Inhaltszusammenfassung

Even though the central nervous system (CNS) is generally regarded as an immune privileged organ, attacks of infiltrated immune cells during autoimmune diseases as Multiple Sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) lead to CNS injury. The invasion of encephalitogenic T cells into the CNS is considered to be the initiatory event of the autoimmune pathology that causes a direct interaction of cells from the immune system and the CNS. This study demonstrates a novel role...Even though the central nervous system (CNS) is generally regarded as an immune privileged organ, attacks of infiltrated immune cells during autoimmune diseases as Multiple Sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) lead to CNS injury. The invasion of encephalitogenic T cells into the CNS is considered to be the initiatory event of the autoimmune pathology that causes a direct interaction of cells from the immune system and the CNS. This study demonstrates a novel role of the cell adhesion molecule L1 (L1) in the crosstalk between immune cells and neurons. For the first time, the adaptive regulation of neuronal L1 expression and the role of L1 expressed by mononuclear cells in a model of neuroinflammation have been described. L1 expression was found in axons in MS lesions and in human T cells, as well as on axons and adjacent CD4 T cells in acute spinal cord EAE plaques. The mRNA expression levels of L1 correlated with the disease stages during the relapsing-remitting EAE model and were confirmed by a significant L1 reduction at the peak disease stage in chronic EAE. The reduction of L1 expression coincided with the up-regulation of its transcriptional repressor REST (RE1-Silencing Transcription Factor). Stimulated CD4 T cells induced L1 down- and REST up-regulation in neurons and caused a severe axonal injury in a contact-dependent manner in co-cultures. CD4 T cell adhesion to neurons and the subsequent axonal injury were prevented by L1-blocking antibodies. In line, antibody- mediated blocking of L1 in wild type C57BL/6J mice as well as a genetic depletion of L1 in neurons (synapsinCre x L1fl/fl) attenuated the severity of EAE and reduced the axonal pathology, while the immune cell infiltration remained unchanged. Moreover, antigen- presenting cells (APC) in chronic active lesions of MS patients and in EAE plaques expressed L1. The cell type-specific L1 depletion in microglia/macrophages (lysozyme-MCre x L1fl/fl) and dendritic cells (CD11cCre x L1fl/fl) attenuated the severity of EAE. The findings of this thesis suggest that neuronal reduction of L1 is beneficial during neuroinflammation and thereby represents an adaptive process of neuronal self-defense that limits immune cell-mediated axonal injury. L1 expression in APCs appeared to be crucial for an efficient disease induction and progression. Altogether our data identified L1 as a relevant factor in neuroinflammation and implicate cell-type specific functions of L1 in neurons, T cells, and APCs during inflammatory disease progression in the CNS.» weiterlesen» einklappen

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DDC Sachgruppe:
Biowissenschaften, Biologie