Increased Immune Complexes of Hypocretin Autoantibodies in Narcolepsy

Aude Deloumeau,Quentin Coquerel,Yves Dauvilliers,Sergueï O Fetissov,Sophie Bayard,Christine Bole-Feysot,Valérie Cochen De Cock,Bertrand Carlander,Pierre Déchelotte,Mel B Feany

doi:10.1371/journal.pone.0013320

Aude Deloumeau, Quentin Coquerel + Show 8 more

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https://doi.org/10.1371/journal.pone.0013320

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Abstract

BackgroundHypocretin peptides participate in the regulation of sleep-wake cycle while deficiency in hypocretin signaling and loss of hypocretin neurons are causative for narcolepsy-cataplexy. However, the mechanism responsible for alteration of the hypocretin system in narcolepsy-cataplexy and its relevance to other central hypersomnias remain unknown. Here we studied whether central hypersomnias can be associated with autoantibodies reacting with hypocretin-1 peptide present as immune complexes.MethodologySerum levels of free and dissociated (total) autoantibodies reacting with hypocretin-1 peptide were measured by enzyme-linked immunosorbent assay and analyzed with regard to clinical parameters in 82 subjects with narcolepsy-cataplexy, narcolepsy without cataplexy or idiopathic hypersomnia and were compared to 25 healthy controls.Principal FindingsSerum levels of total but not free IgG autoantibodies against hypocretin-1 were increased in narcolepsy-cataplexy. Increased levels of complexed IgG autoantibodies against hypocretin-1 were found in all patients groups with a further increase in narcolepsy-cataplexy. Levels of total IgM hypocretin-1 autoantibodies were also elevated in all groups of patients. Increased levels of anti-idiotypic IgM autoantibodies reacting with hypocretin-1 IgG autoantibodies affinity purified from sera of subjects with narcolepsy-cataplexy were found in all three groups of patients. Disease duration correlated negatively with serum levels of hypocretin-1 IgG and IgM autoantibodies and with anti-idiotypic IgM autoantibodies.ConclusionCentral hypersomnias and particularly narcolepsy-cataplexy are characterized by higher serum levels of autoantibodies directed against hypocretin-1 which are present as immune complexes most likely with anti-idiotypic autoantibodies suggesting their relevance to the mechanism of sleep-wake cycle regulation.

Highlights

Hypocretin-1 and hypocretin-2 are two neuropeptides produced by the same precursor molecule and synthesized in neurons of the lateral hypothalamus [1,2]
Central hypersomnias and narcolepsy-cataplexy are characterized by higher serum levels of autoantibodies directed against hypocretin-1 which are present as immune complexes most likely with anti-idiotypic autoantibodies suggesting their relevance to the mechanism of sleep-wake cycle regulation
Further evidence has accumulated supporting the causal role of hypocretin deficiency in the origin of narcolepsy with cataplexy (NC) [8], participation of hypocretin signaling in other forms of central hypersomnia including narcolepsy without cataplexy (NWC) or idiopathic hypersomnia (HI) is less understood, a partial hypocretin deficiency is possible in the former condition [9,10]

Summary

Introduction

Hypocretin-1 (orexin A) and hypocretin-2 (orexin B) are two neuropeptides produced by the same precursor molecule and synthesized in neurons of the lateral hypothalamus [1,2]. Narcolepsy with cataplexy (NC) is characterised by selective loss of hypocretin neurons in the brain with low levels of hypocretin in the cerebro-spinal fluid (CSF) [5,6,7]. Selective loss or reduction of hypocretin neurons in NC together with the tight association with HLA DQB1*0602, the recent finding of polymorphisms in the T-cell receptor alpha locus and the presence of elevated Tribbles homolog 2 antibody levels suggest a possible autoimmune mechanism which so far remains elusive [11,12,13]. Hypocretin peptides participate in the regulation of sleep-wake cycle while deficiency in hypocretin signaling and loss of hypocretin neurons are causative for narcolepsy-cataplexy. The mechanism responsible for alteration of the hypocretin system in narcolepsy-cataplexy and its relevance to other central hypersomnias remain unknown. We studied whether central hypersomnias can be associated with autoantibodies reacting with hypocretin-1 peptide present as immune complexes

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