Narcolepsy: welcome to neuroimmunology!

A recent report in Science Traslational Medicine (1) has deserved a lot of attention by mainstream media. Headlines referred to it as the confirmation that narcolepsy is an autoimmune disease. Narcolepsy is an interesting disease both clinically (sleep attacks, cataplexy, sleep paralysis, visual hallucinations during early sleep and awakening…) and pathophysiologically. Current knowledge points at a selective death or damage in the neurons of the anterior part of the hypothalamus responsible of orexin production. Orexin (or hypocretin) is a secreted proteic neurotransmitter that regulates awakeness and apettite and whose levels in CSF are significantly lower in patients with narcolepsy than in controls. As usual, the exact cause of narcolepsy is unknown, although recent studies suggest that an autoimmune response, probably triggered by an environmental factor (let’s say, a virus), is the key process in its development (2).The paper by De la Herrán-Arita and colleagues reports an interesting, well-performed study that, contrary to what mainstream media say, does not demonstrate that narcolepsy is an autoimmune disease. But we’ll come to that later. The autoimmune hypothesis of narcolepsy is not new at all. Among the genes that have been associated to narcolepsy, most play important roles in the immune system (3). The strongest association was found with the HLA-DQB1*0602 allele, which more than 95% of the narcolepsy patients carry. But other genes, related to the immune system have also been implicated (4). However, as in any other complex disease, genes don’t explain everything. What the HLA system does is to present antigens (the targets of an immune response, regardless of it is against a pathogen or an autoimmune one) to T cells (lymphocytes) and T cells are the ones enabled to kill a cell carrying that antigen or to call other cells so they are the ones killing the antigenic cell.  One

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KIR4.1 antibodies: A revolution in multiple sclerosis

This week we had the opportunity to read a paper in the New England Journal of Medicine, describing, in my opinion, a breakthrough finding in MS. It’s published by Srivastava and coworkers, from the University of Munich. It describes the presence of antibodies against the KIR4.1 potassium channel in almost 50% of MS patients. Maybe i’m biased because my research is focused in autoantibodies in neuroimmune disorders, but, in my opinion is one of the best papers that has been published in MS in many years for different reasons that i will describe later. However, the impact in the mainstream scientific media and in the community has not been very big so far. It has had a media coverage that is, for example, far behind a recent study describing some allele variants having a small genetic risk of developing MS, being, in my opinion, much less important from the patient care point of view. The study is an example of how research should be conducted. From a very good (and old) hypothesis it develops a set of experiments brilliantly designed to achieve, with success, the goal in a completely unbiased approach. The approach is very similar to what Dr Dalmau and co-workers have been doing with autoimmune encephalitis, but it has some key differences that make the study even better if possible. Briefly, the study starts describing a set of patients that react agains glial components of the central nervous system. Then the authors isolate cell membranes from brain tissue (rat and human). They demonstrate reactivity against those membranes and isolate the proteins to which the antibodies are targetted (being that protein KIR4.1). Then they design another set of experiments to confirm the finding. They use ELISA, flow cytometry and immunocytochemistry to define the specificity of the antibodies and their

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Does multiple sclerosis start from the gut?

MS scientific literature is fascinating. Few neurological (and non-neurological) diseases can compete in number of papers, impact factor and mainstream media attention. However many research projects use classical animal models (experimental allergic encephalmyelitis, EAE) and those animal models have been an enormous source of erroneous extrapolations to MS pathogenesis. Many times the EAE model has been a research target itself and not because the results it could provide truly matched with what we want to know about MS. However, despite the noise that animal models generate, it must be aknowledged that they have evolved into more accurate models and have boosted MS research and knowledge. I like the “from bedside to bench” approach and not the other way round but, sometimes, basic research works initiate breakthrough hypothesis that deserve “bedside” research. I bring up this statement after reading the paper Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination by Kerstin Berer and co-workers and published in Nature in October 2011. The hypothesis is beautiful (but not new) and, although it probably needed a lot of experiments and comprobations, methods are pretty simple. They used a mouse model of spontaneous relapsing remitting MS, in which CD4 T cells constitutively express a T cell receptor that recognizes myelin oligodendrocyte glycoprotein peptides. They start with the observation that this model develops MS in variable proportions depending on the research group using the model. Then they wondered if the way these mice were bred had any influence in encephalomyelitis development and bred them in two different conditions: a conventional pathogen free (or SPF) environment or in a complete germ-free environment. In SPF breeding commensal microbiota can grow and animals are only pathogen-free. In germ-free environment animals don’t have commensal microbiota. The main goal was to see if there were differences in MS

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