It is well accepted that autoantibodies specific directed against neuronal proteins, such as acetylcholine receptors and voltage-gated calcium channels, can cause peripheral neurological diseases. Despite the presence of an effective blood brain barrier that is thought to prevent access of antibodies to the central nervous system (CNS), there is also growing circumstantial evidence that antibodies can cause central nervous system disorders. For instance, Rasmussen's encephalitis and some other epilepsies, and stiff person syndrome, are associated with antibodies to glutamate receptors or glutamic acid decarboxylase respectively, and these conditions may respond to immunotherapies.
In addition, we have recently described a form of limbic encephalitis (memory loss, disorientation, seizures, behavioral changes) that is frequently not paraneoplastic and appears to be humorally-mediated. In preliminary studies of patients with this condition, we have shown that it is (a) strongly associated with antibodies to voltage-gated potassium channels (VGKCs) particularly the Kv1.2 subtype that is expressed in the molecular layer of the dentate gyrus; (b) responsive to immunotherapies such as plasma exchange, indicating a humoral immune basis, and (c) sometimes follows a presumed viral infection consistent with a postinfectious autoimmune etiology. We need to induce animal models of this condition, both to investigate how the antibodies affect CNS function and, more generally, to establish approaches to demonstrate a role for autoantibodies in other CNS conditions. Although, we do not know how and where the VGKC antibodies gain access to the CNS, and how they affect CNS functions, we hypothesise that the hippocampus, which strongly expresses the Kv1.2 subtype of VGKC, is a major target of the antibodies.
We will, therefore, test the in vivo and in vitro effects of a neurotoxin that inhibits the function of VGKCs and passively transfer serum or IgG from the patients to mice, using both intracerebral and peripheral routes, with and without substances that we will show can alter the permeability of the blood brain barrier. In addition, we will actively immunize against VGKCs using viral vectors to express the protein with NFκB-inducing kinase, to induce expression of NFκB, or additional cytokines, to stimulate immunity and reproduce some features of natural infections. We will investigate the functional effects on the mice using classical and novel animal behavior paradigms as well as in vitro testing of hippocampal function, and correlate the results with immunological and histological studies on the mouse brain tissue and serological studies on the human and mouse sera. In this way, we will establish the most effective passive and active models of an antibody-mediated CNS disorder.
The models can then, in the future, be used to (a) establish the role of antibodies in other diseases, and (b) study the effects of antibodies to other putative neuronal autoantigens. These studies should lead to better definition of antibody-mediated disorders that are relatively easy to treat effectively, with improved diagnosis and treatment of patients with disabling CNS disorders.