Identifizierung von Schlüsselmechanismen und -molekülen bei der Bildung von tertiär lymphatischen Organen im zentralen Nervensystem in der MP4-induzierten experimentellen autoimmunen Enzephalomyelitis
Molekulare Biologie und Physiologie von Nerven- und Gliazellen
Nuklearmedizin, Strahlentherapie, Strahlenbiologie
Zusammenfassung der Projektergebnisse
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS). Since it is the most common neurological disease in young adults that leads to irreversible deficits and premature retirement, there is socioeconomic need to further dissect the mechanisms underlying the disease. These mechanisms could then be used towards the design of novel drugs and biomarkers that are disease-specific. One of the mechanisms contributing to MS, in particular to its perpetuation, is the development of B cell aggregates in the central nervous system (CNS), which become the site of compartimentalized inflammation. B cell aggregates have been described mainly in secondary progressive MS (SPMS) patients and have been associated with more severe disease and cortical histopathology. B cell aggregates have also been observed in experimental autoimmune encephalomyelitis (EAE), which is the most common animal model of MS. In particular, we have introduced an EAE model, which is induced by active immunization with a fusion protein consisting of myelin basic protein and the hydrophilic domains of proteolipid protein (termed MP4). This model proved to be B cell-dependent and B cell aggregates mainly developed in the cerebellum in the chronic stage of the disease. Our project was aimed to dissect the mechanisms contributing to such CNS B cell aggregate development. On the one hand, we addressed the possible role of lymphoid tissue inducer (LTi) cells, which play a major role in the development of secondary lymphoid organs (SLOs) and have been described to also contribute to formation of ectopic lymphoid tissue, e.g. of Peyer’s patches in the gut. Yet, our data did not provide any evidence for the involvement of this cell type in both the MP4 and in the B cell-independent myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 model. Performing multicolor flow cytometry we did not detect any significant number of LTi cells in the CNS neither in the acute nor in the chronic stage of EAE. On the contrary, we observed a high number of TH17 cells, which indeed share striking similrity with LTi cells and have previously been discussed as key cell type in B cell aggregate formation in EAE. In a second approach, we dissected B cell aggregates using laser capture microdissection and compared the RNA expression of these samples to the RNA isolated from infiltrates near the aggregates, or from the MOG:35-55 cerebellum and from lymph node follicles obtained from both EAE models. RNA sequencing provided severeal interesting target molecules that were significantly upregulated in the B cell aggregates. Among those was osteopontin, which has already been described to be expressed in MS brain lesions. Subsequent immunohistochemistry has revealed microglia to be the main cell population expressing osteopontin in proximity to the B cell aggregates. In addition, osteopontin was found on germinal center B cells in the periphery of MP4-immunized mice. We are going to submit a follow-up grant on the role of osteopontin in the MP4 model in the near feature.
Projektbezogene Publikationen (Auswahl)
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CEACAM1 mediates B cell aggregation in central nervous system autoimmunity. Sci Rep 6:29847 (2016)
Rovituso D, Scheffler L, Wunsch M, Kleinschnitz C, Dörck S, Ulzheimer J, Bayas A, Steinman L, Ergün S, Kuerten S
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The enteric nervous system is a potential autoimmune autoimmune target in multiple sclerosis. Acta Neuropathol 134:281-295 (2017)
Wunsch M, Jabari S, Voussen B, Enders M, Srinivasan S, Cossais F, Wedel T, Boettner M, Schwarz A, Weyer L, Göcer O, Schroeter M, Maeurer M, Woenckhaus M, Pollok K, Radbruch H, Klotz L, Scholz C, Nickel J, Friebe A, Addicks K, Ergün S, Lehmann PV, Kuerten S
