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Building Strength in Neuroimmunology

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Building Strength in Neuroimmunology PROFESSOR ANGELA VINCENT Building strength in neuroimmunology Professor Angela Vincent FRS has had a long and fruitful career in neuroimmunology and has been involved with developing better diagnostics of diseases with an autoimmune basis. Here, she discusses the current priorities of her lab Which experiences from your academic have one of the known antibodies. It is akin to Having been elected to prestigious positions and professional background do you think performing a genetic test to identify a particular such as Fellow of the Academy of Medical have played the biggest role in shaping your form of disease. My laboratory has two main Sciences and Fellow of the Royal Society, research today? aims. First, to help diagnose these patients, and as a past President of the International which we do by running a clinical service that Society for Neuroimmunology, you are well I am a qualified doctor and spent a year working is used by most hospitals in the UK, and many positioned to inspire young women looking to as a doctor, but then turned to science. I was around the world. And second, to identify new enter a career in the field. Is this a significant lucky to experience first-hand the pioneering antibodies, look for them in patients with aspect of your work? research into the function of the neuromuscular diseases for which there is no current diagnostic junction by Nobel laureates Bernhard Katz and test, and study how the antibodies affect I am very committed to helping young people, Bert Sakmann, and Ricardo Miledi at University neurological functions. We are also interested of either sex, fulfil their hopes of combining a College London in the late 1960s, which was in asking whether there were antibodies to clinical career with laboratory-based science, crucial for the understanding of transmission neuronal proteins in some pregnant mothers and act as a mentor through the Academy of across synapses in the peripheral and, later, whose children subsequently developed Medical Sciences, which is highly active in the central nervous system. In 1969, Miledi had diseases such as autism or schizophrenia. this field. I also informally mentor a number already used snake toxins to purify the post- of younger scientists and clinician scientists synaptic ‘acetylcholine receptors’ that received Are you collaborating with any individuals, in Oxford. the acetylcholine signal from the nerve, and groups or institutions that you would like after three very unproductive years in a different to highlight? What are your main objectives over the next department, I began to work with Miledi on five years? these receptors and the neurological disease We collaborate worldwide with neurologists on myasthenia gravis, beginning a collaboration many clinical studies of individual patients and I am already past the normal retirement with neurologist John Newsom-Davis. All examine the antibodies and clinical features of age but would like to complete some of the of my work today stems from these very patients with specific neurological diseases. projects that have been intriguing me over fortuitous experiences. At the moment, we have a particular interest the last decade or two: looking at the relative in improving the diagnosis and treatment roles of serum antibodies and cerebrospinal Can you discuss some of the work taking place possibilities of patients with myasthenia gravis, antibodies in causing central nervous system at the Vincent lab? Why are you focusing on which involves many of the myasthenia centres diseases; showing whether or not maternal antibodies in particular? in the UK, Europe and Japan. We are also antibodies can be an important factor in looking for specific antibodies in children and causing neurodevelopmental disorders If a patient has an antibody to a neuromuscular adults with unexplained epilepsy or psychosis, in the offspring, using a combination of junction or central nervous system receptor, or partly in collaborations with the Institute of serum studies and animal models; and another membrane protein, it is highly likely that Psychiatry in London, and the Universities of exploring whether there is a role for their symptoms will improve if you can reduce Sydney and Groningen. The maternal antibody antibodies in patients with some unexplained the levels of the offending antibodies. Therefore, studies are being performed in collaboration conditions such as pain or sleep disorders. if a patient presents to a neurologist with with the Department of Economics and The main objective must be to leave the symptoms of muscle weakness, or epilepsy, for Business – National Centre for Register-based Neuroimmunology Group in good hands and instance, it is now common to ask whether they Research in Aarhus Denmark. with a sensible strategy for the future. 48 INTERNATIONAL INNOVATION Cultured cells from brain tissue grown in the lab. One large and several small neurons (green) lying on a bed of astrocytes (red). These cultures can be used to show that antibodies in patients bind to the surface of live cells. The nucleus of each cell is in blue. Courtesy of Dr D Menassa, University of Oxford Antibody, brain proteins Starting at the Royal Free Hospital School of Medicine in 1977, and moving to the University of Oxford, UK, in 1988, the Vincent Neuroimmunology Group was created to understand the mechanisms underlying nerve and muscle diseases. The contributions to understanding the links between autoantibodies and neurological diseases has been considerable UP UNTIL THE 1960s the brain and other set up the Neuroimmunology Group at the antibodies to MuSK, resulting in reduced levels components of the nervous system were a Royal Free Hospital School of Medicine. and dispersion of AChR due to inhibition of largely mysterious and uncharted territory of MuSK clustering activity. Understanding which the human body, and neurological diseases AN AUTOIMMUNE BASIS autoantibodies a patient with myasthenia were diagnosed based on descriptions of FOR A NEUROLOGICAL DISEASE gravis is producing, and how they result in symptoms and simple investigations. However, Autoimmunity plays a well-known role in disease, can be key in ensuring they receive during the last few decades the understanding diseases such as diabetes, but less is known the most effective and relevant treatment. of neurological diseases has developed beyond about its role in neurological disorders. In recognition and now almost all disorders autoantibody diseases, the body produces AUTOANTIBODIES AGAINST are investigated in terms of their molecular antibodies that target its own proteins resulting NEURONAL CELL SURFACE TARGETS mechanisms. This paradigm shift was in in loss of these proteins or damage to the cells Since 2001, a number of antibodies to part due to the increasingly interdisciplinary in which they function. The first neurological brain proteins have been discovered nature of research, encompassing clinical disease with autoantibodies was myasthenia by Vincent and others. These include genetics, physiology, pharmacology and gravis, a rare disorder of the neuromuscular autoantibodies against parts of the voltage- molecular biology. “This now allows any junction where communication between the gated potassium channel complex (VGKC) individual disease to be defined at the level nervous system and muscular system is and the N-methyl-D-aspartate receptor of the gene, the protein, the cellular function, impaired, resulting in muscle weakness. At (NMDAR), both linked to brain inflammation the influence on function of the nerve cells, the neuromuscular junction, the acetylcholine (encephalitis) and epileptic seizures. and ultimately, on the behaviour of mouse receptor (AChR) is clustered on the muscle and man,” explains Professor Angela Vincent, surface during development, so that the muscle To measure the antibodies, Vincent uses human who embraced the change in neurology fibre can efficiently receive the chemical embryonic kidney (HEK) cells expressing the early on in her long career, and is now signal (acetylcholine) that is released from expected target of the antibodies. Adding based at the Nuffield Department of Clinical the motor nerve; this signal triggers muscle the serum or cerebrospinal fluid (CSF) of Neurosciences at the University of Oxford. contraction. The AChR clustering is dependent a patient with appropriate symptoms, and on another nerve signal that activates a identifying whether antibodies bind the target Vincent runs the Clinical Neuroimmunology protein, muscle specific kinase (MuSK). expressed by the HEK cells, will determine if service, analysing patient samples for the patient has the specific autoantibodies in diagnosis, and has been well placed to For myasthenia gravis, Vincent and Newsom- their serum or CSF. In some cases, it is also carry out work at the interface between Davis confirmed that the majority of patients helpful to confirm that the antibodies bind to the clinical and experimental sides of with the disease have antibodies to AChR, the surface of live brain neurons that can be science. She originally trained as a doctor resulting in loss of AChR from the muscle cultured in the laboratory (see figure above). but joined the eminent neurologist John fibre surface and consequently the symptoms Newsom-Davis, developing together an observed in the disease. Importantly, they The reason for these elaborate and time- interest in myasthenia gravis, a disease that showed that removing the antibodies with a consuming tests is that autoantibodies leads to
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