Misgeld, Thomas

[["dc.bibliographiccitation.journal","Neurotherapeutics"],["dc.contributor.author","Kalluri, Sudhakar Reddy"],["dc.contributor.author","Srivastava, Rajneesh"],["dc.contributor.author","Kenet, Selin"],["dc.contributor.author","Tanti, Goutam K."],["dc.contributor.author","Dornmair, Klaus"],["dc.contributor.author","Bennett, Jeffrey L."],["dc.contributor.author","Misgeld, Thomas"],["dc.contributor.author","Hemmer, Bernhard"],["dc.contributor.author","Wyss, Matthias T."],["dc.contributor.author","Herwerth, Marina"],["dc.date.accessioned","2022-08-26T07:55:50Z"],["dc.date.available","2022-08-26T07:55:50Z"],["dc.date.issued","2022-07-12"],["dc.description.abstract","Purinergic 2 receptors (P2Rs) contribute to disease-related immune cell signaling and are upregulated in various pathological settings, including neuroinflammation. P2R inhibitors have been used to treat inflammatory diseases and can protect against complement-mediated cell injury. However, the mechanisms behind these anti-inflammatory properties of P2R inhibitors are not well understood, and their potential in CNS autoimmunity is underexplored. Here, we tested the effects of P2R inhibitors on glial toxicity in a mouse model of neuromyelitis optica spectrum disorder (NMOSD). NMOSD is a destructive CNS autoimmune disorder, in which autoantibodies against astrocytic surface antigen Aquaporin 4 (AQP4) mediate complement-dependent loss of astrocytes. Using two-photon microscopy in vivo, we found that various classes of P2R inhibitors prevented AQP4-IgG/complement-dependent astrocyte death. In vitro, these drugs inhibited the binding of AQP4-IgG or MOG-IgG to their antigen in a dose-dependent manner. Size-exclusion chromatography and circular dichroism spectroscopy revealed a partial unfolding of antibodies in the presence of various P2R inhibitors, suggesting a shared interference with IgG antibodies leading to their conformational change. Our study demonstrates that P2R inhibitors can disrupt complement activation by direct interaction with IgG. This mechanism is likely to influence the role of P2R inhibitors in autoimmune disease models and their therapeutic impact in human disease."],["dc.identifier.doi","10.1007/s13311-022-01269-w"],["dc.identifier.pmid","35821382"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/113251"],["dc.identifier.url","https://rdp.sfb274.de/literature/publications/72"],["dc.language.iso","en"],["dc.relation","TRR 274: Checkpoints of Central Nervous System Recovery"],["dc.relation","TRR 274 | B03: Checkpoints of recovery after primary astrocytic lesions in neuromyelitis optica and related animal models"],["dc.relation.eissn","1878-7479"],["dc.relation.issn","1933-7213"],["dc.relation.workinggroup","RG Misgeld"],["dc.title","P2R Inhibitors Prevent Antibody-Mediated Complement Activation in an Animal Model of Neuromyelitis Optica : P2R Inhibitors Prevent Autoantibody Injury"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Brain"],["dc.contributor.author","Herwerth, Marina"],["dc.contributor.author","Kenet, Selin"],["dc.contributor.author","Schifferer, Martina"],["dc.contributor.author","Winkler, Anne"],["dc.contributor.author","Weber, Melanie"],["dc.contributor.author","Snaidero, Nicolas"],["dc.contributor.author","Wang, Mengzhe"],["dc.contributor.author","Lohrberg, Melanie"],["dc.contributor.author","Bennett, Jeffrey L."],["dc.contributor.author","Stadelmann, Christine"],["dc.contributor.author","Misgeld, Thomas"],["dc.date.accessioned","2022-04-01T10:02:49Z"],["dc.date.available","2022-04-01T10:02:49Z"],["dc.date.issued","2022"],["dc.description.abstract","Abstract Neuromyelitis optica (NMO) is a chronic neuroinflammatory disease, which primarily targets astrocytes and often results in severe axon injury of unknown mechanism. NMO patients harbor autoantibodies against the astrocytic water channel protein, aquaporin-4 (AQP4-IgG), which induce complement-mediated astrocyte lysis and subsequent axon damage. Using spinal in vivo imaging in a mouse model of such astrocytopathic lesions, we explored the mechanism underlying NMO-related axon injury. Many axons showed a swift and morphologically distinct ‘pearls-on-string’ transformation also readily detectable in human NMO lesions, which especially affected small caliber axons independently of myelination. Functional imaging revealed that calcium homeostasis was initially preserved in this ‘acute axonal beading’ state, ruling out disruption of the axonal membrane, which sets this form of axon injury apart from previously described forms of traumatic and inflammatory axon damage. Morphological, pharmacological and genetic analyses showed that AQP4-IgG-induced axon injury involved osmotic stress and ionic overload, but does not appear to use canonical pathways of Wallerian-like degeneration. Subcellular analysis of beaded axons demonstrated remodeling of the axonal cytoskeleton in beaded axons, especially local loss of microtubules. Treatment with the microtubule stabilizer epothilone, a therapy in development for traumatic and degenerative axonopathies, prevented axonal beading, while destabilizing microtubules sensitized axons for beading. Our results reveal a distinct form of immune-mediated axon pathology in NMO that mechanistically differs from known cascades of posttraumatic and inflammatory axon loss, and suggest a new strategy for neuroprotection in NMO and related diseases."],["dc.identifier.doi","10.1093/brain/awac079"],["dc.identifier.pmid","35202467"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/106013"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/454"],["dc.identifier.url","https://rdp.sfb274.de/literature/publications/59"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-530"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","TRR 274: Checkpoints of Central Nervous System Recovery"],["dc.relation.eissn","1460-2156"],["dc.relation.issn","0006-8950"],["dc.relation.workinggroup","RG Stadelmann-Nessler"],["dc.relation.workinggroup","RG Misgeld"],["dc.relation.workinggroup","RG Schifferer"],["dc.rights","CC BY-NC 4.0"],["dc.title","A new form of axonal pathology in a spinal model of neuromyelitis optica"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]