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Study Supports Role of Autoimmunity in Narcolepsy

An immune system gene has been strongly associated with a form of narcolepsy, lending strength to the long-held belief that this sleep disorder is an autoimmune disease. The researchers suggest that this finding could have implications not just for narcolepsy, but for a wide range of autoimmune diseases. The gene is TCRA (T-cell receptor alpha), which codes for a receptor protein on T-cells. Narcolepsy is a disorder that causes disabling daytime sleepiness, irresistible bouts of sleep that can strike at any time, and disturbed sleep at night. This new study focused on a special form of the disease called narcolepsy with cataplexy, which is a sudden loss of muscle tone that can cause a person to collapse, with or without falling asleep. Approximately 1 in 2,000 people in the United States have narcolepsy-cataplexy. The symptoms of this disease have been shown to result from the death of a small group of brain cells that normally regulate the sleep-wake cycle by releasing hormone chemicals called hypocretins. Previous work had shown that almost everyone with narcolepsy-cataplexy has the same variant (HLA-DQB*0602) of a major histocompatibility gene. Because of HLA’s prominent role in immunity, it was hypothesized that narcolepsy-cataplexy might be caused by an autoimmune attack on the hypocretin-producing cells in the brain. The new study lends credence to this theory by implicating an immune system gene (TCRA). In a genome-wide scan of approximately 4,000 individuals with the HLA variant, about half of whom had narcolepsy-cataplexy, the researchers showed that those with narcolepsy-cataplexy were much more likely to have unique variants of the TRCA gene. The results indicated that in those with the HLA variant, presence of a TCRA variant increased the risk of narcolepsy-cataplexy by about 20-fold. This research could lead to new approaches to prevention and treatment of narcolepsy-cataplexy. “If we can define the changes in the T-cell receptor associated with narcolepsy-cataplexy, we might be able to develop drugs that block the protein's abnormal activity and prevent the onset of the disorder,” said Dr. Emmanuel Mignot, senior author of the study and director of the Center for Narcolepsy at the Stanford University School of Medicine. The findings might also lead to a better understanding of more common autoimmune disorders such as multiple sclerosis and juvenile diabetes. The scientists report that this is the first documented genetic involvement of the TRCA locus, encoding the major receptor for HLA-peptide presentation to T-cells, in any disease. It is still unclear how specific HLA alleles confer susceptibility to over 100 HLA-associated disorders; thus, narcolepsy may provide new insights on how HLA–TCR interactions contribute to organ-specific autoimmune targeting and may serve as a model for over 100 other HLA-associated disorders. “We’re now getting the main pieces of what’s happening in narcolepsy,” said Dr. Mignot. “What’s most satisfying to me is that we’re bringing this story to a close and that we can use narcolepsy as a model for other diseases.” The image shows the T-cell receptor complex (including the TCRA protein), together with the CD4 co-receptor at the far right. This study was published in the May 3 online edition of Nature Genetics. [NIH release] [Stanford release] [Nature Genetics abstract]