Neuronal membrane antigens in demyelinating diseases

Background The pathogenesis of autoimmune mediated inflammatory diseases of the central nervous system (CNS) is complex and heterogenous. Some of the disorders, such as some types of Paraneoplastic neurological syndrome (PNS) or neuromyelitis optica (NMO), are believed to be antibody-mediated. This hypothesis is based on the presence of highly specific and sensitive antibodies directed against antigens expressed in the nervous system. An increasing spectrum of autoimmune mediated inflammatory CNS diseases with or without tumour association has been described with antibodies targeting neuronal surface or synaptic proteins. Multiple sclerosis (MS) is a chronic, mostly relapsing-remitting autoimmune CNS disease characterized by demyelination and relative preservation of axons, which may occur in the entire CNS. MS is most common in young adults and may lead to physical and psychical impairment. Current concepts of MS pathogenesis support a multifactorial process with clinical, immunological and pathological heterogeneity. Unfortunately, in most MS patients, it has been impossible so far to identify with certainty, which autoantigens are the targets in individual humans. However, there is increasing evidence that antibodies to neuronal surface or synaptic proteins may contribute to tissue damage or influence disease course in some types of demyelinating diseases. Objectives The specific aims of our project are to identify new neuronal membrane antigens involved in the pathophysiology of demyelinating CNS disorders by suitable techniques including flow cytometry and immunocytochemistry in neuronal cell cultures, and screening of a fetal brain cDNA library and to further characterize these antigens with immunoprecipitation and mass spectrometry. Methods We will analyse sera of patients with MS, consisting of different subgroups, each with distinct clinical features as well as NMO, for the presence of antibodies attributed to neuronal surface antigens. We will use flow cytometry and indirect immunofluorescence (IF) on isolated cerebral cortex neurons from postnatal rats and screening of a featl brain cDNA library. To characterize the antigens detected by flow cytometry and IF, we will apply immunoprecipitation and mass spectrometry techniques. Relevance of our study The demonstration that some patients with demyelinating CNS disease harbor antibodies against neuronal membrane antigens that may be pathogenic in vivo is important for diagnosis and will guide treatment strategies and intensify immunotherapy, leading to better outcome of these patients.