ImmunoChip Study Implicates Antigen Presentation to T Cells in Narcolepsy

Juliette Faraco,Francesca Poli,David Kemlink,Vincent Damotte,Sirous Javidi,Emmanuel Mignot,Birgitte Rahbek Kornum,Eimear E Kenny,Poul Jennum,Sebastiaan Overeem,Michel Lecendreux,Susan D Thompson,Gosia Trynka,Rosa Peraita-Adrados,Joachim Hallmayer,Laura Ehrmann,Yves Dauvilliers,Birgit Högl,Christian Gieger,Peter Geisler,Norman Klopp,Giuseppe Plazzi,Geert Mayer,Panos Deloukas,Claudio Bassetti,Mali Einen,Cisca Wijmenga,Birgit Frauscher,Gert Jan Lammers,Juliane Winkelmann,Bertrand Fontaine,Peter Lichtner,Patrick Concannon,Fabio Pizza,Patrice Bourgin,Isabelle Arnulf,Jacques Montplaisir,Stephen S Rich,Tom Rico ,Maxime Bréban ,Suna Önengüt-Gümüşcü ,Alex Désautels ,Gang Li ,Guy A Rouleau ,Soňa Nevšímalová ,Karel Šonka ,Álex Iranzo ,Wei Min Chen

doi:10.1371/journal.pgen.1003270

Abstract

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.

Highlights

Narcolepsy is a life-long sleep disorder caused by the autoimmune-mediated loss of 70,000–90,000 hypocretin-producing neurons in the hypothalamus
The condition is almost completely associated with Human Human Leukocyte Antigen (HLA) DQ0602, a heterodimeric protein encoded by the DQA1*01:02-DQB1*06:02 haplotype (90% versus 25% frequency in European ancestry cases and controls, respectively)
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

Summary

Introduction

Narcolepsy is a life-long sleep disorder caused by the autoimmune-mediated loss of 70,000–90,000 hypocretin (orexin)-producing neurons in the hypothalamus. The condition is almost completely associated with Human HLA DQ0602, a heterodimeric protein encoded by the DQA1*01:02-DQB1*06:02 haplotype (90% versus 25% frequency in European ancestry cases and controls, respectively).

Results

Conclusion