HLA and T cell receptor associations in narcolepsy, a disorder associated with the selective loss of hypocretin neurons (47.17)

Abstract

Abstract Narcolepsy is a life long disorder characterized by severe sleepiness and cataplexy. It affects 1 in 2,000 individuals and is caused by the selective loss of the hypocretin producing neurons in hypothalamus. This cell loss is likely to be autoimmune and recent findings are closing in on some of the key genetic and environmental effects involved. At the genetic level, the disorder is very tightly associated with DQA1*01:02/DQB1*06:02. In addition to the established role of HLA-DQ, a specific T Cell Receptor Alpha J segment polymorphism has been identified as another susceptibility factor. We are currently sequencing the T-cell TCR@ repertoire to explore this further in recent onset narcolepsy cases. At the level of environmental triggers, winter related upper airway infections are believed to be involved, e.g. we have reported an increased presence of antistreptolysin-O antibody, implicating a role for streptococcal infections. In China, studies of disease onset seasonality indicate a 16 fold increase in onset occurrence around spring when compared to early winter. We anticipate that the cause of narcolepsy will likely involve a specific antigen presentation by DQA1*01:02/DQB1*06:02 to a restricted number of pathogenic T-cell subtypes. As immune involvement is increasingly being recognized in neurodegenerative and neuropsychiatric disorders, understanding why the hypocretin neurons in narcolepsy die is likely to increase understanding of these other disorders as well.