Autoantibodies in the pathogenesis of inflammatory and degenerative disorders of the central nervous system
Lead Research Organisation:
University of Oxford
Department Name: Clinical Neurosciences
Abstract
Limbic encephalitis (LE) is characterized by loss of memory, fitting, and confusion, and is usually untreatable. We recently discovered, however, that in a particular form of LE, antibodies generated by the patient‘s own immune system (autoantibodies) targeted a protein in the brain, and seemed to cause nerve cells (neurones) to malfunction. Our discovery led us to try treatments that suppress the immune system, which significantly improved the condition of the majority of patients, and raised the possibility of treating other patients with similar disorders. The theme of this research is how autoantibodies cause brain dysfunction, and in parallel, I will study a disease where antibodies may cause loss of neurones. This condition, narcolepsy, causes sufferers to fall asleep unpredictably, and is due to death of a specific set of neurones. We have a sophisticated model system for studying the role of the immune system in narcolepsy, and by combining the laboratory studies of LE and narcolepsy, with research using samples from patients with the conditions, I hope to make important discoveries that can be translated into new treatments that may even be relevant for other common diseases associated with damage to brain neurones, such as Alzheimer‘s and Parkinson‘s disease.
Technical Summary
Aims and objectives
I will investigate pathogenic mechanisms underlying immune-mediated disorders of the central nervous system (CNS), following on from our recent ground-breaking discovery and characterisation of a novel form of limbic encephalitis (LE) that is associated with autoantibodies against voltage-gated potassium channels (VGKC-LE), and responds to immunomodulatory therapies (Buckley et al, 2001). Autoantibody-mediated diseases of the peripheral nervous system are well recognised; however, the blood brain barrier (BBB) is conventionally thought to restrict antibody pathogenicity in the CNS. Despite this, preliminary data suggest that autoantibodies have a directly pathogenic role in VGKC-LE, rather than being markers for cell-mediated immunity. This project will investigate the pathogenicity of these autoantibodies. In parallel, I will investigate the role of antibodies in a model where there is targeted loss of specific CNS neurones. Thus the project addresses both reversible and neurodegenerative aspects of CNS immunopathology, and has a broad and fundamental relevance to neuroimmunology.
Methodology
Having demonstrated in preliminary experiments that immunoglobulins (IgG) can cross the intact BBB and enter the CNS, I will determine the effects of biological and environmental factors on the extent and distribution of IgG penetration. To investigate pathogenic effects of IgG, I will use two different models of VGKC-LE that I am currently developing. Using a wide range of techniques that my collaborators and I have already established, I will assess effects of experimental manipulations on disease phenotype and severity. Patient-derived antibodies will be used in the models, and laboratory tests will be correlated with clinical variation to further refine our understanding of the pathogenic mechanisms underlying VGKC-LE. I will apply similar techniques to investigate the interactions between humoral and cell-mediated immunity in a model of immune-mediated neurodegeneration developed with our recent MRC Brain Sciences II funding (2005).
Scientific opportunities
The major scientific opportunities are two-fold: firstly our discovery of VGKC-LE, the first reversible CNS disease that is clearly associated with a putatively pathogenic autoantibody, provides an excellent framework for studying disease mechanism. Secondly, our unique and powerful model of immune-mediated targeted cell loss combined with our established collaborations, will allow us to address fundamental molecular, physiological and behavioural questions that will be relevant to the whole field of neurodegeneration.
Medical opportunities
The striking feature of VGKC-LE that distinguishes it from other forms of LE is the significant improvement that occurs with treatment. Understanding the pathogenesis of VGKC-LE and other immune-mediated CNS disorders could radically alter our therapeutic outlook with improved outcomes for patients.
I will investigate pathogenic mechanisms underlying immune-mediated disorders of the central nervous system (CNS), following on from our recent ground-breaking discovery and characterisation of a novel form of limbic encephalitis (LE) that is associated with autoantibodies against voltage-gated potassium channels (VGKC-LE), and responds to immunomodulatory therapies (Buckley et al, 2001). Autoantibody-mediated diseases of the peripheral nervous system are well recognised; however, the blood brain barrier (BBB) is conventionally thought to restrict antibody pathogenicity in the CNS. Despite this, preliminary data suggest that autoantibodies have a directly pathogenic role in VGKC-LE, rather than being markers for cell-mediated immunity. This project will investigate the pathogenicity of these autoantibodies. In parallel, I will investigate the role of antibodies in a model where there is targeted loss of specific CNS neurones. Thus the project addresses both reversible and neurodegenerative aspects of CNS immunopathology, and has a broad and fundamental relevance to neuroimmunology.
Methodology
Having demonstrated in preliminary experiments that immunoglobulins (IgG) can cross the intact BBB and enter the CNS, I will determine the effects of biological and environmental factors on the extent and distribution of IgG penetration. To investigate pathogenic effects of IgG, I will use two different models of VGKC-LE that I am currently developing. Using a wide range of techniques that my collaborators and I have already established, I will assess effects of experimental manipulations on disease phenotype and severity. Patient-derived antibodies will be used in the models, and laboratory tests will be correlated with clinical variation to further refine our understanding of the pathogenic mechanisms underlying VGKC-LE. I will apply similar techniques to investigate the interactions between humoral and cell-mediated immunity in a model of immune-mediated neurodegeneration developed with our recent MRC Brain Sciences II funding (2005).
Scientific opportunities
The major scientific opportunities are two-fold: firstly our discovery of VGKC-LE, the first reversible CNS disease that is clearly associated with a putatively pathogenic autoantibody, provides an excellent framework for studying disease mechanism. Secondly, our unique and powerful model of immune-mediated targeted cell loss combined with our established collaborations, will allow us to address fundamental molecular, physiological and behavioural questions that will be relevant to the whole field of neurodegeneration.
Medical opportunities
The striking feature of VGKC-LE that distinguishes it from other forms of LE is the significant improvement that occurs with treatment. Understanding the pathogenesis of VGKC-LE and other immune-mediated CNS disorders could radically alter our therapeutic outlook with improved outcomes for patients.