| dc.contributor.advisor | Flügel, Alexander Prof. Dr. | |
| dc.contributor.author | Hosang, Leon | |
| dc.date.accessioned | 2019-10-24T09:51:31Z | |
| dc.date.available | 2020-06-29T22:50:03Z | |
| dc.date.issued | 2019-10-24 | |
| dc.identifier.uri | http://hdl.handle.net/21.11130/00-1735-0000-0005-1284-1 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-7695 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-7695 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 570 | de |
| dc.title | The role of the lung in shaping CNS autoimmunity | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Flügel, Alexander Prof. Dr. | |
| dc.date.examination | 2019-07-01 | |
| dc.description.abstracteng | The lung was recently identified as a central site of T cell reprogramming in experimental autoimmune encephalomyelitis (EAE), a rodent model of multiple sclerosis (MS). While residing in the pulmonary tissue, central nervous system (CNS) antigen-reactive T cells become equipped with the potential to transgress the blood-brain barrier and induce CNS autoimmune disease. In order to better understand the involvement of the lung in the development and progression of EAE, we established an acute EAE model induced by intratracheal (i.tr.) immunization with the myelin antigen myelin basic protein (MBP). Effector-memory T cells reactive against MBP were activated within the lung tissue and induced severe clinical signs of EAE. The activation process was highly efficient: antigen doses about 100 to 1000 times lower than used for subcutaneous (s.c.) immunization were sufficient to trigger MBP-specific T cells to induce EAE. This effect was reproducible in animals which carry low numbers of neonatally transferred MBP-specific memory T cells embedded in their immune repertoire and lung. These observations could be of relevance in context of MS: Minute amounts of pathogenic epitopes resembling self-antigens in the airways of patients with a matching HLA haplotype expression could be sufficient to induce the activation of dormant autoreactive T cells in a process referred to as molecular mimicry, and consequently trigger disease. In order to identify local factors that can potentially contribute to the efficiency of the lung in triggering autoimmunity, we focused on the recently identified lung microbiota. Intratracheal administration of a locally acting antibiotic induced changes in the lung microbiota composition and significantly reduced EAE. The treatment did neither interfere with T cell activation within the lung nor change the expression profile of the transferred T cells. Moreover, EAE amelioration was also observed following s.c. immunization and in a transfer EAE model using in vitro activated T cells, suggesting that a distal rather than a local lung-intrinsic mechanism could be causative. We observed that i.tr. antibiotic treatment induced a reduced MHCII expression in the CNS, potentially indicative of a functional impairment in the capacity of microglia or local macrophages to present antigen and consequently trigger CNS inflammation. Taken together, we observed that the lung represents a highly efficient environment for the activation of autoaggressive T cells and the initiation of CNS autoimmunity, and the lung microbiota appears to be involved in its regulation. How exactly this crosstalk between lung and CNS is mediated remains to be further investigated. | de |
| dc.contributor.coReferee | Reichardt, Holger Prof. Dr. | |
| dc.subject.eng | EAE | de |
| dc.subject.eng | experimental autoimmune encephalomyelitis | de |
| dc.subject.eng | MS | de |
| dc.subject.eng | multiple sclerosis | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-21.11130/00-1735-0000-0005-1284-1-0 | |
| dc.affiliation.institute | Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB) | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.description.embargoed | 2020-06-29 | |
| dc.identifier.ppn | 1679966421 | |