Mechanisms behind T cell-mediated neuroinflammation
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Abstract
Multiple sclerosis (MS) is a chronic demyelinating inflammatory and neurodegenerative autoimmune disease of the central nervous system (CNS) causing long-term neurological disability. According to our current understanding, MS is mainly driven by autoreactive lymphocytes, which are thought to orchestrate repetitive CNS invasions by immune cells, resulting in the destruction of the myelin sheath and the neuronal compartment. This thesis focuses on the mechanisms behind T cell-mediated neuroinflammation in the context of the murine MS model experimental autoimmune encephalomyelitis (EAE). At first the impact and fate of distinct T cell subsets in the course of EAE, especially during the second wave of CNS infiltration was addressed. While Th1 and Th2 cells infiltrated the CNS less efficiently than Th17 cells a strong influence of the second wave of autoreactive T cells on the EAE-inducing population was observed. Th1 and Th2 reduced EAE severity, presumably by competing with Th17 cells, by promoting plasticity of the EAE-inducing population, and by expressing more anti-inflammatory cytokines in response to contact with the neuronal compartment. Secondly the ambivalent role of the neuronal adhesion molecule ICAM-5 was investigated in the context of EAE. It was demonstrated that membrane bound ICAM-5 is not essential as an adhesion molecule for T cell-mediated neuroinflammation. However, the shedded soluble form, sICAM-5, shows regulatory features in immune responses, probably by inhibiting T cell (re)stimulation via antigen presenting cells. Thus, sICAM5 might serve locally as an endogenous neuronal defense mechanism during ongoing neuroinflammation. Thirdly the potential of axonal and neuronal ion-channel blocking in preventing neurodegeneration in EAE was tested. We investigated the effect of the antiepileptic drug Lamotrigine (LTG) by using intravital live imaging. Intriguingly, a reduction of intraneuronal free calcium concentrations, as an early sign for neuronal damage, was observed by the application of low-dose LTG but not in axons or if given in high-dose. Clinical EAE studies confirmed that ion-channel blocking by low-dose LTG improves neurological deficits. Taken together this thesis gives new insights beginning with the contribution of distinct T cell in the perpetuation of CNS inflammation, across a potential neuronal defense mechanism as an endogenous response to T cells, up to the prevention of neurodegeneration as the consequence of the detrimental cascade of T cell-mediated neuroinflammation.