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Analysis of autoimmune lesions in grey matter

dc.contributor.advisorFlügel, Alexander Prof. Dr.
dc.contributor.authorHermann, Moritz
dc.date.accessioned2018-06-14T08:31:32Z
dc.date.available2018-06-14T08:31:32Z
dc.date.issued2018-06-14
dc.identifier.urihttp://hdl.handle.net/11858/00-1735-0000-002E-E421-A
dc.identifier.urihttp://dx.doi.org/10.53846/goediss-6926
dc.language.isoengde
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc570de
dc.titleAnalysis of autoimmune lesions in grey matterde
dc.typedoctoralThesisde
dc.contributor.refereeFlügel, Alexander Prof. Dr.
dc.date.examination2018-02-20
dc.description.abstractengIn the present thesis I demonstrated that pathogenic TβSyn cells of wild-type and receptor-transgenic origins could be reliably generated and used for inducing passive transfer EAE; active EAE could be reproducibly induced in receptor-transgenic rats. Both inductions were possible without pre-treatment of recipient animals with pertussis toxin or cyclophosphamide. I additionally described the possibility to induce multiple independent bouts of inflammation and EAE by repeated transfer of TβSynTG(T/T) cells into βSynTG(T/+) recipients. Additionally, I presented evidence supporting the hypothesis that local re-activation, not cell-intrinsic properties, determined T-cell homing into the target CNS tissue. Motility and gene-expression were highly similar between TβSyn and TMBP cells prior to CNS infiltration. Intravascular crawling of TβSyn cells was found to be dependent on VLA-4, but not LFA-1 or CXCR3, as it has been previously described for TMBP-cell mediated EAE in the Lewis rat. Subsequently, the motility parameters and gene expression of TβSyn cells in the brain suggested an activated state of these cells and resembled the parameters described for locally re-activated TMBP cells located inside the SC. Local overexpression of the βSyn antigen led to an increased recruitment of TβSyn cells into the cortex, further emphasizing the importance of antigen-recognition for T-cell homing. Addressing the consequence of T-cell mediated inflammation in the brain, I demonstrated that transfer of TβSyn cells, but not of TMBP cells, mediated a transient reduction in synaptic spine density on cortical neurons, thereby providing a direct link between local inflammation and alterations in neuronal connectivity. Finally, I showed that active EAE as well as the repeated transfer of TβSynTG(T/T) cells induced neurodegeneration in βSynTG(T/+) rats, indicated by cortical atrophy. Taken together, several hallmarks of MS could be reproduced here by targeting the neuronal antigen βSyn, namely meningeal inflammation, synaptopathy and cortical atrophy. These observations recommend the βSyn neuronal EAE model as a suitable model for immune cell-mediated, inflammation-driven cortical neurodegeneration in MS and further underline the importance of researching the neuronal and grey matter aspects of the disease.de
dc.contributor.coRefereeReichardt, Holger Prof. Dr.
dc.subject.engMSde
dc.subject.engEAEde
dc.subject.engSynucleinde
dc.subject.engRatde
dc.subject.engMRIde
dc.subject.engT cellde
dc.subject.engLesionsde
dc.subject.engCNSde
dc.subject.engInflammationde
dc.subject.engIntravital Microscopyde
dc.subject.engAAVde
dc.subject.engNGSde
dc.identifier.urnurn:nbn:de:gbv:7-11858/00-1735-0000-002E-E421-A-3
dc.affiliation.instituteGöttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB)de
dc.subject.gokfullBiologie (PPN619462639)de
dc.identifier.ppn1024598349


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