Weber, Martin S.

[["dc.bibliographiccitation.artnumber","201"],["dc.bibliographiccitation.journal","Frontiers in Immunology"],["dc.bibliographiccitation.volume","10"],["dc.contributor.author","Häusser-Kinzel, Silke"],["dc.contributor.author","Weber, Martin S."],["dc.date.accessioned","2019-07-09T11:50:12Z"],["dc.date.available","2019-07-09T11:50:12Z"],["dc.date.issued","2019"],["dc.description.abstract","Our pathophysiological concept of the most common central nervous system demyelinating disease, multiple sclerosis, strikingly evolved by recent discoveries suggesting that B lymphocytes substantially contribute in its initiation and chronic propagation. In this regard, activated B cells are nowadays considered to act as important antigen-presenting cells for the activation of T cells and as essential source of pro-inflammatory cytokines. Hereby, they create a milieu in which other immune cells differentiate and join an orchestrated inflammatory infiltration of the CNS. Without a doubt, this scientific leap was critically pioneered by the empirical use of anti-CD20 antibodies in recent clinical MS trials, which revealed that the therapeutic removal of immature and mature B cells basically halted development of new inflammatory flares in otherwise relapsing MS patients. This stabilization occurred largely independent of any indirect effect on plasma cell-produced antibody levels. On the contrary, peripherally produced autoantibodies are probably the most important B cell component in two other CNS demyelinating diseases which are currently in the process of being delineated as separate disease entities. The first one is neuromyelitis optica in which an antibody response against aquaporin-4 targets and destroys astrocytes, the second, likely distinct entity embraces a group of patients containing antibodies against myelin oligodendrocyte glycoprotein. In this review, we will describe and summarize pro-inflammatory B cell properties in these three CNS demyelinating disorders; we will however also provide an overview on the emerging concept that B cells or B cell subsets may exert immunologically counterbalancing properties, which may be therapeutically desirable to maintain and foster in inflammatory CNS demyelination. In an outlook, we will discuss accordingly, how this potentially important aspect can be harnessed to advance future B cell-directed therapeutic approaches in multiple sclerosis and related diseases."],["dc.identifier.doi","10.3389/fimmu.2019.00201"],["dc.identifier.pmid","30800132"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15881"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59722"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.publisher","Frontiers Media S.A."],["dc.relation.eissn","1664-3224"],["dc.relation.issn","1664-3224"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","610"],["dc.title","The Role of B Cells and Antibodies in Multiple Sclerosis, Neuromyelitis Optica, and Related Disorders."],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","218"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","International Journal of Molecular Sciences"],["dc.bibliographiccitation.volume","20"],["dc.contributor.affiliation","Häusler, Darius; \t\t \r\n\t\t Institute of Neuropathology, University Medical Center, 37099 Göttingen, Germany, darius.haeusler@med.uni-goettingen.de"],["dc.contributor.affiliation","Weber, Martin S.; \t\t \r\n\t\t Institute of Neuropathology, University Medical Center, 37099 Göttingen, Germany, martin.weber@med.uni-goettingen.de\t\t \r\n\t\t Department of Neurology, University Medical Center, 37099 Göttingen, Germany, martin.weber@med.uni-goettingen.de"],["dc.contributor.author","Häusler, Darius"],["dc.contributor.author","Weber, Martin S."],["dc.date.accessioned","2019-07-09T11:49:57Z"],["dc.date.available","2019-07-09T11:49:57Z"],["dc.date.issued","2019"],["dc.date.updated","2022-09-06T14:14:55Z"],["dc.description.abstract","The exact cause of multiple sclerosis (MS) remains elusive. Various factors, however, have been identified that increase an individual's risk of developing this central nervous system (CNS) demyelinating disease and are associated with an acceleration in disease severity. Besides genetic determinants, environmental factors are now established that influence MS, which is of enormous interest, as some of these contributing factors are relatively easy to change. In this regard, a low vitamin D status is associated with an elevated relapse frequency and worsened disease course in patients with MS. The most important question, however, is whether this association is causal or related. That supplementing vitamin D in MS is of direct therapeutic benefit, is still a matter of debate. In this manuscript, we first review the potentially immune modulating mechanisms of vitamin D, followed by a summary of current and ongoing clinical trials intended to assess whether vitamin D supplementation positively influences the outcome of MS. Furthermore, we provide emerging evidence that excessive vitamin D treatment via the T cell-stimulating effect of secondary hypercalcemia, could have negative effects in CNS demyelinating disease. This jointly merges into the balancing concept of a therapeutic window of vitamin D in MS."],["dc.identifier.doi","10.3390/ijms20010218"],["dc.identifier.pmid","30626090"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15815"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59662"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation.eissn","1422-0067"],["dc.relation.issn","1422-0067"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","610"],["dc.title","Vitamin D Supplementation in Central Nervous System Demyelinating Disease-Enough Is Enough"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","640"],["dc.bibliographiccitation.issue","5"],["dc.bibliographiccitation.journal","Brain Pathology"],["dc.bibliographiccitation.lastpage","657"],["dc.bibliographiccitation.volume","29"],["dc.contributor.author","Traub, Jan"],["dc.contributor.author","Traffehn, Sarah"],["dc.contributor.author","Ochs, Jasmin"],["dc.contributor.author","Häusser‐Kinzel, Silke"],["dc.contributor.author","Stephan, Schirin"],["dc.contributor.author","Scannevin, Robert"],["dc.contributor.author","Brück, Wolfgang"],["dc.contributor.author","Metz, Imke"],["dc.contributor.author","Weber, Martin S."],["dc.date.accessioned","2019-12-02T09:57:51Z"],["dc.date.accessioned","2021-10-27T13:21:40Z"],["dc.date.available","2019-12-02T09:57:51Z"],["dc.date.available","2021-10-27T13:21:40Z"],["dc.date.issued","2019"],["dc.description.abstract","n multiple sclerosis (MS), the effect of dimethyl fumarate (DMF) treatment is primarily attributed to its capacity to dampen pathogenic T cells. Here, we tested whether DMF also modulates B cells, which are newly recognized key players in MS, and to which extent DMF restricts ongoing loss of oligodendrocytes and axons in the central nervous system (CNS). Therefore, blood samples and brain tissue from DMF-treated MS patients were analyzed by flow cytometry or histopathological examination, respectively. Complementary mechanistic studies were conducted in inflammatory as well as non-inflammatory CNS demyelinating mouse models. In this study, DMF reduced the frequency of antigen-experienced and memory B cells and rendered remaining B cells less prone to activation and production of pro-inflammatory cytokines. Dissecting the functional consequences of these alterations, we found that DMF ameliorated a B cell-accentuated experimental autoimmune encephalomyelitis model by diminishing the capacity of B cells to act as antigen-presenting cells for T cells. In a non-inflammatory model of toxic demyelination, DMF limited oligodendrocyte apoptosis, promoted maturation of oligodendrocyte precursors and reduced axonal damage. In a CNS biopsy of a DMF-treated MS patient, we equivalently observed higher numbers of mature oligodendrocytes as well as a reduced extent of axonal damage when compared to a cohort of treatment-naïve patients. In conclusion, we showed that besides suppressing T cells, DMF dampens pathogenic B cell functions, which probably contributes to its clinical effectiveness in relapsing MS. DMF treatment may furthermore limit chronically ongoing CNS tissue damage, which may reduce long-term disability in MS apart from its relapse-reducing capacity."],["dc.identifier.doi","10.1111/bpa.12711"],["dc.identifier.pmid","30706542"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/16772"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/92039"],["dc.language.iso","en"],["dc.notes.intern","Migrated from goescholar"],["dc.relation.eissn","1750-3639"],["dc.relation.issn","1750-3639"],["dc.relation.issn","1015-6305"],["dc.relation.orgunit","Universitätsmedizin Göttingen"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","610"],["dc.title","Dimethyl fumarate impairs differentiated B cells and fosters central nervous system integrity in treatment of multiple sclerosis"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","7"],["dc.bibliographiccitation.journal","Brain sciences"],["dc.bibliographiccitation.volume","7"],["dc.contributor.author","Kinzel, Silke"],["dc.contributor.author","Weber, Martin S"],["dc.date.accessioned","2019-07-09T11:43:37Z"],["dc.date.available","2019-07-09T11:43:37Z"],["dc.date.issued","2017-06-22"],["dc.description.abstract","In central nervous system (CNS) demyelinating disorders, such as multiple sclerosis (MS), neuromyelitis optica (NMO) and related NMO-spectrum disorders (NMO-SD), a pathogenic role for antibodies is primarily projected into enhancing ongoing CNS inflammation by directly binding to target antigens within the CNS. This scenario is supported at least in part, by antibodies in conjunction with complement activation in the majority of MS lesions and by deposition of anti-aquaporin-4 (AQP-4) antibodies in areas of astrocyte loss in patients with classical NMO. A currently emerging subgroup of AQP-4 negative NMO-SD patients expresses antibodies against myelin oligodendrocyte glycoprotein (MOG), again suggestive of their direct binding to CNS myelin. However, both known entities of anti-CNS antibodies, anti-AQP-4- as well as anti-MOG antibodies, are predominantly found in the serum, which raises the questions why and how a humoral response against CNS antigens is raised in the periphery, and in a related manner, what pathogenic role these antibodies may exert outside the CNS. In this regard, recent experimental and clinical evidence suggests that peripheral CNS-specific antibodies may indirectly activate peripheral CNS-autoreactive T cells by opsonization of otherwise unrecognized traces of CNS antigen in peripheral compartments, presumably drained from the CNS by its newly recognized lymphatic system. In this review, we will summarize all currently available data on both possible roles of antibodies in CNS demyelinating disorders, first, directly enhancing damage within the CNS, and second, promoting a peripheral immune response against the CNS. By elaborating on the latter scenario, we will develop the hypothesis that peripheral CNS-recognizing antibodies may have a powerful role in initiating acute flares of CNS demyelinating disease and that these humoral responses may represent a therapeutic target in its own right."],["dc.description.abstract","In central nervous system (CNS) demyelinating disorders, such as multiple sclerosis (MS), neuromyelitis optica (NMO) and related NMO-spectrum disorders (NMO-SD), a pathogenic role for antibodies is primarily projected into enhancing ongoing CNS inflammation by directly binding to target antigens within the CNS. This scenario is supported at least in part, by antibodies in conjunction with complement activation in the majority of MS lesions and by deposition of anti-aquaporin-4 (AQP-4) antibodies in areas of astrocyte loss in patients with classical NMO. A currently emerging subgroup of AQP-4 negative NMO-SD patients expresses antibodies against myelin oligodendrocyte glycoprotein (MOG), again suggestive of their direct binding to CNS myelin. However, both known entities of anti-CNS antibodies, anti-AQP-4- as well as anti-MOG antibodies, are predominantly found in the serum, which raises the questions why and how a humoral response against CNS antigens is raised in the periphery, and in a related manner, what pathogenic role these antibodies may exert outside the CNS. In this regard, recent experimental and clinical evidence suggests that peripheral CNS-specific antibodies may indirectly activate peripheral CNS-autoreactive T cells by opsonization of otherwise unrecognized traces of CNS antigen in peripheral compartments, presumably drained from the CNS by its newly recognized lymphatic system. In this review, we will summarize all currently available data on both possible roles of antibodies in CNS demyelinating disorders, first, directly enhancing damage within the CNS, and second, promoting a peripheral immune response against the CNS. By elaborating on the latter scenario, we will develop the hypothesis that peripheral CNS-recognizing antibodies may have a powerful role in initiating acute flares of CNS demyelinating disease and that these humoral responses may represent a therapeutic target in its own right."],["dc.identifier.doi","10.3390/brainsci7070070"],["dc.identifier.pmid","28640199"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/14594"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/58928"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.publisher","MDPI"],["dc.relation.eissn","2076-3425"],["dc.relation.issn","2076-3425"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","610"],["dc.title","The Role of Peripheral CNS-Directed Antibodies in Promoting Inflammatory CNS Demyelination."],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","2048"],["dc.bibliographiccitation.issue","10"],["dc.bibliographiccitation.journal","International journal of molecular sciences"],["dc.bibliographiccitation.volume","18"],["dc.contributor.affiliation","Lehmann-Horn, Klaus; \t\t \r\n\t\t Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany, klaus.lehmann-horn@tum.de\t\t \r\n\t\t Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany, klaus.lehmann-horn@tum.de"],["dc.contributor.affiliation","Kinzel, Silke; \t\t \r\n\t\t Institute of Neuropathology, University Medical Center, Georg August University, 37099 Göttingen, Germany, silke.kinzel@med.uni-goettingen.de"],["dc.contributor.affiliation","Weber, Martin; \t\t \r\n\t\t Institute of Neuropathology, University Medical Center, Georg August University, 37099 Göttingen, Germany, martin.weber@med.uni-goettingen.de\t\t \r\n\t\t Department of Neurology, University Medical Center, Georg August University, Robert-Koch-Str. 40, 37099 Göttingen, Germany, martin.weber@med.uni-goettingen.de"],["dc.contributor.author","Lehmann-Horn, Klaus"],["dc.contributor.author","Kinzel, Silke"],["dc.contributor.author","Weber, Martin S."],["dc.date.accessioned","2019-07-09T11:44:47Z"],["dc.date.available","2019-07-09T11:44:47Z"],["dc.date.issued","2017-09-23"],["dc.date.updated","2022-09-05T17:52:00Z"],["dc.description.abstract","B cells, plasma cells and antibodies may play a key role in the pathogenesis of multiple sclerosis (MS). This notion is supported by various immunological changes observed in MS patients, such as activation and pro-inflammatory differentiation of peripheral blood B cells, the persistence of clonally expanded plasma cells producing immunoglobulins in the cerebrospinal fluid, as well as the composition of inflammatory central nervous system lesions frequently containing co-localizing antibody depositions and activated complement. In recent years, the perception of a respective pathophysiological B cell involvement was vividly promoted by the empirical success of anti-CD20-mediated B cell depletion in clinical trials; based on these findings, the first monoclonal anti-CD20 antibody-ocrelizumab-is currently in the process of being approved for treatment of MS. In this review, we summarize the current knowledge on the role of B cells, plasma cells and antibodies in MS and elucidate how approved and future treatments, first and foremost anti-CD20 antibodies, therapeutically modify these B cell components. We will furthermore describe regulatory functions of B cells in MS and discuss how the evolving knowledge of these therapeutically desirable B cell properties can be harnessed to improve future safety and efficacy of B cell-directed therapy in MS."],["dc.identifier.doi","10.3390/ijms18102048"],["dc.identifier.pmid","28946620"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/14901"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59096"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation.eissn","1422-0067"],["dc.relation.issn","1422-0067"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","610"],["dc.title","Deciphering the Role of B Cells in Multiple Sclerosis-Towards Specific Targeting of Pathogenic Function."],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]