Crosstalk between the lung microenvironment and CNS autoimmunity

von Roger Cugota Canals
Dissertation
Datum der mündl. Prüfung:2022-05-13
Erschienen:2023-05-08
Betreuer:Prof. Dr. Alexander Flügel
Gutachter:Prof. Dr. Alexander Flügel
Gutachter:Prof. Dr. Jürgen Wienands
Gutachter:Prof. Dr. Holger Reichardt
Gutachter:Prof. Dr. Christine Stadelmann-Nessler
Gutachter:Prof. Dr. Dr. Hannelore Ehrenreich
Gutachter:Prof. Dr. Martin Weber
Zum Verlinken/Zitieren: http://dx.doi.org/10.53846/goediss-9873

 

 

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Englisch

The contribution of the lung in shaping CNS autoimmunity is gaining relevance in the last years. Central nervous system (CNS) reactive T cells can acquire in the lung the potential to invade the CNS in experimental autoimmune encephalomyelitis, an animal model for Multiple sclerosis. Furthermore, the lung microbiota by modulating the microglial phenotype can act on the effector phase of the CNS autoreactive process and regulate the disease severity. Finally, the lung can also represent a trigger site for CNS autoimmunity. Indeed, very low doses of CNS antigen delivered intra-trachea are sufficient to trigger myelin-reactive T cells to induce EAE. As a repercussion of its main task of gas-exchange, the lung represents the most extensive surface in contact with the outside environment and is the organ with the highest level of oxygenation in the body. In this work, in order to identify pulmonary factors that can potentially contribute to the efficiency of the lung in triggering autoimmunity, we investigated if oxygen availability determines the function of CNS-reactive T cells in the context of CNS autoimmunity. In vitro, we could observe that an oxygen-deprived atmosphere impaired proliferation and effector functions of myelin-reactive T cells stimulated with the cognate antigen. These functional changes were associated with a global reprogramming of the transcriptional profile. The hypoxic stimulus, rather that impairing, triggered an upregulation of numerous transcripts mainly involved in glucose metabolism and cell signalling events. These transcriptional changes were clinical relevant. Indeed myelin-reactive T cells stimulated in a hypoxic environment and retransferred in vivo proliferated less than the normoxic counterpart did and induced a milder disease. Taken together, our results indicated that the T cells are able to adapt their function to a broad range of environmental oxygen conditions by rapidly switching their metabolism and transcriptional profile. In the lung, the unique oxygen conditions favour T cells activation and proliferation and therefore contribute to the capacity of the lung to trigger CNS autoimmunit
Keywords: Neuroimmunolgoy; Multiple sclerosis; Experimental Autoimmune Encephalomyelitis
 
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