Identifying Potential Molecular Mimics of Orexin Peptides and Receptors in Support of a T cell- Mediated Autoimmune Basis for Narcolepsy Type 1

Abstract

Narcolepsy is a neurological sleep disorder with a biological basis that is characterized by excessive daytime sleepiness (EDS), cataplexy (type 1 only), hypnagogic hallucinations, and abnormal sleep cycles. Narcolepsy type 1 (NT1) is caused by the selective destruction of orexin(hypocretin)-producing neurons in the lateral hypothalamus. Orexin in a neurotransmitter that is essential for maintaining arousal, wakefulness, and appetite. The mechanism of targeted neuronal cell death is unknown, but the literature has created a hypothesis of T cell-mediated autoimmunity caused by molecular mimicry. The genetic predispositions of the MHC class II molecule (DQ0602), T cell receptor D (TCRD), and others are not a sufficient cause but combination with an environmental trigger (Influenza A, Streptococcus pyogenes, Pandemrix 2009 H1N1 Vaccine) could mediate the attack. This thesis focuses on finding amino acid sequence homology between orexin, its receptors, and infectious pathogens of humans using blastp to begin to identify peptides with mimicry to host peptides and potential to be presented by MHC class II on antigen presenting cells for TCR targeting. The results show peptide mimicry with many protein epitopes from Influenza A and B, Streptococcus pyogenes, and many bacterial species. This experiment is the first step in identify peptides with sequence homology for further characterization to find structural homology and mimicry.