The role of mast cell activation in neuroinflammation

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Inflammatory diseases of the central nervous system (CNS) are associated with severe physical and mental impairments and are therefore a great burden for both patients and Health Care systems. Multiple Sclerosis (MS) is an inflammatory CNS disease affecting about 1,000,000 patients world wide, and is viewed as a classical autoimmune disease. In contrast to MS, Alzheimer's disease (AD), the most frequent dementia of the elderly and an important cause of disablement and death, has not been regarded as an inflammatory disease for decades. However, evidence is accumulating that AD is also driven by immune mechanisms. Within the projects proposed here we want to elucidate the role of activation of mast cells (MCs) in the pathogenesis of MS and AD. In experimental autoimmune encephalitis (EAE), a model for MS, Toll-like Receptor (TLR)-mediated immune responses have been shown to crucially affect severity of disease via the adaptor molecule MyD88, and data is available that MCs promote disease as well. Using a mouse model of EAE, we aim to test our hypothesis that TLR-mediated activation of MCs is centrally involved in both initiation and progression of MS. Based on the hypothesis that similarities exist between pathogenesis of MS and AD, we furthermore want to study the role of innate immunity in AD by using transgenic mouse models, and whether innate immune activation of MCs plays a central role here. Finally, we want to evaluate the effect of pharmacological inhibition of MCs in these diseases.