Narcolepsy-Associated HLA Class I Alleles Implicate Cell-Mediated Cytotoxicity

Tafti, Mehdi; Lammers, Gert J; Dauvilliers, Yves; Overeem, Sebastiaan; Mayer, Geert; Nowak, Jacek; Pfister, Corinne; Dubois, Valérie; Eliaou, Jean-François; Eberhard, Hans-Peter; Liblau, Roland; Wierzbicka, Aleksandra; Geisler, Peter; Bassetti, Claudio L; Mathis, Johannes; Lecendreux, Michel; Khatami, Ramin; Heinzer, Raphaël; Haba-Rubio, José; Feketeova, Eva; ... (2016). Narcolepsy-Associated HLA Class I Alleles Implicate Cell-Mediated Cytotoxicity. Sleep, 39(3), pp. 581-587. American Academy of Sleep Medicine 10.5665/sleep.5532

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OBJECTIVE Narcolepsy with cataplexy is tightly associated with the HLA class II allele DQB1*06:02. Evidence indicates a complex contribution of HLA class II genes to narcolepsy susceptibility with a recent independent association with HLA-DPB1. The cause of narcolepsy is supposed be an autoimmune attack against hypocretin-producing neurons. Despite the strong association with HLA class II, there is no evidence for CD4+ T-cell-mediated mechanism in narcolepsy. Since neurons express class I and not class II molecules, the final effector immune cells involved might include class I-restricted CD8+ T-cells. DESIGN HLA class I (A, B, and C) and II (DQB1) genotypes were analyzed in 944 European narcolepsy with cataplexy patients and in 4043 control subjects matched by country of origin. All patients and controls were DQB1*06:02 positive and class I associations were conditioned on DQB1 alleles. RESULTS HLA-A*11:01 (OR = 1.49 [1.18-1.87] P = 7.0*10-4), C*04:01 (OR = 1.34 [1.10-1.63] P = 3.23*10-3), and B*35:01 (OR=1.46 [1.13-1.89] P = 3.64*10-3) were associated with susceptibility to narcolepsy. Analysis of polymorphic class I amino-acids revealed even stronger associations with key antigen-binding residues HLA-A-Tyr9 (OR = 1.32 [1.15-1.52] P = 6.95*10-5) and HLA-C-Ser11 (OR=1.34 [1.15-1.57] P = 2.43*10-4). CONCLUSIONS Our findings provide a genetic basis for increased susceptibility to infectious factors or an immune cytotoxic mechanism in narcolepsy, potentially targeting hypocretin neurons.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Neurology

UniBE Contributor:

Bassetti, Claudio and Mathis, Johannes

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0161-8105

Publisher:

American Academy of Sleep Medicine

Language:

English

Submitter:

Romina Theiler

Date Deposited:

15 Mar 2016 14:01

Last Modified:

27 Oct 2016 11:07

Publisher DOI:

10.5665/sleep.5532

PubMed ID:

26518595

Uncontrolled Keywords:

CD4; CD8; autoimmunity; cytotoxicity; hypocretin/orexin

BORIS DOI:

10.7892/boris.76941

URI:

https://boris.unibe.ch/id/eprint/76941

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