Abstract
Researchers have hypothesized that narcolepsy type 1 (NT1) is caused by an autoimmune process since the 1990s, when narcolepsy was first found to be associated with the human leukocyte antigen (HLA) DQB1*06:02/DQA1*01:02 (DQ0602). In 2000, NT1 was discovered to be due to the selective loss of the hypocretin (HCRT, also known as orexin)-producing neurons in the hypothalamus [1–3]; and in 2010, Pandemrix, an H1N1 flu vaccine used in northern Europe, triggered numerous new cases of narcolepsy, further supporting an autoimmune trigger [4].
In the last year, several groups have established that people with NT1 have autoreactive T cells targeting the prepro-hypocretin peptides [5–8]. In addition, T cells expressing specific T-cell receptor alpha (TCRα) J24 gene segments cross-react with the C-terminal ends of HCRT-1 and HCRT-2 when presented by DQ0602 [6, 7, 9]; specifically, NT1 is associated with an F to L polymorphism in the CDR3 region of J24 [6]. Considered together, these findings suggest that hypocretin neurons are directly injured by these T cells, resulting in NT1, and that medications that inhibit migration of T cells into the brain could halt the destruction of the hypocretin neurons.
Given these new discoveries, we treated a young woman soon after NT1 onset with natalizumab (Tysabri), a drug that inhibits T cells and other leukocytes from crossing the blood-brain barrier, and then tracked her clinical symptoms and cerebrospinal fluid (CSF) hypocretin over time.