CD4+ T-Cell Reactivity to Orexin/Hypocretin in Patients With Narcolepsy Type 1

Introduction: Narcolepsy type 1 is accompanied by a selective loss of orexin/hypocretin (hcrt) neurons in the lateral hypothalamus caused by yet unknown mechanisms. Epidemiologic and genetic associations strongly suggest an immune-mediated pathogenesis of the disease. Methods: We compared specific T-cell reactivity to orexin/hcrt peptides in peripheral blood mononuclear cells of narcolepsy type 1 patients to healthy controls by a carboxyfluorescein succinimidyl ester proliferation assay. Orexin/hcrt-specific T-cell reactivity was also determined by cytokine (interferon gamma and granulocyte- macrophage colony-stimulating factor) analysis. Individuals were considered as responders if the cell division index of CD3(+)CD4(+) T cells and both stimulation indices of cytokine secretion exceeded the cutoff 3. Additionally, T-cell reactivity to orexin/hcrt had to be confirmed by showing reactivity to single peptides present in different peptide pools. Results: Using these criteria, 3/15 patients (20%) and 0/13 controls (0%) showed orexin/hcrt-specific CD4(+) T-cell proliferation (p=.2262). The heterogeneous reactivity pattern did not allow the identification of a preferential target epitope. Conclusions: A significant role of orexin/hcrt-specific T cells in narcolepsy type 1 patients could not be confirmed in this study. Further studies are needed to assess the exact role of CD4(+) T cells and possible target antigens in narcolepsy type 1 patients.