| dc.contributor.advisor | Flügel, Alexander Prof. Dr. | |
| dc.contributor.author | Strauß, Judith | |
| dc.date.accessioned | 2019-10-24T09:46:23Z | |
| dc.date.available | 2020-03-19T23:50:02Z | |
| dc.date.issued | 2019-10-24 | |
| dc.identifier.uri | http://hdl.handle.net/21.11130/00-1735-0000-0005-1283-2 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-7694 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-7694 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 570 | de |
| dc.title | Elucidating the mechanisms of disease-triggering myelin-specific autoantibodies | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Flügel, Alexander Prof. Dr. | |
| dc.date.examination | 2019-03-21 | |
| dc.description.abstracteng | Although T cells are commonly known to be the driving force of disease pathogenesis in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), B cells and their soluble effector molecules (autoantibodies) also contribute substantially to disease development. We found that administration of a monoclonal antibody (Ab) specific for myelin oligodendrocyte glycoprotein (MOG; 8.18C5) induced significant disease acceleration after immunization and in adoptive transfer EAE. The aim of this study was to characterize the mechanism(s) by which α-MOG antibodies (α-MOG Abs) exert their pathogenic function within the CNS. Previous studies had mainly focused on the demyelinating capacity of autoantibodies. Here an additional mechanism by which autoantibodies act in the CNS is described. It could be demonstrated by two-photon microscopy flanked by histological analysis and flow cytometry that around the onset of EAE α-MOG Abs did not bind to myelin directly but rather accumulated in both CNS-resident and infiltrating myeloid cells. In vitro, uptake of α-MOG Abs complexed with myelin particles was significantly faster and more efficient than uptake of an isotype control antibody and led to an upregulation of MHC II in cultured microglia. Consequently, α-MOG antibody (α-MOG Ab) primed microglia were able to reactivate resting T cells more efficiently than in the presence of antigen alone or control antibodies. Using a T-cell activation reporter (Nur77 GFP) we further demonstrated ex vivo that the percentage of activated CD4+ T cells in the CNS was significantly elevated in α-MOG Ab treated animals. In the absence of Fcγ receptors (FcγR I-IV KO mice), which are also important for the uptake of immune complexes in vitro, no disease acceleration was observed after α-MOG Ab treatment. Imaging based analysis further revealed that in FcγR I-IV KO mice α-MOG Ab deposits were considerably reduced on cells but were instead found on myelin fibers. Accordingly, the numbers of reactivated T cells remained at the same level as in animals treated with isotype control antibodies. Based on these observations, the following mechanism can be proposed: autoantibodies bind endogenously- released myelin particles within the CNS and form immune complexes which are subsequently taken up by Fcγ receptor bearing myeloid cells. The targeting of myelin components to these cells capable of antigen presentation increases the availability of presented antigen for incoming pathogenic T cells. This, in turn, facilitates their reactivation and results in a more pronounced and aggravated inflammatory response. | de |
| dc.contributor.coReferee | Wienands, Jürgen Prof. Dr. | |
| dc.subject.eng | Autoantibodies | de |
| dc.subject.eng | Experimental autoimmune encephalomyelitis | de |
| dc.subject.eng | Multiple Sclerosis | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-21.11130/00-1735-0000-0005-1283-2-0 | |
| dc.affiliation.institute | Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB) | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.description.embargoed | 2020-03-19 | |
| dc.identifier.ppn | 1679966405 | |