Recent advances in the identification of susceptibility genes and environmental exposures provide broad support for a post-infectious autoimmune basis for narcolepsy/hypocretin (orexin) deficiency. We genotyped loci associated with other autoimmune and inflammatory diseases in 1,886 individuals with hypocretin-deficient narcolepsy and 10,421 controls, all of European ancestry, using a custom genotyping array (ImmunoChip). Three loci located outside the Human Leukocyte Antigen (HLA) region on chromosome 6 were significantly associated with disease risk. In addition to a strong signal in the T cell receptor alpha (TRA@), variants in two additional narcolepsy loci, Cathepsin H ( CTSH ) and Tumor necrosis factor (ligand) superfamily member 4 ( TNFSF4 , also called OX40L ), attained genome-wide significance. These findings underline the importance of antigen presentation by HLA Class II to T cells in the pathophysiology of this autoimmune disease. Author Summary While there is now broad consensus that narcolepsy-hypocretin deficiency results from a highly specific autoimmune attack on hypocretin cells, little is understood regarding the initiation and progression of the underlying autoimmune process. We have taken advantage of a unique high-density genotyping platform (the ImmunoChip) designed to study variants in genes known to be important to autoimmune and inflammatory diseases. Our study of nearly 2000 narcolepsy cases compared to 10,000 controls underscored important roles for HLA DQB1*06:02 and the T cell receptor alpha genes and implicated two additional genes, Cathepsin H and TNFSF4/OX40L , in disease pathogenesis. These findings are particularly important, as these encoded proteins have key roles in antigen processing, presentation, and T cell response, and they suggest that specific interactions at the immunological synapse constitute the pathway to the disease. Further studies of these genes and encoded proteins may therefore reveal the mechanism leading to this highly selective and unique autoimmune disease.
【초록키워드】 Inflammatory diseases, T cells, susceptibility, Human, variant, human leukocyte antigen, progression, variants, Autoimmune disease, Gene, T cell, tumor necrosis factor, pathophysiology, environmental exposure, Control, pathway, Alpha, Autoimmune, HLA, Antigen presentation, T cell receptor, genotyping, mechanism, T cell response, Ligand, Interaction, HLA class II, in addition to, tumor necrosis, leukocyte, Support, deficiency, disease pathogenesis, Consensus, Narcolepsy, chromosome, chromosome 6, autoimmune attack, Author, individual, class, antigen processing, loci, selective, disease risk, inflammatory disease, genome-wide significance, autoimmune and inflammatory diseases, Cathepsin H, CTSH, encoded proteins, HLA DQB1*06:02, hypocretin cells, ImmunoChip, immunological synapse, narcolepsy-hypocretin deficiency, OX40L, post-infectious autoimmune, TNFSF4, TNFSF4/OX40L, while, Genes, presentation, recent, European, controls, compared, significantly, addition, the disease, unique, genotyped, implicated, study variant, encoded protein, high-density genotyping platform, 【제목키워드】 T cells,