Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy
| العنوان: | Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy |
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| المؤلفون: | Guo Luo, Markku Partinen, Holden T. Maecker, Mélodie Bonvalet, Aditya Ambati, Emmanuel Mignot, Xuhuai Ji, Ling Lin |
| المساهمون: | Clinicum, Department of Neurosciences, Neurologian yksikkö, University of Helsinki, HUS Neurocenter |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America |
| بيانات النشر: | Proceedings of the National Academy of Sciences, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | CD4-Positive T-Lymphocytes, Male, CD4(+) T-CELLS, 0301 basic medicine, narcolepsy, PANDEMRIX, VARIANTS, medicine.disease_cause, Autoantigens, 3124 Neurology and psychiatry, Autoimmunity, Epitopes, Influenza A Virus, H1N1 Subtype, Immunology and Inflammation, 0302 clinical medicine, HLA-DQ beta-Chains, Pandemrix, Child, NEURONS, Multidisciplinary, HLA-DQB1, Vaccination, autoimmunity, Intracellular Signaling Peptides and Proteins, ASSOCIATION, Middle Aged, Biological Sciences, ABSENCE, 3. Good health, Molecular mimicry, Hemagglutinins, DQ0602, PNAS Plus, Influenza A virus, Female, CATAPLEXY, TCR, Adult, Adolescent, Receptors, Antigen, T-Cell, chemical and pharmacologic phenomena, Biology, 03 medical and health sciences, Immune system, Antigen, Influenza, Human, medicine, Humans, Orexins, tetramer, Molecular Mimicry, T-cell receptor, 3112 Neurosciences, medicine.disease, 030104 developmental biology, ANTIBODIES, ONSET, Immunology, AUTOANTIBODIES, Peptides, 030217 neurology & neurosurgery, Narcolepsy |
| الوصف: | Significance This work shows that the amidated terminal ends of the secreted hypocretin (HCRT) peptides (HCRTNH2) are autoantigens in type 1 narcolepsy, an autoimmune disorder targeting HCRT neurons. The autoimmune process is usually initiated by influenza A flu infections, and a particular piece of the hemagglutinin (HA) flu protein of the pandemic 2009 H1N1 strain was identified as a likely trigger. This HA epitope has homology with HCRTNH2 and T cells cross-reactive to both epitopes are involved in the autoimmune process by molecular mimicry. Genes associated with narcolepsy mark the particular HLA heterodimer (DQ0602) involved in presentation of these antigens and modulate expression of the specific T cell receptor segments (TRAJ24 and TRBV4-2) involved in T cell receptor recognition of these antigens, suggesting causality. 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. |
| تدمد: | 1091-6490 0027-8424 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::da7984b342713f2394ec7252f97e5b3bTest https://doi.org/10.1073/pnas.1818150116Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....da7984b342713f2394ec7252f97e5b3b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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