In Vitro Treg Immunosuppression Assay of GITR Proteins Could Elucidate the Autoimmune-mediated Mechanism Underlying Type 1 Narcolepsy

Abstract

Abstract: Type 1 narcolepsy is a hypersomnia sleep disorder characterized by excessive daytime sleep and shallow NREM nighttime sleep. Deficiency of hypocretin-1 secreting neurons in the lateral hypothalamus is the primary cause of the disorder and studies demonstrated that these neurons were solely diminished in a brain region of remarkable heterogeneous neuronal population. Specific destruction of targeted neurons could be achieved via antigen presentation to immune cells, a characteristic of cell-mediated response in the adaptive immune system. Given that hypocretin-1 neurons were exclusively targeted, this cultivated significant interest in searching for an autoimmune-mediated mechanism but studies currently lack adequate knowledge and consistent results. In this research proposal, it is hypothesized that enhanced glucocorticoid-induced TNFR-related (GITR) protein expression in T regulatory (Treg) cells results in defective suppression capacity of CD4+CD25+ T helper cells and defective self-tolerance thereby promoting destruction of hypocretin-1 secreting-neurons in the lateral hypothalamus of narcoleptics. The proposal devises a correlational study to measure cerebrospinal fluid (CSF) hypocretin-1 levels that were inversely proportional to GITR expression levels in Treg cells to assess the autoimmune nature of the disorder. This study is aimed at investigating how defective T regulatory cells respond in type 1 narcolepsy patients via CSF hypocretin-1 measurement and in vitro human T regulatory cell suppression assay.