Hermann, Moritz

In 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

eDiss Georg-August-University Göttingen

Analysis of autoimmune lesions in grey matter

https://ediss.uni-goettingen.de/bitstream/11858/00-1735-0000-002E-E421-A/1/PhD%20thesis_Moritz%20Hermann_eDiss.pdf

Analysis of autoimmune lesions in grey matter

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eDiss Georg-August-University Göttingen