS. Using in vivo optical coherence tomography imaging, visual function testing and histologic assessment, we observed a reduction in retinal neurodegeneration with 4-AP in models of experimental optic neuritis and optic nerve crush. These effects were not related to an anti-inflammatory mode of action or a direct impact on retinal ganglion cells. Rather, histology and in vitro experiments indicated 4-AP stabilization of myelin and oligodendrocyte precursor cells associated with increased nuclear translocation of the nuclear factor of activated T cells. In experimental optic neuritis, 4-AP potentiated the effects of immunomodulatory treatment with fingolimod. As extended release 4-AP is already licensed for symptomatic multiple sclerosis treatment, we performed a retrospective, multicentre optical coherence tomography study to longitudinally compare retinal neurodegeneration between 52 patients on continuous 4-AP therapy and 51 matched controls. In line with the experimental data, during concurrent 4-AP therapy, degeneration of the macular retinal nerve fibre layer was reduced over 2 years. These results indicate disease-modifying effects of 4-AP beyond symptomatic therapy and provide support for the design of a prospective clinical study using visual function and retinal structure as outcome parameters.
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http://dx.doi.org/10.1093/brain/awaa062DOI Listing
April 2020

Retinal inner nuclear layer volume reflects inflammatory disease activity in multiple sclerosis; a longitudinal OCT study.

Mult Scler J Exp Transl Clin 2019 Jul-Sep;5(3):2055217319871582. Epub 2019 Sep 5.

Department of Neurology, Amsterdam UMC, Vrije Universiteit Amsterdam, the Netherlands.

Background: The association of peripapillary retinal nerve fibre layer (pRNFL) and ganglion cell-inner plexiform layer (GCIPL) thickness with neurodegeneration in multiple sclerosis (MS) is well established. The relationship of the adjoining inner nuclear layer (INL) with inflammatory disease activity is less well understood.

Objective: The objective of this paper is to investigate the relationship of INL volume changes with inflammatory disease activity in MS. In this longitudinal, multi-centre study, optical coherence tomography (OCT) and clinical data (disability status, relapses and MS optic neuritis (MSON)) were collected in 785 patients with MS (68.3% female) and 92 healthy controls (63.4% female) from 11 MS centres between 2010 and 2017 and pooled retrospectively. Data on pRNFL, GCIPL and INL were obtained at each centre.

Results: There was a significant increase in INL volume in eyes with new MSON during the study ( = 61/1562, β = 0.01 mm,  < .001). Clinical relapses (other than MSON) were significantly associated with increased INL volume (β = 0.005,  = .025). INL volume was independent of disease progression (β = 0.002 mm,  = .474).

Conclusion: Our data demonstrate that an increase in INL volume is associated with MSON and the occurrence of clinical relapses. Therefore, INL volume changes may be useful as an outcome marker for inflammatory disease activity in MSON and MS treatment trials.
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http://dx.doi.org/10.1177/2055217319871582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728683PMC
September 2019

Optical coherence tomography in myelin-oligodendrocyte-glycoprotein antibody-seropositive patients: a longitudinal study.

J Neuroinflammation 2019 Jul 25;16(1):154. Epub 2019 Jul 25.

Institute of Clinical Neuroimmunology, Ludwig-Maximilians University, Marchioninistr. 15, 81377, Munich, Germany.

Background: Serum antibodies against myelin-oligodendrocyte-glycoprotein (MOG-IgG) are detectable in a proportion of patients with acute or relapsing neuroinflammation. It is unclear, if neuro-axonal damage occurs only in an attack-dependent manner or also progressively. Therefore, this study aimed to investigate longitudinally intra-retinal layer changes in eyes without new optic neuritis (ON) in MOG-IgG-seropositive patients.

Methods: We included 38 eyes of 24 patients without ON during follow-up (F/U) [median years (IQR)] 1.9 (1.0-2.2) and 56 eyes of 28 age- and sex-matched healthy controls (HC). The patient group's eyes included 18 eyes without (Eye) and 20 eyes with history of ON (Eye). Using spectral domain optical coherence tomography (OCT), we acquired peripapillary retinal nerve fiber layer thickness (pRNFL) and volumes of combined ganglion cell and inner plexiform layer (GCIP), inner nuclear layer (INL), and macular volume (MV). High-contrast visual acuity (VA) was assessed at baseline.

Results: At baseline in Eye, pRNFL (94.3 ± 15.9 μm, p = 0.36), INL (0.26 ± 0.03 mm, p = 0.11), and MV (2.34 ± 0.11 mm, p = 0.29) were not reduced compared to HC; GCIP showed thinning (0.57 ± 0.07 mm; p = 0.008), and VA was reduced (logMAR 0.05 ± 0.15 vs. - 0.09 ± 0.14, p = 0.008) in comparison to HC. Longitudinally, we observed pRNFL thinning in models including all patient eyes (annual reduction - 2.20 ± 4.29 μm vs. - 0.35 ± 1.17 μm, p = 0.009) in comparison to HC. Twelve Eye with other than ipsilateral ON attacks ≤ 6 months before baseline showed thicker pRNFL at baseline and more severe pRNFL thinning in comparison to 6 Eye without other clinical relapses.

Conclusions: We observed pRNFL thinning in patients with MOG-IgG during F/U, which was not accompanied by progressive GCIP reduction. This effect could be caused by a small number of Eye with other than ipsilateral ON attacks within 6 months before baseline. One possible interpretation could be a reduction of the swelling, which could mean that MOG-IgG patients show immune-related swelling in the CNS also outside of an attack's target area.
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http://dx.doi.org/10.1186/s12974-019-1521-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657100PMC
July 2019

Optimal intereye difference thresholds by optical coherence tomography in multiple sclerosis: An international study.

Ann Neurol 2019 05 10;85(5):618-629. Epub 2019 Apr 10.

Department of Neurology, New York University School of Medicine, New York, NY.

Objective: To determine the optimal thresholds for intereye differences in retinal nerve fiber and ganglion cell + inner plexiform layer thicknesses for identifying unilateral optic nerve lesions in multiple sclerosis. Current international diagnostic criteria for multiple sclerosis do not include the optic nerve as a lesion site despite frequent involvement. Optical coherence tomography detects retinal thinning associated with optic nerve lesions.

Methods: In this multicenter international study at 11 sites, optical coherence tomography was measured for patients and healthy controls as part of the International Multiple Sclerosis Visual System Consortium. High- and low-contrast acuity were also collected in a subset of participants. Presence of an optic nerve lesion for this study was defined as history of acute unilateral optic neuritis.

Results: Among patients (n = 1,530), receiver operating characteristic curve analysis demonstrated an optimal peripapillary retinal nerve fiber layer intereye difference threshold of 5μm and ganglion cell + inner plexiform layer threshold of 4μm for identifying unilateral optic neuritis (n = 477). Greater intereye differences in acuities were associated with greater intereye retinal layer thickness differences (p ≤ 0.001).

Interpretation: Intereye differences of 5μm for retinal nerve fiber layer and 4μm for macular ganglion cell + inner plexiform layer are robust thresholds for identifying unilateral optic nerve lesions. These thresholds may be useful in establishing the presence of asymptomatic and symptomatic optic nerve lesions in multiple sclerosis and could be useful in a new version of the diagnostic criteria. Our findings lend further validation for utilizing the visual system in a multiple sclerosis clinical trial setting. Ann Neurol 2019;85:618-629.
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http://dx.doi.org/10.1002/ana.25462DOI Listing
May 2019

Blimp1 Prevents Methylation of Foxp3 and Loss of Regulatory T Cell Identity at Sites of Inflammation.

Cell Rep 2019 02;26(7):1854-1868.e5

Klinikum Rechts der Isar, Department of Experimental Neuroimmunology, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Feodor-Lynen-Str. 17, 81377 Munich, Germany. Electronic address:

Foxp3 regulatory T (Treg) cells restrict immune pathology in inflamed tissues; however, an inflammatory environment presents a threat to Treg cell identity and function. Here, we establish a transcriptional signature of central nervous system (CNS) Treg cells that accumulate during experimental autoimmune encephalitis (EAE) and identify a pathway that maintains Treg cell function and identity during severe inflammation. This pathway is dependent on the transcriptional regulator Blimp1, which prevents downregulation of Foxp3 expression and "toxic" gain-of-function of Treg cells in the inflamed CNS. Blimp1 negatively regulates IL-6- and STAT3-dependent Dnmt3a expression and function restraining methylation of Treg cell-specific conserved non-coding sequence 2 (CNS2) in the Foxp3 locus. Consequently, CNS2 is heavily methylated when Blimp1 is ablated, leading to a loss of Foxp3 expression and severe disease. These findings identify a Blimp1-dependent pathway that preserves Treg cell stability in inflamed non-lymphoid tissues.
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http://dx.doi.org/10.1016/j.celrep.2019.01.070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389594PMC
February 2019

Myeloid-derived suppressor cells control B cell accumulation in the central nervous system during autoimmunity.

Nat Immunol 2018 12 29;19(12):1341-1351. Epub 2018 Oct 29.

Department of Experimental Neuroimmunology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) have been characterized in the context of malignancies. Here we show that PMN-MDSCs can restrain B cell accumulation during central nervous system (CNS) autoimmunity. Ly6G cells were recruited to the CNS during experimental autoimmune encephalomyelitis (EAE), interacted with B cells that produced the cytokines GM-CSF and interleukin-6 (IL-6), and acquired properties of PMN-MDSCs in the CNS in a manner dependent on the signal transducer STAT3. Depletion of Ly6G cells or dysfunction of Ly6G cells through conditional ablation of STAT3 led to the selective accumulation of GM-CSF-producing B cells in the CNS compartment, which in turn promoted an activated microglial phenotype and lack of recovery from EAE. The frequency of CD138 B cells in the cerebrospinal fluid (CSF) of human subjects with multiple sclerosis was negatively correlated with the frequency of PMN-MDSCs in the CSF. Thus PMN-MDSCs might selectively control the accumulation and cytokine secretion of B cells in the inflamed CNS.
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http://dx.doi.org/10.1038/s41590-018-0237-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6241855PMC
December 2018

Association of Retinal Ganglion Cell Layer Thickness With Future Disease Activity in Patients With Clinically Isolated Syndrome.

JAMA Neurol 2018 09;75(9):1071-1079

NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Importance: Clinically isolated syndrome (CIS) describes a first clinical incident suggestive of multiple sclerosis (MS). Identifying patients with CIS who have a high risk of future disease activity and subsequent MS diagnosis is crucial for patient monitoring and the initiation of disease-modifying therapy.

Objective: To investigate the association of retinal optical coherence tomography (OCT) results with future disease activity in patients with CIS.

Design, Setting, And Participants: This prospective, longitudinal cohort study took place between January 2011 and May 2017 at 2 German tertiary referral centers. A total of 179 patients with CIS were screened (80 in Berlin and 99 in Munich). Patients underwent neurological examination, magnetic resonance imaging (MRI), and OCT. Only eyes with no previous optic neuritis were considered for OCT analysis.

Main Outcomes And Measures: The primary outcome was not meeting the no evidence of disease activity (NEDA-3) criteria; secondary outcomes were MS diagnosis (by the 2010 McDonald criteria) and worsening of disability. The primary measure was OCT-derived ganglion cell and inner plexiform layer thickness; the secondary measures included peripapillary retinal nerve fiber layer thickness, inner nuclear layer thickness, and MRI-derived T2-weighted lesions.

Results: A total of 97 of the 179 screened patients (54.2%) were enrolled in the study at a median of 93 (interquartile range [IQR], 62-161) days after a first demyelinating event. The median follow-up duration (Kaplan-Meier survival time) was 729 (IQR, 664-903) days. Of 97 patients with CIS (mean age 33.6 [7.9] years; 61 [62.9%] female), 58 (59%) did not meet NEDA-3 criteria during the follow-up period. A Kaplan-Meier analysis showed a significant probability difference in not meeting NEDA-3 criteria by ganglion cell and inner plexiform later thickness (thinnest vs thickest tertile: hazard ratio [HR], 3.33 [95% CI, 1.70-6.55; P < .001; log-rank P = .001). A follow-up diagnosis of MS was more likely for patients with low ganglion cell and inner plexiform layer thickness (thinnest vs thickest tertile: HR, 4.05 [95% CI, 1.93-8.50]; P < .001). Low peripapillary retinal nerve fiber layer thickness likewise indicated risk of not meeting NEDA-3 criteria (thinnest vs thickest tertile: HR, 2.46 [95% CI, 1.29-4.66]; P = .01; log-rank P = .02). Inner nuclear layer thickness and T2-weighted lesion count were not associated with not meeting NEDA-3 criteria.

Conclusions And Relevance: Retinal ganglion cell and inner plexiform layer thickness might prove a valuable imaging marker for anticipating future disease activity and diagnosis of MS in patients with CIS, which can potentially support patient monitoring and initiation of disease-modifying therapy.
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http://dx.doi.org/10.1001/jamaneurol.2018.1011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143115PMC
September 2018

Optical coherence tomography angiography indicates associations of the retinal vascular network and disease activity in multiple sclerosis.

Mult Scler 2019 02 5;25(2):224-234. Epub 2018 Jan 5.

Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany/ Department of Experimental Neuroimmunology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.

Background: Patients with multiple sclerosis (MS) and clinically isolated syndrome (CIS) may show alterations of retinal layer architecture as measured by optical coherence tomography. Little is known about changes in the retinal vascular network during MS.

Objective: To characterize retinal vessel structures in patients with MS and CIS and to test for associations with MS disease activity.

Method: In all, 42 patients with MS or CIS and 50 healthy controls underwent retinal optical coherence tomography angiography (OCT-A) with analysis of the superficial and deep vascular plexuses and the choriocapillaries. We tested OCT-A parameters for associations with retinal layer volumes, history of optic neuritis (ON), and the retrospective disease activity.

Results: Inner retinal layer volumes correlated positively with the density of both the superficial and deep vascular plexuses. Eyes of MS/CIS patients with a history of ON revealed reduced vessel densities of the superficial and deep vascular plexuses as compared to healthy controls. Higher choriocapillary vessel densities were associated with ongoing inflammatory disease activity during 24 months prior to OCT-A examination in MS and CIS patients.

Conclusion: Optic neuritis is associated with rarefaction of the superficial and deep retinal vessels. Alterations of the choriocapillaries might be linked to disease activity in MS.
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http://dx.doi.org/10.1177/1352458517750009DOI Listing
February 2019

Effectors of Th1 and Th17 cells act on astrocytes and augment their neuroinflammatory properties.

J Neuroinflammation 2017 Oct 16;14(1):204. Epub 2017 Oct 16.

Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.

Background: Autoreactive Th1 and Th17 cells are believed to mediate the pathology of multiple sclerosis in the central nervous system (CNS). Their interaction with microglia and astrocytes in the CNS is crucial for the regulation of the neuroinflammation. Previously, we have shown that only Th1 but not Th17 effectors activate microglia. However, it is not clear which cells are targets of Th17 effectors in the CNS.

Methods: To understand the effects driven by Th17 cells in the CNS, we induced experimental autoimmune encephalomyelitis in wild-type mice and CD4 T cell-specific integrin α4-deficient mice where trafficking of Th1 cells into the CNS was affected. We compared microglial and astrocyte response in the brain and spinal cord of these mice. We further treated astrocytes with supernatants from highly pure Th1 and Th17 cultures and assessed the messenger RNA expression of neurotrophic factors, cytokines and chemokines, using real-time PCR. Data obtained was analyzed using the Kruskal-Wallis test.

Results: We observed in α4-deficient mice weak microglial activation but comparable astrogliosis to that of wild-type mice in the regions of the brain populated with Th17 infiltrates, suggesting that Th17 cells target astrocytes and not microglia. In vitro, in response to supernatants from Th1 and Th17 cultures, astrocytes showed altered expression of neurotrophic factors, pro-inflammatory cytokines and chemokines. Furthermore, increased expression of chemokines in Th1- and Th17-treated astrocytes enhanced recruitment of microglia and transendothelial migration of Th17 cells in vitro.

Conclusion: Our results demonstrate the delicate interaction between T cell subsets and glial cells and how they communicate to mediate their effects. Effectors of Th1 act on both microglia and astrocytes whereas Th17 effectors preferentially target astrocytes to promote neuroinflammation.
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http://dx.doi.org/10.1186/s12974-017-0978-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5644084PMC
October 2017

Fatigue in multiple sclerosis: Associations with clinical, MRI and CSF parameters.

Mult Scler 2018 07 25;24(8):1115-1125. Epub 2017 May 25.

Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany/Neuroimaging Center, Technische Universität München, Munich, Germany.

Background: Damage of different brain structures has been related to fatigue. Alternatively, functional alterations of central nervous system (CNS) cells by the inflammatory milieu within the CNS may be responsible for the development of fatigue.

Aim: To investigate the effect of structural brain damage and inflammatory cerebrospinal fluid (CSF) changes on fatigue in multiple sclerosis (MS).

Methods: We determined the association of different clinical, CSF and magnetic resonance imaging (MRI) parameters with prevalence and severity of fatigue, as measured by the Fatigue Scale for Motor and Cognitive Functions in 68 early MS patients (discovery cohort). We validated our findings in two MS cohorts: the MRI validation cohort ( N = 233) for the clinical and MRI parameters, and the CSF validation cohort ( N = 81) for the clinical and CSF parameters.

Results: Fatigue was associated with clinical disability. Fatigue did not correlate with any CSF parameter but correlated negatively with total and cortical grey matter volume. However, when controlling for Expanded Disability Status Scale (EDSS) in a multivariate model, these associations lost significance.

Conclusion: Disability and disease duration best explain fatigue severity but none of the tested MRI or CSF parameter was reliably associated with fatigue.
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http://dx.doi.org/10.1177/1352458517712078DOI Listing
July 2018

Association of Retinal Architecture, Intrathecal Immunity, and Clinical Course in Multiple Sclerosis.

JAMA Neurol 2017 07;74(7):847-856

Department of Neurology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany2Department of Experimental Neuroimmunology, Technische Universität München, Munich, Germany5Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

Importance: Biomarkers to estimate long-term outcomes in patients with multiple sclerosis (MS) and to assign patients to individual treatment regimens are urgently needed.

Objective: To assess whether retinal layer volumes are correlated with immune cell subsets and immunoglobulin indices in the cerebrospinal fluid and whether retinal layer volumes alone or in combination with intrathecal variables are associated with worsening of disease in patients with relapsing-remitting MS.

Design, Setting, And Participants: This observational cohort study included 312 patients with relapsing-remitting MS in 2 independent cohorts (72 patients with short disease duration [cohort 1] and 240 patients with longer disease duration [cohort 2]) treated at a single German university hospital from April 15, 2013, through November 11, 2015.

Main Outcomes And Measures: The common ganglion cell and inner plexiform layer (GCIPL) and inner nuclear layer (INL) volumes were tested for association with the immunoglobulin indices and the frequencies of immune cells in the cerebrospinal fluid (including B cells, T cells, and natural killer cells) (cohort 1). Volumes of GCIPL alone (cohorts 1 and 2) or GCIPL corrected for intrathecal B-cell frequencies (cohort 1) were tested for their association with worsening disability.

Results: A total of 312 patients (212 women [67.9%] and 100 men [32.1%]; median age, 34.0 years [interquartile range (IQR), 28.0-42.0 years]) were available for analysis. In cohort 1 (50 women [69.4%] and 22 men [30.6%]; median age, 31.0 years [IQR, 26.3-38.3 years]), with short disease durations (median, 1.0 months [IQR, 1.0-2.0 months]), low GCIPL volumes were associated with increased intrathecal B-cell frequencies (median, 1.96% [IQR, 1.45%-4.20%]) and intrathecal IgG synthesis (median cerebrospinal fluid/serum IgG index, 0.78 [IQR, 0.53-1.07]). The INL volumes correlated with the frequencies of intrathecal CD56bright natural killer cells (r = 0.28; P = .007). Individuals with low GCIPL volumes (<1.99 mm3) had a 6.4-fold risk for worsening disability during follow-up compared with patients with higher GCIPL values (95% CI, 1.7-24.2; P = .007). This finding was reproduced in cohort 2 (162 women [67.5%] and 78 men [32.5%]; median age, 34.0 years [IQR, 29.0-42.0 years]) consisting of patients with longer disease durations (median, 36.0 months [IQR, 21.0-60.0 months]) (hazard ratio, 2.4; 95% CI, 1.2-4.8; P = .02). In both cohorts, INL volumes correlated with the prospective increase in T2 lesion load and the number of gadolinium-enhancing lesions.

Conclusions And Relevance: Retinal layers reflect different aspects of disease activity during MS. Loss of GCIPL is associated with intrathecal B-cell immunity and constitutes an independent risk factor for worsening disability, whereas high INL volumes are associated with activity on magnetic resonance imaging in the brain parenchyma. Thus, retinal optical coherence tomography might be a means to support stratification of patients with MS for different therapeutic regimens.
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http://dx.doi.org/10.1001/jamaneurol.2017.0377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5822191PMC
July 2017

Microstructural visual system changes in AQP4-antibody-seropositive NMOSD.

Neurol Neuroimmunol Neuroinflamm 2017 May 22;4(3):e334. Epub 2017 Feb 22.

NeuroCure Clinical Research Center (F.C.O., J.K., H.Z., C.C., F.S., J.B.-S., M.S., F.P., A.U.B.), and Department of Neurology (J.K., F.S., J.B.-S., K.R., F.P.), Charité-Universitätsmedizin Berlin; Department of Neurology (B.K., T.K.), Klinikum rechts der Isar, and Department of Experimental Neuroimmunology (T.K.), Technische Universität München; Munich Cluster for Systems Neurology (SyNergy) (T.K.), Germany; Clinical Ophthalmology and Eye Health (A.K.), Central Clinical School, Save Sight Institute, Sydney, Australia; and Experimental and Clinical Research Center (F.P.), Max Delbrueck Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Germany.

Objective: To trace microstructural changes in patients with aquaporin-4 antibody (AQP4-ab)-seropositive neuromyelitis optica spectrum disorders (NMOSDs) by investigating the afferent visual system in patients without clinically overt visual symptoms or visual pathway lesions.

Methods: Of 51 screened patients with NMOSD from a longitudinal observational cohort study, we compared 6 AQP4-ab-seropositive NMOSD patients with longitudinally extensive transverse myelitis (LETM) but no history of optic neuritis (ON) or other bout (NMOSD-LETM) to 19 AQP4-ab-seropositive NMOSD patients with previous ON (NMOSD-ON) and 26 healthy controls (HCs). Foveal thickness (FT), peripapillary retinal nerve fiber layer (pRNFL) thickness, and ganglion cell and inner plexiform layer (GCIPL) thickness were measured with optical coherence tomography (OCT). Microstructural changes in the optic radiation (OR) were investigated using diffusion tensor imaging (DTI). Visual function was determined by high-contrast visual acuity (VA). OCT results were confirmed in a second independent cohort.

Results: FT was reduced in both patients with NMOSD-LETM ( = 3.52e) and NMOSD-ON ( = 1.24e) in comparison with HC. Probabilistic tractography showed fractional anisotropy reduction in the OR in patients with NMOSD-LETM ( = 0.046) and NMOSD-ON ( = 1.50e) compared with HC. Only patients with NMOSD-ON but not NMOSD-LETM showed neuroaxonal damage in the form of pRNFL and GCIPL thinning. VA was normal in patients with NMOSD-LETM and was not associated with OCT or DTI parameters.

Conclusions: Patients with AQP4-ab-seropositive NMOSD without a history of ON have microstructural changes in the afferent visual system. The localization of retinal changes around the Müller-cell rich fovea supports a retinal astrocytopathy.
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http://dx.doi.org/10.1212/NXI.0000000000000334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322864PMC
May 2017

Deletional tolerance prevents AQP4-directed autoimmunity in mice.

Eur J Immunol 2017 03 25;47(3):458-469. Epub 2017 Jan 25.

Klinikum rechts der Isar, Department of Neurology, Technical University of Munich, Munich, Germany.

Neuromyelitis optica (NMO) is an autoimmune disorder of the central nervous system (CNS) mediated by antibodies to the water channel protein AQP4 expressed in astrocytes. The contribution of AQP4-specific T cells to the class switch recombination of pathogenic AQP4-specific antibodies and the inflammation of the blood-brain barrier is incompletely understood, as immunogenic naturally processed T-cell epitopes of AQP4 are unknown. By immunizing Aqp4 mice with full-length murine AQP4 protein followed by recall with overlapping peptides, we here identify AQP4(201-220) as the major immunogenic IA -restricted epitope of AQP4. We show that WT mice do not harbor AQP4(201-220)-specific T-cell clones in their natural repertoire due to deletional tolerance. However, immunization with AQP4(201-220) of Rag1 mice reconstituted with the mature T-cell repertoire of Aqp4 mice elicits an encephalomyelitic syndrome. Similarly to the T-cell repertoire, the B-cell repertoire of WT mice is "purged" of AQP4-specific B cells, and robust serum responses to AQP4 are only mounted in Aqp4 mice. While AQP4(201-220)-specific T cells alone induce encephalomyelitis, NMO-specific lesional patterns in the CNS and the retina only occur in the additional presence of anti-AQP4 antibodies. Thus, failure of deletional T-cell and B-cell tolerance against AQP4 is a prerequisite for clinically manifest NMO.
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http://dx.doi.org/10.1002/eji.201646855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5359142PMC
March 2017

Retinal inner nuclear layer volume reflects response to immunotherapy in multiple sclerosis.

Brain 2016 11;139(11):2855-2863

Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 Munich, Germany.

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http://dx.doi.org/10.1093/brain/aww219DOI Listing
November 2016

Successful Replication of GWAS Hits for Multiple Sclerosis in 10,000 Germans Using the Exome Array.

Genet Epidemiol 2015 Dec 26;39(8):601-8. Epub 2015 Oct 26.

Max-Planck-Institut für Psychiatrie, Munich, Germany.

Genome-wide association studies (GWAS) successfully identified various chromosomal regions to be associated with multiple sclerosis (MS). The primary aim of this study was to replicate reported associations from GWAS using an exome array in a large German study. German MS cases (n = 4,476) and German controls (n = 5,714) were genotyped using the Illumina HumanExome v1-Chip. Genotype calling was performed with the Illumina Genome Studio(TM) Genotyping Module, followed by zCall. Single-nucleotide polymorphisms (SNPs) in seven regions outside the human leukocyte antigen (HLA) region showed genome-wide significant associations with MS (P values < 5 × 10(-8) ). These associations have been reported previously. In addition, SNPs in three previously reported regions outside the HLA region yielded P values < 10(-5) . The effect of nine SNPs in the HLA region remained (P < 10(-5) ) after adjustment for other significant SNPs in the HLA region. All of these findings have been reported before or are driven by known risk loci. In summary, findings from previous GWAS for MS could be successfully replicated. We conclude that the regions identified in previous GWAS are also associated in the German population. This reassures the need for detailed investigations of the functional mechanisms underlying the replicated associations.
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http://dx.doi.org/10.1002/gepi.21933DOI Listing
December 2015

Prevalence of neuropathic pain in early multiple sclerosis.

Mult Scler 2016 08 19;22(9):1224-30. Epub 2015 Oct 19.

Department of Neurology, Technische Universität München, Germany

Background: Pain is considered a frequent symptom in multiple sclerosis. Neuropathic pain is the type of pain most closely related to the pathology of multiple sclerosis and its prevalence estimates vary largely.

Objective: We prospectively assessed the prevalence of neuropathic pain in patients with early multiple sclerosis and investigated the association of neuropathic pain with other clinical parameters.

Methods: A total of 377 outpatients with multiple sclerosis at an early disease stage were included in this prospective study. Mean disease duration was 4.2 years, mean Expanded Disability Status Scale (EDSS) score was 1.6, 96.8% of patients were classified as having relapsing-remitting multiple sclerosis. Neuropathic pain was assessed using the PainDETECT questionnaire (PDQ). Depression, fatigue and cognition were assessed using the Beck Depression Inventory (BDI), the Fatigue Scale for Motor and Cognitive Functions (FSMC) and the Paced Auditory Serial Addition Test.

Results: PDQ scores indicative of neuropathic pain were found in 4.2% of patients. Regression analysis revealed EDSS, BDI and FMSC scores as strongest predictors of PDQ scores.

Conclusions: Neuropathic pain appears to be less frequent in early multiple sclerosis than expected and is significantly associated with disability, depression and fatigue. The assessment and therapy of pain in multiple sclerosis should thus take into account neuropsychiatric symptoms already at early disease stages.
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http://dx.doi.org/10.1177/1352458515613643DOI Listing
August 2016

Optical coherence tomography indicates disease activity prior to clinical onset of central nervous system demyelination.

Mult Scler 2016 06 11;22(7):893-900. Epub 2015 Sep 11.

Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Germany/Munich Cluster for Systems Neurology (SyNergy), Germany

Background: Establishing biomarkers for predicting disease activity in demyelinating disease of the central nervous system is crucial for designing appropriate disease modifiying treatment strategies.

Objective: To investigate retinal findings and disease activity in patients with radiologically isolated and clinically isolated syndromes.

Methods: We performed retinal optical coherence tomography and cerebral magnetic resonance imaging in healthy control individuals (n=19), in individuals with non-specific white matter lesions (n=18), and in patients with clinically isolated syndromes (n=18) and radiologically isolated syndromes (n=20).

Results: Reduced volume of retinal nerve fibre layer and increased volume of inner nuclear layer at baseline correlated with subsequent disease activity as measured by an increase in cerebral T2 lesion load in patients with radiologically isolated syndromes. Reduced volume of retinal nerve fibre layer and increased volumes of inner and outer nuclear layer were associated with progression into multiple sclerosis in patients with clinically isolated syndromes.

Conclusion: Patients with radiologically and clinically isolated syndromes behave similarly concerning paraclinical disease activity in cerebral magnetic resonance imaging. In both conditions, reduction of retinal nerve fibre layer and increased inner nuclear layer and outer nuclear layer volumes predict disease activity and are associated with progression into multiple sclerosis.
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http://dx.doi.org/10.1177/1352458515604496DOI Listing
June 2016

Genetic variants are major determinants of CSF antibody levels in multiple sclerosis.

Brain 2015 Mar 22;138(Pt 3):632-43. Epub 2015 Jan 22.

18 Danish Multiple Sclerosis Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Immunological hallmarks of multiple sclerosis include the production of antibodies in the central nervous system, expressed as presence of oligoclonal bands and/or an increased immunoglobulin G index-the level of immunoglobulin G in the cerebrospinal fluid compared to serum. However, the underlying differences between oligoclonal band-positive and -negative patients with multiple sclerosis and reasons for variability in immunoglobulin G index are not known. To identify genetic factors influencing the variation in the antibody levels in the cerebrospinal fluid in multiple sclerosis, we have performed a genome-wide association screen in patients collected from nine countries for two traits, presence or absence of oligoclonal bands (n = 3026) and immunoglobulin G index levels (n = 938), followed by a replication in 3891 additional patients. We replicate previously suggested association signals for oligoclonal band status in the major histocompatibility complex region for the rs9271640*A-rs6457617*G haplotype, correlated with HLA-DRB1*1501, and rs34083746*G, correlated with HLA-DQA1*0301 (P comparing two haplotypes = 8.88 × 10(-16)). Furthermore, we identify a novel association signal of rs9807334, near the ELAC1/SMAD4 genes, for oligoclonal band status (P = 8.45 × 10(-7)). The previously reported association of the immunoglobulin heavy chain locus with immunoglobulin G index reaches strong evidence for association in this data set (P = 3.79 × 10(-37)). We identify two novel associations in the major histocompatibility complex region with immunoglobulin G index: the rs9271640*A-rs6457617*G haplotype (P = 1.59 × 10(-22)), shared with oligoclonal band status, and an additional independent effect of rs6457617*G (P = 3.68 × 10(-6)). Variants identified in this study account for up to 2-fold differences in the odds of being oligoclonal band positive and 7.75% of the variation in immunoglobulin G index. Both traits are associated with clinical features of disease such as female gender, age at onset and severity. This is the largest study population so far investigated for the genetic influence on antibody levels in the cerebrospinal fluid in multiple sclerosis, including 6950 patients. We confirm that genetic factors underlie these antibody levels and identify both the major histocompatibility complex and immunoglobulin heavy chain region as major determinants.
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http://dx.doi.org/10.1093/brain/awu405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408440PMC
March 2015

Neutralizing IL-17 protects the optic nerve from autoimmune pathology and prevents retinal nerve fiber layer atrophy during experimental autoimmune encephalomyelitis.

J Autoimmun 2015 Jan 1;56:34-44. Epub 2014 Oct 1.

Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Straße 22, 81675 München, Germany; Munich Cluster for Systems Neurology (SyNergy), München, Germany. Electronic address:

Optic neuritis is a common inflammatory manifestation of multiple sclerosis (MS). In experimental autoimmune encephalomyelitis (EAE), the optic nerve is affected as well. Here, we investigated whether autoimmune inflammation in the optic nerve is distinct from inflammation in other parts of the central nervous system (CNS). In our study, inflammatory infiltrates in the optic nerve and the brain were characterized by a high fraction of Ly6G(+) granulocytes whereas in the spinal cord, macrophage infiltrates were predominant. At the peak of disease, IL-17 mRNA abundance was highest in the optic nerve as compared with other parts of the CNS. The ratio of IL-17 vs IFN-γ producing CD4(+) T cells was higher in the optic nerve and brain than in the spinal cord and more effector CD4(+) T cells were committed to the Th17 transcriptional program in the optic nerve than in the spinal cord. IL-17 producing γδ T cells but rather not Ly6G(+) granulocytes themselves contributed to IL-17 production. Optical coherence tomography (OCT) studies on murine eyes revealed a decline in thickness of the retinal nerve fiber layer (RNFL) and the common layer of ganglion cells and inner plexiform layer (GCL+) after the recovery from motor symptoms indicating that autoimmune inflammation induced a significant atrophy of optic nerve fibers during EAE. Neutralization of IL-17 by treatment with anti-IL-17 antibodies reduced but did not abrogate motor symptoms of EAE. However, RNFL and GCL+ atrophy were completely prevented by blocking IL-17. Thus, the optic nerve compartment is particularly prone to support IL-17 mediated inflammatory responses during CNS autoimmunity and structural integrity of the retina can be preserved by neutralizing IL-17.
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http://dx.doi.org/10.1016/j.jaut.2014.09.003DOI Listing
January 2015

Novel monoclonal antibodies for therapy of multiple sclerosis.

Expert Opin Biol Ther 2014 Apr 28;14(4):503-13. Epub 2014 Feb 28.

Technische Universität München, Klinikum rechts der Isar, Department of Neurology , Ismaninger Str. 22, 81675 Munich , Germany +49 89 4140 4601 ; +49 89 4140 7681 ;

Introduction: Monoclonal antibodies play an important role in the therapy of different autoimmune diseases. With the introduction of natalizumab, the importance of monoclonal antibodies in the therapy of multiple sclerosis (MS) has dramatically increased during the past years.

Areas Covered: In this review, we will focus on newly approved and emerging antibodies for MS therapy. Based on published original articles and citable meeting abstracts, we will discuss their mode of action as well as data on efficacy and safety.

Expert Opinion: Natalizumab was a breakthrough in MS therapy. However, side effects of this monoclonal antibody limit its use. The risk/benefit ratios of new biologicals in MS therapy are not yet clear. High-yield process daclizumab might qualify as first-line MS therapy, unless hepatotoxicity becomes a relevant safety concern. Alemtuzumab has been approved for MS therapy in Europe but will be reserved for selected patients with highly active disease due to frequent induction of potentially dangerous secondary autoimmune phenomena. Ocrelizumab will likely also be licensed as a second-line therapy in highly active MS. Neutralizing antibodies to interleukin (IL)-17A and blocking antibodies to leucine rich repeat and Ig domain containing 1 might be the most interesting upcoming new antibodies as both offer a new and pathophysiologically relevant approach in MS therapy.
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http://dx.doi.org/10.1517/14712598.2014.887676DOI Listing
April 2014

From red to white urine: a patient's nightmare with a rather benign outcome.

BMC Nephrol 2012 Feb 1;13. Epub 2012 Feb 1.

Department of Nephrology & Hypertension, University of Erlangen-Nuremberg, Ulmenweg 18, 91054 Erlangen, Germany.

Background: Chyluria is a medical condition with presence of chyle in the urine. The disease is most prevalent in endemic regions of Africa and the Indian subcontinent where it is mostly caused by parasitic infections, particularly lymphatic filariasis due to wucheria bancrofti. Non-parasitic chyluria, however, is a very rare finding.

Case Presentation: We report the case of a 48 year old woman who developed a lymphorenal fistula with chyluria following ureterrenoscopy with biopsies taken for urological work-up of persistent macrohematuria. Renal biopsy confirmed the diagnosis of benign familial hematuria due to thin basement nephropathy, a condition frequently associated with episodes of macrohematuria.

Conclusions: This case highlights a rare case of non-parasitic chyluria as a complication of urological work-up for macrohematuria of benign nature.
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http://dx.doi.org/10.1186/1471-2369-13-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3297526PMC
February 2012

Effect of the plasminogen-plasmin system on hypertensive renal and cardiac damage.

J Hypertens 2011 Aug;29(8):1602-12

Department of Nephrology and Hypertension, Universität Erlangen-Nürnberg, Erlangen, Germany.

Background: The plasminogen-plasmin system affects tissue fibrosis, presumably by interacting with metalloproteinases (MMPs) and macrophage recruitment. This study tests the influence of plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (tPa) on angiotensin II-mediated hypertensive kidney and heart injury.

Method: Hypertension was induced by continuous angiotensin II (Ang II) infusion via osmotic mini-pumps over 4 weeks. The effects of Ang II infusion were determined in mice lacking PAI-1 (PAI-1), mice lacking tPa (tPa), and wild-type mice. Normotensive mice of the respective genotype served as controls. Blood pressure was recorded by continuous radiotelemetric intra-arterial measurements.

Results: Ang II infusion significantly enhanced arterial blood pressure in all groups. However, the increase in blood pressure was more pronounced in the tPa group. Albuminuria was highest in hypertensive wild-type compared to the other Ang II-infused groups. Hypertensive PAI-1 mice exhibited less glomerulosclerosis, higher nephrin immunostaining, and lower renal interstitial collagen I deposition. Gelatin zymography revealed higher activity of MMP-2 in hypertensive PAI-1, whereas no differences were observed in macrophage infiltration. tPa deficiency did not alter kidney fibrosis, although hypertensive tPa revealed less renal expression of fibrotic genes, less macrophage infiltration, and reduced MMP-2 activity. On the other hand, hypertension-induced fibrosis as well as macrophage infiltration in the heart was profoundly enhanced in PAI-1 mice. Fibrin staining revealed perivascular exudations in the myocardium of hypertensive PAI-1 suggesting vascular leakage.

Conclusion: These findings underscore the unexpectedly complex role of plasminogen activation for hypertensive target organ damage.
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http://dx.doi.org/10.1097/HJH.0b013e32834840e8DOI Listing
August 2011