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Lennon and her team discovered what the target of that antibody was and discovered that it was the water channel, aquaporin-4, that was expressed on astrocytes. Aquaporin-4 is expressed in the CNS perivascular and peripial end-feet that are in direct contact with the basal lamina of the endothelium and the pia mater. And this is exactly what we saw when we looked at patient IgG binding to the mouse tissue. It's also highly expressed in the ependymal cells and subependymal layers lining the ventricles and in the hypothalamus. Interestingly, it's not found in neurons or oligodendrocytes. And in fact, this discovery really resulted in a seismic shift in our thinking about central nervous system inflammatory demyelinating diseases. Because most of the focus up until then had been on oligodendrocytes. NMO-IgG targets AQP4 - Where in the brain is AQP4? 2,3 Vanda Lennon actually began to request samples be sent to our Neuroimmunology Laboratory for testing on tissue IF. And what was found was that about 70% of patients with the phenotype of NMO actually had immunoglobulins that were binding to mouse tissue in this pattern. For example, the antibodies seem to be binding to the pia around the cerebellum and midbrain. But also, interestingly, around blood vessels in a very similar distribution to what Claudia Lucchinetti had described as the immunoglobulin deposition around vessels. This pattern became known as NMO-IgG. In other words, it was an antibody pattern that was specific to NMO. Brian Weinshenker, who had shown that plasmapheresis was a benefit in patients with this type of disorder, that Dr. It was around this time that discussions occurred between Dr. Claudia Lucchinetti and Dr. Lucchinetti suggested that this disease was antibody mediated. They had very destructive, long lesions in their spinal cords. They had eosinophilic infiltration they had the deposition of immunoglobulins around vessels. And also there was evidence of complement deposition around vessels in a rim and rosette pattern. And based on this pathology, Dr. Pathological Hallmarksĭevic’s disease, or neuromyelitis optica, has a characteristic immunopathology. And this was actually a study published in 2002 by Claudia Lucchinetti from Mayo Clinic, where she looked at patients that fulfilled the clinical and radiological criteria - remember this was prior to the discovery of the antibody. And she found that patients with NMO had pathology that looked different to multiple sclerosis. So let's take it from the start. Devic, in 1894, described patients that had bilateral optic neuritis and myelitis. These generally occurred simultaneously or in quick succession. Patients had a severe course, and this was considered quite an extremely rare condition, and it was termed Devic’s disease. Other terms have been used for this condition: neuromyelitis optica, which remains, and optic spinal multiple sclerosis is the term that was used in Asia prior to the discovery of the biomarker.
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NMO: Devic’s disease traditional definition (1894)
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Over the next 20 minutes, I'm hopefully going to give you an update on neuromyelitis optica spectrum disorder. I'm going to give you an update on how we detect aquaporin-4 antibodies. I'm going to talk to you about the discovery of the antibody, and how Mayo Clinic has spent essentially the last 16 years working on optimizing the assays that we use to detect this antibody so that we can provide you with the best, most sensitive and specific assay available. We'll talk a little bit about the pros and cons of different methodologies. And then we'll talk about what the optimal specimen is to send or submit for testing. In addition, I will also provide you with some information as to why testing for aquaporin-4 antibody is so important, and why early diagnosis and treatment is important. And I'll give you a brief update on the recent advances made in terms of therapy. My name is Sean Pittock. I'm a professor of Neurology and director of the Neuroimmunology Laboratory at the Mayo Clinic. And it's my pleasure to speak to you today to provide an update, 2021, on Aquaporin-4 IgG flow cytometry assay.