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dc.contributor.advisor Brück, Wolfgang Prof. Dr.
dc.contributor.author Avendaño Guzmán, Erika
dc.date.accessioned 2018-12-07T08:46:41Z
dc.date.available 2018-12-07T08:46:41Z
dc.date.issued 2018-12-07
dc.identifier.uri http://hdl.handle.net/11858/00-1735-0000-002E-E52B-E
dc.language.iso eng de
dc.relation.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc 610 de
dc.title Evaluating the function of the Aryl Hydrocarbon Receptor in CNS autoimmunity de
dc.type doctoralThesis de
dc.contributor.referee Nave, Klaus-Armin Prof. Dr.
dc.date.examination 2018-10-17
dc.description.abstracteng The aryl hydrocarbon receptor (AhR) is a ligand activated transcription factor highly expressed within the immune and nervous system. Structurally diverse endogenous and synthetic ligands activate AhR, including dietary, microbial and physiological compounds, suggesting a potential cross-talk between AhR’s signaling, diet, microbiome, and immune system. The aim of the present thesis was to evaluate if endogenous AhR ligands influence the development of spontaneous CNS autoimmunity. For this purpose, double transgenic opticospinal (OSE) mice carrying myelin oligodendrocyte glycoprotein (MOG) specific T and B cell receptors were generated with or without AhR competent dendritic cells (DC), CD4+ T cells, regulatory T cells (Tregs) or astrocytes. The spontaneous EAE incidence significantly increased in OSE animals with AhR deleted in DC (OSE AhRΔDC), but not in OSE mice devoid of AhR in CD4+ T cells, Tregs or astrocytes. OSE AhRΔDC CX3CR1EGFP/+ reporter mice were generated in order to assess the antigen presenting cells (APCs) of the lamina propria (LP), where MOG specific CD4+ T cells are likely activated in the OSE mouse model. AhR deficiency of DC increased the frequency of CX3CR1int DC and correspondingly decreased the frequency of CX3CR1- DC. The presence of CX3CR1int DC and CX3CR1- DC was confirmed by immunohistochemistry in the LP of CD11ctdTomato CX3CR1eGFP reporter mice. CX3CR1int DC showed higher MHCII expression than CX3CR1- DC. Thus, might be better equipped to initiate the activation of MOG specific naïve T cells. Compared to OSE AhRfl/fl control littermates, OSE AhRΔDC mice showed higher frequencies of IFNγ+ transgenic CD4+ T cells in the LP and increased MOG specific IgG2a antibodies in the sera. Furthermore, supplementing a single AhR ligand to the diet of OSE mice, spontaneous EAE was almost completely abolished. Finally, it was aimed to define the relevant cellular players mediating the therapeutic efficacy of the presumed and clinically relevant AhR agonist, Laquinimod, against EAE. Laquinimod significantly protected AhRΔDC, AhRΔCD4, AhRΔTreg and AhRΔAstro mice, but its protective effect was less sustained in AhRΔDC mice. In summary, this work provides evidence showing that the physiological concentrations of AhR ligands modulate CNS autoimmunity via AhR competent DC. de
dc.contributor.coReferee Flügel, Alexander Prof. Dr.
dc.contributor.thirdReferee Reichardt, Holger Prof. Dr.
dc.subject.eng Multiple Sclerosis de
dc.subject.eng aryl hydrocarbon receptor de
dc.subject.eng experimental autoimmune encephalomyelitis de
dc.subject.eng dendritic cells de
dc.subject.eng quinoline-3-carboxamide de
dc.identifier.urn urn:nbn:de:gbv:7-11858/00-1735-0000-002E-E52B-E-1
dc.affiliation.institute Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB) de
dc.subject.gokfull Biologie (PPN619462639) de
dc.identifier.ppn 1042163219

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