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Characterization of immune responses in the meninges

dc.contributor.advisorFlügel, Alexander Prof. Dr.
dc.contributor.authorMerlini, Arianna
dc.titleCharacterization of immune responses in the meningesde
dc.contributor.refereeFlügel, Alexander Prof. Dr.
dc.description.abstractengMultiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), which is characterized by plaque-like demyelination in both white and grey matter and diffuse neurodegeneration. A T cell-driven autoimmune response against CNS antigens is the initiating event in the MS pathogenesis, as demonstrated in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). In EAE, CNS-reactive T cells reach the CNS through pial vessels and accumulate in the leptomeninges, from where they invade the CNS parenchyma. Also in human MS, the leptomeninges were shown to be a site of inflammation, and their involvement correlates with disease severity. The role of the leptomeninges as a crucial checkpoint for the initiation of the disease has been therefore well documented. On the other hand, it remains unknown whether the outer meningeal layers, i.e. the dura mater, can contribute to the development of neuro-inflammation in EAE and be a site for T-cell trafficking to and from the CNS. Moreover, it has not been investigated whether CNS-invading T cells can also possibly leave the CNS via the dura. Recent studies proposed that the dura might represent an exit route for cells and solutes from the CNS, which could travel to the deep cervical lymph nodes via the dura lymphatics. In this work we show that, unlike the leptomeninges, the dura is largely spared by the neuro-inflammatory process of EAE. We were able to identify several properties of the dura which may account for its marginal involvement. First, dura vessels were not permissive to T cell trafficking due to the lower expression of ligands that are necessary for the adhesion of effector CNS-reactive T cells. Further, activation of T cells in the dura during EAE was lower when compared to the leptomeninges and prevented the formation of a local inflammatory process. This was not due to intrinsic defects in T cells reaching the dura, nor to incompetence of the dura antigen presenting cells (APCs) in activating the T cells. In fact, when inflammation was induced in the dura, T cells readily accumulated there. Instead, the low activation of CNS-reactive T cells in the dura was due to the low availability of the cognate antigen: dura APCs failed to spontaneously present myelin or neuronal antigens to autoreactive T cells, while APCs of the leptomeninges or CNS parenchyma were able to spontaneously reactivate CNS-reactive T cells. We also found that trafficking of CNS-reactive T cells through the lymphatic vessels of the dura and deep cervical lymph nodes is very limited during EAE. More importantly, we did not detect neither antigen drainage nor T cell activation in these structures. Consequently, depletion of the lymphatic system did not have any effect on EAE clinical course or immune cell infiltration in the CNS. These data allowed us to conclude that the dura lymphatics and deep cervical lymph nodes play a marginal role, if any, in EAE development and severity. In conclusion, this work highlights the uneven involvement of the meningeal compartments to the neuro-inflammatory process of EAE. Although the dura possesses all the cellular and anatomical components to mount an effective immune response, T cell trafficking and activation during EAE is functionally confined to the leptomeninges, where endothelial vessels are permissive to T cell adhesion and local APCs can process and present CNS
dc.contributor.coRefereeStaiger, Jochen Prof. Dr.
dc.subject.engexperimental autoimmune encephalomyelitisde
dc.subject.engmultiple sclerosisde
dc.affiliation.instituteGöttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB)de
dc.subject.gokfullBiologie (PPN619462639)de

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