Abstract |
Type 1 narcolepsy (T1N) is caused by hypocretin/ orexin (HCRT) neuronal loss. Association with the HLA DQB1*06:02/DQA1*01:02 (98% vs. 25%) heterodimer (DQ0602), T cell receptors (TCR) and other immune loci suggest autoimmunity but autoantigens are unknown. Onset is seasonal and associated with influenza A, notably pandemic 2009 H1N1 (pH1N1) infection and vaccination ( Pandemrix). Peptides derived from HCRT and influenza A, including pH1N1, were screened for DQ0602 binding and presence of cognate DQ0602 tetramer- peptide-specific CD4+ T cells tested in 35 T1N cases and 22 DQ0602 controls. Higher reactivity to influenza pHA273-287 (pH1N1 specific), PR8 (H1N1 pre-2009 and H2N2)-specific NP17-31 and C-amidated but not native version of HCRT54-66 and HCRT86-97 (HCRTNH2) were observed in T1N. Single-cell TCR sequencing revealed sharing of CDR3β TRBV4-2-CASSQETQGRNYGYTF in HCRTNH2 and pHA273-287-tetramers, suggesting molecular mimicry. This public CDR3β uses TRBV4-2, a segment modulated by T1N-associated SNP rs1008599, suggesting causality. TCR-α/β CDR3 motifs of HCRT54-66-NH2 and HCRT86-97-NH2 tetramers were extensively shared: notably public CDR3α, TRAV2-CAVETDSWGKLQF-TRAJ24, that uses TRAJ24, a chain modulated by T1N-associated SNPs rs1154155 and rs1483979. TCR-α/β CDR3 sequences found in pHA273-287, NP17-31, and HCRTNH2 tetramer-positive CD4+ cells were also retrieved in single INF-γ-secreting CD4+ sorted cells stimulated with Pandemrix, independently confirming these results. Our results provide evidence for autoimmunity and molecular mimicry with flu antigens modulated by genetic components in the pathophysiology of T1N.
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Authors | Guo Luo, Aditya Ambati, Ling Lin, Mélodie Bonvalet, Markku Partinen, Xuhuai Ji, Holden Terry Maecker, Emmanuel Jean-Marie Mignot |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 115
Issue 52
Pg. E12323-E12332
(12 26 2018)
ISSN: 1091-6490 [Electronic] United States |
PMID | 30541895
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2018 the Author(s). Published by PNAS. |
Chemical References |
- Autoantigens
- Epitopes
- HCRT protein, human
- HLA-DQ beta-Chains
- HLA-DQB1 antigen
- Hemagglutinins
- Intracellular Signaling Peptides and Proteins
- Orexins
- Peptides
- Receptors, Antigen, T-Cell
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Topics |
- Adolescent
- Adult
- Autoantigens
(metabolism)
- Autoimmunity
(immunology)
- CD4-Positive T-Lymphocytes
(immunology)
- Child
- Epitopes
(immunology)
- Female
- HLA-DQ beta-Chains
- Hemagglutinins
- Humans
- Influenza A Virus, H1N1 Subtype
(immunology)
- Influenza A virus
(immunology, pathogenicity)
- Influenza, Human
(immunology)
- Intracellular Signaling Peptides and Proteins
(genetics)
- Male
- Middle Aged
- Molecular Mimicry
(immunology)
- Narcolepsy
(immunology)
- Orexins
(genetics, immunology, metabolism)
- Peptides
(genetics)
- Receptors, Antigen, T-Cell
(genetics)
- Vaccination
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