While nearly all narcoleptic patients express DQB1*0602, expression of DQB1*0602 is not limited to narcoleptic individuals between 12% and 38% of the general population are carries of this allele. In contrast, the closely related DQB1*0601 allele, which differs at only nine residues, protects against developing narcolepsy, suggesting that peptide-binding differences between these two alleles determine whether they predispose to or protect against narcolepsy. The significant association with DQB1*0602 strongly suggest an interaction between a specific T cell receptors subtype leading to the destruction of hypocretin-producing neurons. An autoimmune basis for the hypocretin cell loss in narcolepsy has long been suspected due to its strong genetic association with selected HLA alleles. HLA encodes multiple subtypes of HLA class I and II proteins that present foreign peptides to T cells during infections, thereby triggering immune responses via T cell receptors activation. In autoimmunity, self-peptides are believed to be mistakenly perceived as foreign, thus leading to tissue destruction, which often occurs in context of specific HLA alleles.
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