Is Human Narcolepsy an Autoimmune Disorder?

In the September 2000 issue of the journal ‘Neuron’, Dr. Jerome Siegel, Professor of Psychiatry and Biobehavioral Sciences at the University of California at Los Angeles, and Chief of Neurobiology Research at the Veterans Administration in Sepulveda, along with colleagues like Thomas C. Thannickal and Lalini Ramanathan, published data from his research into the possibility that the cause of human narcolepsy was an autoimmune problem.

The researchers acquired and examined the lateral hypothalamic regions of the brains of four deceased narcoleptic people and twelve neurologically normal people. By marking them with stains that indicated the presence of hypocretin neurons and melanin concentrating hormone (MCH) neurons, they were able to observe that the number of hypocretin neurons in a normal or healthy hypothalamus is about 70,000, whereas in the hypothalamus of the brains of narcoleptic patients, there are only about 3000 to 10,000 hypocretin containing cells The image on the right is part of the data that they published in 2000, and shows the observable differences in the number of hypocretin cells in normal and narcoleptic brains. All neurons in the figure are from the levels indicated in A and B. C and D are low power photomicrographs in which many Hypocretin cell bodies and processes are visible in the normal brain and only a few in the narcoleptic. Arrows in D indicate stained hypocretin cell bodies that can be seen more clearly at higher magnifications in E, F, G and H. This was a very evident loss of hypocretin neurons in narcoleptic brains – about 85 to 95 percent less on average than the normal brains. Surprisingly, there was no marked difference in the number of MCH cells, showing that in narcolepsy it is only the loss of hypocretin containing cells that is significant.

The most important discovery of this research team that led to the autoimmune hypothesis of narcolepsy was that the narcoleptic brains also exhibited marked signs of an inflammatory process called gliosis, which leaves behind scar tissue in the place of the healthy cells like the hypocretin neurons, and is linked to neuronal degeneration. This might be linked to an autoimmune attack that specifically targets hypocretin cells and could explain their degeneration in the lateral hypothalamus where the gliosis was observed. The graph on the left, part of the research that was published by Siegel et al in 2000, shows the marked difference in gliosis in the hypothalamus and thalamus of narcoleptic (black) and normal (white) brains. These findings indicate that the replacement of the missing hypocretin cells may reverse some of the symptoms of narcolepsy, and this has been the focus of recent work in Siegel's lab which also uses the canine model.

Another theory that has been proposed is that the cell death is caused by a specific toxin/poison that might be produced by the body itself, or ingested or inhaled from the environment in some way, but no further research has been published on this hypothesis, and it is a less likely to be a cause of narcolepsy than an autoimmune disease that targets hypocretin containing cells.

A similar study led by Emmanuel Mignot, of the Stanford Medical Center, was published at the same time in the September 2000 issue of “Nature”. Dr. Mignot and his colleagues looked at the nature of hypocretin cells in the hypothalamuses of six narcoleptic brains and also conducted many genetic screenings of narcoleptic patients. In the neuropathology tests, they, like Siegel’s team, found that concentration of hypocretin cells was “undetectable” in the hypothalamic brain tissue and cerebrospinal fluid of narcoleptic patients.