Elevated Tribbles homolog 2–specific antibody levels in narcolepsy patients

Cvetkovic-Lopes, Vesna; Bayer, Laurence; Dorsaz, Stéphane; Maret, Stéphanie; Pradervand, Sylvain; Dauvilliers, Yves; Lecendreux, Michel; Lammers, Gert Jan; Donjacour, Claire E H M; Pasquier, Renaud Du; Pfister, Corinne; Petit, Brice; Hor, Hyun; Mühlethaler, Michel; Tafti, Mehdi

doi:10.1172/jci41366

Cited by 278 publications

(193 citation statements)

References 29 publications

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“…Antibodies directed against several intracellular or membrane-bound neuronal autoantigens have been detected in the serum of narcolepsy patients (9)(10)(11). In particular, a recent study reported that 85% of Finnish T1N patients carrying the HLA-DQB1*06:02 allele and vaccinated with Pandemrix presented antibodies against the orexin receptor type 2.…”

Section: Discussionmentioning

confidence: 99%

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

Bernard‐Valnet

Yshii

Quériault

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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111

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Narcolepsy with cataplexy is a rare and severe sleep disorder caused by the destruction of orexinergic neurons in the lateral hypothalamus. The genetic and environmental factors associated with narcolepsy, together with serologic data, collectively point to an autoimmune origin. The current animal models of narcolepsy, based on either disruption of the orexinergic neurotransmission or neurons, do not allow study of the potential autoimmune etiology. Here, we sought to generate a mouse model that allows deciphering of the immune mechanisms leading to orexin + neuron loss and narcolepsy development. We generated mice expressing the hemagglutinin (HA) as a "neo-self-antigen" specifically in hypothalamic orexin + neurons (called Orex-HA), which were transferred with effector neo-self-antigen-specific T cells to assess whether an autoimmune process could be at play in narcolepsy. Given the tight association of narcolepsy with the human leukocyte antigen (HLA) HLA-DQB1*06:02 allele, we first tested the pathogenic contribution of CD4 Th1 cells. Although these T cells readily infiltrated the hypothalamus and triggered local inflammation, they did not elicit the loss of orexin + neurons or clinical manifestations of narcolepsy. In contrast, the transfer of cytotoxic CD8 T cells (CTLs) led to both T-cell infiltration and specific destruction of orexin + neurons. This phenotype was further aggravated upon repeated injections of CTLs. In situ, CTLs interacted directly with MHC class I-expressing orexin + neurons, resulting in cytolytic granule polarization toward neurons. Finally, drastic neuronal loss caused manifestations mimicking human narcolepsy, such as cataplexy and sleep attacks. This work demonstrates the potential role of CTLs as final effectors of the immunopathological process in narcolepsy.arcolepsy with cataplexy, referred to as type 1 narcolepsy (T1N), is a rare and chronic neurological disease characterized by excessive daytime sleepiness, sudden loss of muscle tone triggered by emotions (cataplexy), sleep paralysis, hypnagogic hallucinations, and fragmented nocturnal sleep (1). T1N is caused by a defective neurotransmission by the orexin/hypocretin neuropeptide and is associated with a selective and almost complete loss (85-100%) of orexinergic neurons in the hypothalamus (2, 3). The mechanisms leading to this neuronal loss are not yet elucidated, although current evidence points to an autoimmune process. Indeed, T1N is tightly associated with the human leukocyte antigen (HLA) HLA-DQB1*06:02 allele, carried by 98.4% of patients vs. 17.7% of the general European population (4). An independent association with HLA class I alleles was recently revealed in two independent studies (5, 6). Additionally, an association with polymorphisms in the T-cell receptor (TCR) α chain locus was found and replicated (7,8). Moreover, autoantibodies recognizing different antigenic targets expressed in the central nervous system (CNS) have been identified in the serum and cerebrospinal fluid (CSF) of narcoleptic patients (9-11)....

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Section: Discussionmentioning

confidence: 99%

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

Bernard‐Valnet

Yshii

Quériault

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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111

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“…In support of the autoimmune hypothesis underlying narcolepsy, autoantibodies against Tribbles homolog 2 (TRIB2), a protein synthesized in hypocretin neurons, are evident in a proportion of patients with narcolepsy, a finding that has been replicated in three separate studies. [10][11][12] In addition, the surge of cases of narcolepsy following pandemic H1N1 infection and mass vaccination with Pandemrix (GlaxoSmithKline, Brentford, Middlesex, UK) lends further support to an autoimmune etiology, [13][14][15][16] likely due to serum antibodies to H1N1 nucleoprotein in patients with vaccine-associated narcolepsy cross-reacting with the hypocretin receptor 2 (an effect observed following Pandremix, but not Focetria [Novartis, Novartis International AG, Basel, Switzerland] vaccination). 17 However, in the absence of formal identification and detailed understanding of the mechanisms linking autoimmunity with the destruction of hypocretin neurons, no disease-modifying therapies for narcolepsy have yet been developed.…”

mentioning

confidence: 99%

Intravenous Immunoglobulin Therapy in Pediatric Narcolepsy: A Nonrandomized, Open-Label, Controlled, Longitudinal Observational Study

Lecendreux

Berthier

Corny

et al. 2017

Journal of Clinical Sleep Medicine

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Study Objectives: Previous case reports of intravenous immunoglobulins (IVIg) in pediatric narcolepsy have shown contradictory results. Methods: This was a nonrandomized, open-label, controlled, longitudinal observational study of IVIg use in pediatric narcolepsy with retrospective data collection from medical files obtained from a single pediatric national reference center for the treatment of narcolepsy in France. Of 56 consecutively referred patients with narcolepsy, 24 received IVIg (3 infusions administered at 1-mo intervals) in addition to standard care (psychostimulants and/or anticataplectic agents), and 32 continued on standard care alone (controls). Results: For two patients in each group, medical files were unavailable. Of the 22 IVIg patients, all had cerebrospinal fluid (CSF) hypocretin ≤ 110 pg/mL and were HLA-DQB1*06:02 positive. Of the 30 control patients, 29 were HLA-DQB1*06:02 positive and of those with available CSF measurements, all 12 had hypocretin ≤ 110 pg/mL. Compared with control patients, IVIg patients had shorter disease duration, shorter latency to sleep onset, and more had received H1N1 vaccination. Mean (standard deviation) follow-up length was 2.4 (1.1) y in the IVIg group and 3.9 (1.7) y in controls. In multivariate-adjusted linear mixed-effects analyses of change from baseline in Ullanlinna Narcolepsy Scale (UNS) scores, high baseline UNS, but not IVIg treatment, was associated with a reduction in narcolepsy symptoms. On time-to-event analysis, among patients with high baseline UNS scores, control patients achieved a UNS score < 14 (indicating remission) less rapidly than IVIg patients (adjusted hazard ratio 0.18; 95% confidence interval: 95% confidence interval: 0.03, 0.95; p = 0.043). Shorter or longer disease duration did not influence treatment response in any analysis. Conclusions: Overall, narcolepsy symptoms were not significantly reduced by IVIg. However, in patients with high baseline symptoms, a subset of IVIgtreated patients achieved remission more rapidly than control patients. I NTRO DUCTI O NNarcolepsy is a debilitating and currently an incurable neurological condition with a characteristic constellation of symptoms, including excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, hypnagogic hallucinations, and disturbed nocturnal sleep.Until recently, and at the time patients in this study were treated, the disorder was categorized into narcolepsy with cataplexy and narcolepsy without cataplexy according to the revised second edition of the International Classification of Sleep Disorders (ICSD).1 ICSD-2-revised has now been replaced by ICSD-3, which classifies narcolepsy into type 1 and type 2 narcolepsy. 2The majority of patients with type 1 narcolepsy have hypocretin deficiency (cerebrospinal fluid [CSF] hypocretin-1 level ≤ 110 pg/ mL), which is considered to result from an autoimmune-mediated loss of hypocretin-secreting neurons in those who are genetically predisposed (most commonly those with human leucocyte antigen [HLA] DQB1*06:02 haplotype). The...

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“…Recently, Tribbles homolog 2 (Trib2) was reported as a candidate antigen involved in the destruction of orexin neurons (16). Trib2 was shown to be abundantly expressed in orexin neurons, and levels of Trib2-specific antibodies were much higher in patients with narcolepsy, especially shortly after the disease onset, 7 although it is still unknown if Trib2-specific antibodies are directly involved in cell death, or if the antibody production is a consequence of cell damage by other unknown mechanisms (17).…”

Section: Human Narcolepsy and Orexin Deficiencymentioning

confidence: 99%

Orexin deficiency and narcolepsy

Sakurai¹

2013

Current Opinion in Neurobiology

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Orexin deficiency results in the sleep disorder narcolepsy in many mammalian species, including mice, dogs, and humans, suggesting that the orexin system is particularly important for normal regulation of sleep/wakefulness states, and especially for maintenance of wakefulness. This review discusses animal models of narcolepsy; the contribution of each orexin receptor subtype to the narcoleptic phenotypes; and the etiology of orexin neuronal death. It also raises the possibility of novel therapies targeting the orexin system for sleep disorders including insomia and narcolepsycataplexy.

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Elevated Tribbles homolog 2–specific antibody levels in narcolepsy patients

Cited by 278 publications

References 29 publications

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

Intravenous Immunoglobulin Therapy in Pediatric Narcolepsy: A Nonrandomized, Open-Label, Controlled, Longitudinal Observational Study

Orexin deficiency and narcolepsy

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