title: The role of the endothelial cell adhesion molecule MAdCAM-1 in neuroinflammation
Creators: name: Terbrack, Elisa
Publisher: name: Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
Year: 2024

description: Within the last years, the small intestine has come more and more into focus in multiple scle- rosis (MS) research. This included the various pathways and regulatory checkpoints of im- mune cell migration, some of which have already been studied in detail for the central ner- vous system (CNS), and which are currently under investigation in the intestine. The basic idea was that autoreactive lymphocytes may be activated in the intestine and cause autoim- mune diseases like MS. Blocking this process could be a possible approach to develop new drugs for MS patients. The aim of this study was therefore to examine the role of the endo- thelial cell adhesion molecule MAdCAM-1 in the regulation of lymphocyte homing to the in- testinal tract in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). The focus of this thesis was on the regulation of MAdCAM-1 expression in the course of EAE and the resulting clinical and immunological changes in its absence. We used MAdCAM-1 knockout mice to further determine its role in EAE. First, we investigated the expression of MAdCAM-1 in different organs at different time points of EAE in wildtype mice utilizing qPCR. Further on, FACS-analysis was employed to determine cell numbers and populations. Addi- tionally, we stained sections of the spinal cord in EAE-induced mice regarding demyelination and axonal damage. In adoptive transfer-EAE (at-EAE), we analyzed the cytokine production of specific target groups using MOG-recall and ELISA. Based on the clinical symptoms of the mice, which remarks in ascending flaccid palsy and concomitant weight loss after 9-14 days, we were able to show that the group of knockout mice exhibited a later disease onset and had a milder course of symptoms. Consistent with this findings, the analyses of cell numbers and types showed a significant reduction of proin- flammatory T cells in the small intestine and spinal cord of knockout mice compared to the wildtype mice. Histologically, the milder clinical course of the MAdCAM-1 knockout mice cor- related with a distinctly lower number of inflammatory-related lesions in the spinal cord, as well as less severe axonal damage. We were also able to detect relevant differences in the intestine, where the count of Peyer's patches was significantly lower in the knockout animals, accompanied by reduced numbers of immune cells. Additionally, T cells and antigen-presenting cells (APC) were decreased in the lamina propria of MAdCAM-1 knockout mice in the course of EAE. Since some studies postulated a connection between a complete absence of MAdCAM-1 and an impaired embryonic development of the immune system, we performed part of the experiments as at-EAE. Using this method, we showed that MAdCAM-1 knockout mice were equally susceptible to EAE compared to wildtype animals. Overall, this work demonstrates that the cell adhesion molecule MAdCAM-1 has a decisive influence on the course and severity of EAE by enabling immune cell migration into different organs, especially the small intestine. However, it remains to be clarified to what extent these results can be transferred to humans and whether treatment with a receptor blocker against MAdCAM-1 represents a possible therapeutic option for patients with MS.