Elevated Tribbles homolog 2–specific antibody levels in narcolepsy patients
Vesna Cvetkovic-Lopes, Laurence Bayer, Stéphane Dorsaz, Stéphanie Maret, Sylvain Pradervand, Yves Dauvilliers, Michel Lecendreux, Gert-Jan Lammers, Claire E.H.M. Donjacour, Renaud A. Du Pasquier, Corinne Pfister, Brice Petit, Hyun Hor, Michel Mühlethaler, Mehdi Tafti
Vesna Cvetkovic-Lopes, Laurence Bayer, Stéphane Dorsaz, Stéphanie Maret, Sylvain Pradervand, Yves Dauvilliers, Michel Lecendreux, Gert-Jan Lammers, Claire E.H.M. Donjacour, Renaud A. Du Pasquier, Corinne Pfister, Brice Petit, Hyun Hor, Michel Mühlethaler, Mehdi Tafti
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Research Article Autoimmunity

Elevated Tribbles homolog 2–specific antibody levels in narcolepsy patients

Abstract

Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and attacks of muscle atonia triggered by strong emotions (cataplexy). Narcolepsy is caused by hypocretin (orexin) deficiency, paralleled by a dramatic loss in hypothalamic hypocretin-producing neurons. It is believed that narcolepsy is an autoimmune disorder, although definitive proof of this, such as the presence of autoantibodies, is still lacking. We engineered a transgenic mouse model to identify peptides enriched within hypocretin-producing neurons that could serve as potential autoimmune targets. Initial analysis indicated that the transcript encoding Tribbles homolog 2 (Trib2), previously identified as an autoantigen in autoimmune uveitis, was enriched in hypocretin neurons in these mice. ELISA analysis showed that sera from narcolepsy patients with cataplexy had higher Trib2-specific antibody titers compared with either normal controls or patients with idiopathic hypersomnia, multiple sclerosis, or other inflammatory neurological disorders. Trib2-specific antibody titers were highest early after narcolepsy onset, sharply decreased within 2–3 years, and then stabilized at levels substantially higher than that of controls for up to 30 years. High Trib2-specific antibody titers correlated with the severity of cataplexy. Serum of a patient showed specific immunoreactivity with over 86% of hypocretin neurons in the mouse hypothalamus. Thus, we have identified reactive autoantibodies in human narcolepsy, providing evidence that narcolepsy is an autoimmune disorder.

Authors

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

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Figure 3

Double immunohistochemistry with hypocretin antibody and a high Trib2-specific antibody-containing serum of a narcolepsy with cataplexy patient.

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Double immunohistochemistry with hypocretin antibody and a high Trib2-sp...
(A) Coronal section through the mouse hypothalamus, stained with anti-hypocretin antibody. (B) The same section stained with the patient’s serum. (C) Merged hypocretin-serum staining showing that the vast majority of hypocretin-positive neurons are costained by the patient’s serum. (D–F) Higher magnification views of the dashed regions in A–C confirm the double labeling of hypocretin neurons. Overall, 87% of hypocretin neurons are costained by the serum. (G) Another mouse hypothalamic section stained with anti-hypocretin antibody. (H) Immunoreactivity with the same patient’s serum as in B but after preabsorption of Trib2-specific antibodies with excess Trib2 peptide. (I) Merged image showing that the vast majority of hypocretin neurons are only stained with hypocretin antibody. Only 8% of hypocretin neurons are double labeled. (J–L) Higher magnification views of the dashed regions in G–I confirm that serum depletion of Trib2-specific antibodies results in the absence of double staining. Scale bar: 20 μm.