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While much has been learned about the cause of narcolepsy-cataplexy in humans and animal models we still do not known whether narcolepsy is an autoimmune disorder resulting from the degeneration of hypocretin neurons. Indeed, studies showing the absence of prepro-hypocretin mRNA and hypocretin immunoreactivity from the lateral hypothalamic area of human brains,21,22 are consistent with this possibility. However, attempts to confirm this autoimmune hypothesis directly96,97 have been, to date, unsuccessful.

Studies in peripheral blood have failed to reveal any evidence of humoral or cellular autoimmune processes in narcoleptics. Using ELISA, no IgG autoantibodies directed against Hcrt-1, Hcrt-2, or prepro-hypocretin overlapping peptides have been detected in the serum of narcolepsy patients. However, the absence of anti-hypocretin antibodies does not preclude the possibility of other auto-antibodies directed against other antigens expressed by hypocretin neurons. For example, in Myasthenia Gravis (MG, a peripheral nervous system autoimmune disorder directed against the neuromuscular junction), pathogenic anti-acetylcholine receptor autoantibodies can be detected in the peripheral blood of most patients and can transfer the disease when injected into mice. However, 15% of patients with MG have no detectable anti-acetylcholine receptor antibody in their blood, yet their serum can still transfer the disease, which raises the possibility that other pathogenic (neutralizing) auto-antibodies exist, specific for other, as of yet undetermined auto-antigens.

Mono-lymphocytic secretion of TNF-alpha and other proinflammatory cytokines such as IL-beta, IL-1 RA, IL-2 and TNF-beta have also been studied and found to be no different between HLA DR2 positive narcoleptic patients and controls.98 Only IL-6 secretion was found to be higher in narcoleptics. While a major peripheral cellular inflammatory reaction in narcolepsy is also unlikely given the lack of difference between T-cell subsets and natural killer (NK) activity in these two populations, this does not exclude the presence of a local proinflammatory cellular process within the central nervous system. While studies of hypocretin neurons in narcoleptic brains have not detected any inflammatory infiltrates in the hypothalamus,21,22 non-specific gliosis has been observed.22 Furthermore, while CNS microglial class II expression is not significantly different between narcoleptics and control subjects, brains used for these studies may have contained inflammatory infiltrates which were present at the time of disease onset, but which have since abated. Based on measurements of CSF Hcrt-1, the disease process is likely rapidly progressive, given the already low or absent Hcrt-1 levels in patients who are diagnosed early in the disease process.

Indeed, further research is required to better characterize the circumstances surrounding the onset of narcolepsy symptoms, including environmental factors that may trigger the disease in those so genetically predisposed. Furthermore, atypical cases of narcolepsy should be carefully investigated in relation to CSF Hcrt-1 levels, in order to better describe the spectrum of the "narcolepsy borderland". Whether CSF Hcrt-1 levels correlate with progression of narcolepsy symptoms also requires further study, as this may provide the opportunity to either halt or possibly reverse the progression of disease with immunosuppressive medications. While there has been one report99 of an unsuccessful attempt using high-dose prednisone, CSF Hcrt-1 levels were already undetectable at presentation in this individual, suggesting that the physiological process responsible for his narcolepsy had likely already reached an irreversible stage. More recently, immune modulation using intravenous immunoglobulin has been shown to be temporarily effective in one patient treated very close to disease onset.100 This exciting result suggests that it may be possible to stop the development of narcolepsy in some cases using immunomodulation.

Finally, it would be hoped that hypocretin-based therapies could be devised, and replace the symptomatic treatments currently available. The effects of Hcrt-1 administration on sleep and narcolepsy symptoms have been studied.101,102 Intraventricular administration of Hcrt-1 in wild type rodents and normal canines is strongly wake-promoting.102 This effect is likely mediated in part by the Hcrtr2, the same dose of Hcrt-1 has no effect in Hcrtr2-mutated narcoleptic dogs.103 Problematically however, hypocretin does not cross the blood brain barrier significantly and a centrally penetrable agonist will most likely need to be devised to be effective. It may also be that the field will benefit from current research in the area of stem cell research and transplantation. In type I Diabetes Mellitus, an autoimmune disorder where insulin-producing cells have been destroyed, transplantation of islet cells in the liver can lead to a permanent cure, providing donor cells can be identified. One day it may be possible to transplant hypocretin cells into the CNS, effectively reversing the deficiency of hypocretin. Transplantation studies using fetal hypothalamic cells and hypocretin-deficient rodent models are now being conducted to test the feasibility of this theory.

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Responses

  • bailey
    How to get hypocretin past blood brain barrier?
    8 years ago

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