Innate immunity in the pathogenesis of initial MS lesions

Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system, which is commonly believed to be driven by autoimmunity. However, recent studies on the immunopathology of the lesions revealed a profound heterogeneity in the patterns of tissue injury between patients and some of these patterns are profoundly different from those seen in the paradigmatic experimental model of brain autoimmune disease, experimental autoimmune encephalomyelitis. Preliminary studies from our laboratory suggest that initial lesions in a subset of patients may at least in part be driven by innate immunity and that these lesions can be modelled experimentally by local injection of bacterial lipopolysaccharide into the spinal cord white matter. Furthermore, we were able to show that fibrin precipitation within the lesions may play a key role in TLR-mediated activation of microglia. Aim of the present study is to define the sequence of events and pathogenetic mechanisms involved in the formation of these lesions by immunopathology and pathway directed microarray studies. Key pathways involved in the pathogenesis of the lesions will further be analysed in functional experimental studies. It is expected that these studies will unravel new mechanisms of tissue injury in multiple sclerosis, which may become future targets for therapeutic intervention.

Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system, which is commonly believed to be driven by autoimmunity. However, recent studies on the immunopathology of the lesions revealed a profound heterogeneity in the patterns of tissue injury between patients and some of these patterns are profoundly different from those seen in the paradigmatic experimental model of brain autoimmune disease, experimental autoimmune encephalomyelitis. Preliminary studies from our laboratory suggest that initial lesions in a subset of patients may at least in part be driven by innate immunity and that these lesions can be modelled experimentally by local injection of bacterial lipopolysaccharide into the spinal cord white matter. Furthermore, we were able to show that fibrin precipitation within the lesions may play a key role in TLR-mediated activation of microglia. Aim of the present study is to define the sequence of events and pathogenetic mechanisms involved in the formation of these lesions by immunopathology and pathway directed microarray studies. Key pathways involved in the pathogenesis of the lesions will further be analysed in functional experimental studies. It is expected that these studies will unravel new mechanisms of tissue injury in multiple sclerosis, which may become future targets for therapeutic intervention.