Abstract
ABSTRACTAfter encounter with a central nervous system (CNS)-derived autoantigen, lymphocytes leave the lymph nodes and enter the CNS. This event leads only rarely to subsequent tissue damage. Genes relevant to CNS pathology after cell infiltration are largely undefined. Myelin-oligodendrocyte-glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS), a chronic autoimmune disease of the CNS that results in disability. To assess genes that are involved in encephalitogenicity and subsequent tissue damage mediated by CNS-infiltrating cells, we performed a DNA microarray analysis from cells derived from lymph nodes and eluted from CNS in LEW.1AV1 (RT1av1) rats immunized with MOG 91-108. The data was compared to immunizations with adjuvant alone or naive rats and to immunizations with the immunogenic but not encephalitogenic MOG 73-90 peptide. Here, we show involvement of Cd38, Cxcr4 and Akt and confirm these findings by the use of Cd38-knockout (B6.129P2-Cd38tm1Lnd/J) mice, S1P-receptor modulation during EAE and quantitative expression analysis in individuals with MS. The hereby-defined underlying pathways indicate cellular activation and migration pathways mediated by G-protein-coupled receptors as crucial events in CNS tissue damage. These pathways can be further explored for novel therapeutic interventions.
Highlights
Multiple sclerosis (MS) is a disease of the central nervous system (CNS) that leads to chronic inflammation, demyelination, and axonal and neuronal loss, resulting in disability (Noseworthy et al, 2000; Weissert, 2013)
Similar to the analysis of lymph node (LN) cells, we found that Cd38 and Cxcr4 mRNA was strongly increased in CNS-infiltrating cells
In cells eluted from the CNS, we found upregulation of Cxcr4 (Fig. 1B) and Cd38 (Fig. 1C) in MOG 91-108-immunized LEW.1AV1 (RT1av1) rats (n=6) compared to rats immunized with MOG 73-90 (n=6, ANOVA, Cxcr4 and Cd38 each P
Summary
Multiple sclerosis (MS) is a disease of the central nervous system (CNS) that leads to chronic inflammation, demyelination, and axonal and neuronal loss, resulting in disability (Noseworthy et al, 2000; Weissert, 2013). Myelin-oligodendrocyte-glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in rats reproduces major aspects of the human pathology The induction of active EAE in LEW MHC congenic rat strains and Dark Agouti (DA) (RT1av1) rats does not require the application of pertussis toxin like in mice. MT leads by binding and signaling through Toll-like receptors (TLRs) to an activation program in a number of cell types and is a systemic ‘danger signal’ (Mills, 2011)
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