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  • 1
    Online Resource
    Online Resource
    Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity
    Proceedings of the National Academy of Sciences ; 2021
    In:  Proceedings of the National Academy of Sciences Vol. 118, No. 1 ( 2021-01-05)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 118, No. 1 ( 2021-01-05)
    Abstract: 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 ( n NationMS = 946, n BIONAT = 990). Additionally, effect-modification by medication and photosensitivity-associated MC1R 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 MC1R :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.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2018457118
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2021
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  • 2
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    K2P18.1 translates T cell receptor signals into thymic regulatory T cell development
    Springer Science and Business Media LLC ; 2022
    In:  Cell Research Vol. 32, No. 1 ( 2022-01), p. 72-88
    Details
    In: Cell Research, Springer Science and Business Media LLC, Vol. 32, No. 1 ( 2022-01), p. 72-88
    Abstract: It remains largely unclear how thymocytes translate relative differences in T cell receptor (TCR) signal strength into distinct developmental programs that drive the cell fate decisions towards conventional (Tconv) or regulatory T cells (Treg). Following TCR activation, intracellular calcium (Ca 2+ ) is the most important second messenger, for which the potassium channel K 2P 18.1 is a relevant regulator. Here, we identify K 2P 18.1 as a central translator of the TCR signal into the thymus-derived Treg (tTreg) selection process. TCR signal was coupled to NF-κB-mediated K 2P 18.1 upregulation in tTreg progenitors. K 2P 18.1 provided the driving force for sustained Ca 2+ influx that facilitated NF-κB- and NFAT-dependent expression of FoxP3, the master transcription factor for Treg development and function. Loss of K 2P 18.1 ion-current function induced a mild lymphoproliferative phenotype in mice, with reduced Treg numbers that led to aggravated experimental autoimmune encephalomyelitis, while a gain-of-function mutation in K 2P 18.1 resulted in increased Treg numbers in mice. Our findings in human thymus, recent thymic emigrants and multiple sclerosis patients with a dominant-negative missense K 2P 18.1 variant that is associated with poor clinical outcomes indicate that K 2P 18.1 also plays a role in human Treg development. Pharmacological modulation of K 2P 18.1 specifically modulated Treg numbers in vitro and in vivo. Finally, we identified nitroxoline as a K 2P 18.1 activator that led to rapid and reversible Treg increase in patients with urinary tract infections. Conclusively, our findings reveal how K 2P 18.1 translates TCR signals into thymic T cell fate decisions and Treg development, and provide a basis for the therapeutic utilization of Treg in several human disorders.
    Type of Medium: Online Resource
    ISSN: 1001-0602 , 1748-7838
    URL: Article
    DOI: 10.1038/s41422-021-00580-z
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 3
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    Complete Epstein-Barr virus seropositivity in a large cohort of patients with early multiple sclerosis
    BMJ ; 2020
    In:  Journal of Neurology, Neurosurgery & Psychiatry Vol. 91, No. 7 ( 2020-07), p. 681-686
    Details
    In: Journal of Neurology, Neurosurgery & Psychiatry, BMJ, Vol. 91, No. 7 ( 2020-07), p. 681-686
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 0022-3050 , 1468-330X
    URL: Article
    DOI: 10.1136/jnnp-2020-322941
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2020
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  • 4
    Online Resource
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    Table_3.DOCX
    Frontiers Media SA ; 2019
    In:  Frontiers in Immunology Vol. 10 ( 2019-7-30)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 10 ( 2019-7-30)
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2019.01779
    DOI: 10.3389/fimmu.2019.01779.s001
    DOI: 10.3389/fimmu.2019.01779.s002
    DOI: 10.3389/fimmu.2019.01779.s003
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2019
    detail.hit.zdb_id: 2606827-8
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  • 5
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    A Case of Progressive Multifocal Leukoencephalopathy in a Fumaric Acid-Treated Psoriasis Patient With Severe Lymphopenia Among Other Risk Factors
    SAGE Publications ; 2021
    In:  Journal of Central Nervous System Disease Vol. 13 ( 2021-01), p. 117957352110377-
    Details
    In: Journal of Central Nervous System Disease, SAGE Publications, Vol. 13 ( 2021-01), p. 117957352110377-
    Abstract: Progressive multifocal leukoencephalopathy (PML) is a potentially fatal condition caused by a brain infection with JC polyomavirus (JCV), which occurs almost exclusively in immunocompromised patients. Modern immunosuppressive and immunomodulatory treatments for cancers and autoimmune diseases have been accompanied by increasing numbers of PML cases. We report a psoriasis patient treated with fumaric acid esters (FAEs) with concomitant hypopharyngeal carcinoma and chronic alcohol abuse who developed PML. Grade 4 lymphopenia at the time point of PML diagnosis suggested an immunocompromised state. This case underscores the importance of immune cell monitoring in patients treated with FAEs, even more so in the presence of additional risk factors for an immune dysfunction.
    Type of Medium: Online Resource
    ISSN: 1179-5735 , 1179-5735
    URL: Article
    DOI: 10.1177/11795735211037798
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2021
    detail.hit.zdb_id: 2586873-1
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  • 6
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    Intrathecal B-cell accumulation and axonal damage distinguish MRI-based benign from aggressive onset in MS
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Neurology - Neuroimmunology Neuroinflammation Vol. 6, No. 5 ( 2019-09), p. e595-
    Details
    In: Neurology - Neuroimmunology Neuroinflammation, Ovid Technologies (Wolters Kluwer Health), Vol. 6, No. 5 ( 2019-09), p. e595-
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 2332-7812
    URL: Article
    DOI: 10.1212/NXI.0000000000000595
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 2767740-0
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  • 7
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    Increased cerebrospinal fluid albumin and immunoglobulin A fractions forecast cortical atrophy and longitudinal functional deterioration in relapsing-remitting multiple sclerosis
    SAGE Publications ; 2019
    In:  Multiple Sclerosis Journal Vol. 25, No. 3 ( 2019-03), p. 338-343
    Details
    In: Multiple Sclerosis Journal, SAGE Publications, Vol. 25, No. 3 ( 2019-03), p. 338-343
    Abstract: 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 IgA and CSF IgM 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.
    Type of Medium: Online Resource
    ISSN: 1352-4585 , 1477-0970
    URL: Article
    DOI: 10.1177/1352458517748474
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2019
    detail.hit.zdb_id: 2008225-3
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  • 8
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    Association of obesity with disease outcome in multiple sclerosis
    BMJ ; 2023
    In:  Journal of Neurology, Neurosurgery & Psychiatry Vol. 94, No. 1 ( 2023-01), p. 57-61
    Details
    In: Journal of Neurology, Neurosurgery & Psychiatry, BMJ, Vol. 94, No. 1 ( 2023-01), p. 57-61
    Abstract: Obesity reportedly increases the risk for developing multiple sclerosis (MS), but little is known about its association with disability accumulation. Methods This nationwide longitudinal cohort study included 1066 individuals with newly diagnosed MS from the German National MS cohort. Expanded Disability Status Scale (EDSS) scores, relapse rates, MRI findings and choice of immunotherapy were compared at baseline and at years 2, 4 and 6 between obese (body mass index, BMI ≥30 kg/m 2 ) and non-obese (BMI 〈 30 kg/m 2 ) patients and correlated with individual BMI values. Results Presence of obesity at disease onset was associated with higher disability at baseline and at 2, 4 and 6 years of follow-up (p 〈 0.001). Median time to reach EDSS 3 was 0.99 years for patients with BMI ≥30 kg/m 2  and 1.46 years for non-obese patients. Risk to reach EDSS 3 over 6 years was significantly increased in patients with BMI ≥30 kg/m 2 compared with patients with BMI 〈 30 kg/m 2 after adjustment for sex, age, smoking (HR 1.87; 95% CI 1.3 to 2.6; log-rank test p 〈 0.001) and independent of disease-modifying therapies. Obesity was not significantly associated with higher relapse rates, increased number of contrast-enhancing MRI lesions or higher MRI T2 lesion burden over 6 years of follow-up. Conclusions Obesity in newly diagnosed patients with MS is associated with higher disease severity and poorer outcome. Obesity management could improve clinical outcome of MS.
    Type of Medium: Online Resource
    ISSN: 0022-3050 , 1468-330X
    URL: Article
    DOI: 10.1136/jnnp-2022-329685
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2023
    detail.hit.zdb_id: 1480429-3
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  • 9
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    Continuous reorganization of cortical information flow in multiple sclerosis: A longitudinal fMRI effective connectivity study
    Springer Science and Business Media LLC ; 2020
    In:  Scientific Reports Vol. 10, No. 1 ( 2020-01-21)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2020-01-21)
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-020-57895-x
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2615211-3
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  • 10
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    Network alterations underlying anxiety symptoms in early multiple sclerosis
    Springer Science and Business Media LLC ; 2022
    In:  Journal of Neuroinflammation Vol. 19, No. 1 ( 2022-12)
    Details
    In: Journal of Neuroinflammation, Springer Science and Business Media LLC, Vol. 19, No. 1 ( 2022-12)
    Abstract: Anxiety, often seen as comorbidity in multiple sclerosis (MS), is a frequent neuropsychiatric symptom and essentially affects the overall disease burden. Here, we aimed to decipher anxiety-related networks functionally connected to atrophied areas in patients suffering from MS. Methods Using 3-T MRI, anxiety-related atrophy maps were generated by correlating longitudinal cortical thinning with the severity of anxiety symptoms in MS patients. To determine brain regions functionally connected to these maps, we applied a technique termed “atrophy network mapping”. Thereby, the anxiety-related atrophy maps were projected onto a large normative connectome ( n  = 1000) performing seed‐based functional connectivity. Finally, an instructed threat paradigm was conducted with regard to neural excitability and effective connectivity, using transcranial magnetic stimulation combined with high-density electroencephalography. Results Thinning of the left dorsal prefrontal cortex was the only region that was associated with higher anxiety levels. Atrophy network mapping identified functional involvement of bilateral prefrontal cortex as well as amygdala and hippocampus. Structural equation modeling confirmed that the volumes of these brain regions were significant determinants that influence anxiety symptoms in MS. We additionally identified reduced information flow between the prefrontal cortex and the amygdala at rest, and pathologically increased excitability in the prefrontal cortex in MS patients as compared to controls. Conclusion Anxiety-related prefrontal cortical atrophy in MS leads to a specific network alteration involving structures that resemble known neurobiological anxiety circuits. These findings elucidate the emergence of anxiety as part of the disease pathology and might ultimately enable targeted treatment approaches modulating brain networks in MS.
    Type of Medium: Online Resource
    ISSN: 1742-2094
    URL: Article
    DOI: 10.1186/s12974-022-02476-0
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2156455-3
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