Wellcome Trust Clinical PhD Programme at the University of Oxford: 'Autoimmunity in idiopathic epilepsies and encephalopathies of childhood'. (360G-Wellcome-097091_Z_11_Z)

Immune mechanisms are thought to be involved in the pathological disease process in a significant number of childhood (and adult) epileptic syndromes, and seizure related disorders (i.e. encephalitis). The hypothesis that the body's immune system plays an important role in these disorders is based on the following observations: 1) Occurrence of highly specific autoantibodies to important neuronal proteins (VGKC-complex proteins, NMDAR, AMPAR, GABAbRs), in the blood and spinal fluid of affected patients. 2) Beneficial and/or curative effects of immunotherapies. 3) Association of these illnesses with factors that are known to trigger autoimmune disorders, for example preceding exposure to a viral illness or immunisation. The goals of this project will be to; 1) Test patients' sera and CSF samples to identify autoantibodies to specific neuronal membrane/cell surface proteins, using a variety of established assays including immunoprecipitation of radiolabelled antigens (VGKC-complexes) and binding to cells transfected with specific proteins (eg. NMDARs). Attempt to identify new antigens using immunohistochemistry/immunofluoresence on brain tissue sections and neuronal cell cultures (eg. hippocampal), followed by immunoprecipitation, mass spectroscopsy and proteomic analysis. 2) Perform transfer of IgG from carefully selected patients to rodents with in vivo studies to demonstrate antibody mechanisms/pathogenicity. 3) Collect clinical information to classify the affected children and relate the antibody reactivies to their clinical syndromes This integration of basic science research and clinical work will serve to increase understanding of the pathogenic role of auotantibodies in childhood seizure disorders.