tetano
Editor, Senior Moderator
[h=1]Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy[/h] Guo Luo, Aditya Ambati, Ling Lin, M?lodie Bonvalet, Markku Partinen, Xuhuai Ji, Holden Terry Maecker, and Emmanuel Jean-Marie Mignot
PNAS December 26, 2018 115 (52) E12323-E12332; published ahead of print December 12, 2018 https://doi.org/10.1073/pnas.1818150116
[h=2]Significance[/h] This work shows that the amidated terminal ends of the secreted hypocretin (HCRT) peptides (HCRT[SUB]NH2[/SUB]) 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 HCRT[SUB]NH2[/SUB] 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.
[h=2]Abstract[/h] 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[SUP]+[/SUP] T cells tested in 35 T1N cases and 22 DQ0602 controls. Higher reactivity to influenza pHA[SUB]273?287[/SUB] (pH1N1 specific), PR8 (H1N1 pre-2009 and H2N2)-specific NP[SUB]17?31[/SUB] and C-amidated but not native version of HCRT[SUB]54?66[/SUB] and HCRT[SUB]86?97[/SUB] (HCRT[SUB]NH2[/SUB]) were observed in T1N. Single-cell TCR sequencing revealed sharing of CDR3β TRBV4-2-CASSQETQGRNYGYTF in HCRT[SUB]NH2[/SUB] and pHA[SUB]273?287[/SUB]-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 HCRT[SUB]54?66-NH2[/SUB] and HCRT[SUB]86?97-NH2[/SUB] 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 pHA[SUB]273?287[/SUB], NP[SUB]17?31[/SUB], and HCRT[SUB]NH2[/SUB] tetramer-positive CD4[SUP]+[/SUP] cells were also retrieved in single INF-γ?secreting CD4[SUP]+[/SUP] 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.
full article
https://www.pnas.org/content/115/52/E12323
PNAS December 26, 2018 115 (52) E12323-E12332; published ahead of print December 12, 2018 https://doi.org/10.1073/pnas.1818150116
- Contributed by Emmanuel Jean-Marie Mignot, November 17, 2018 (sent for review October 25, 2018; reviewed by Roland S. Liblau and Joseph S. Takahashi)
[h=2]Significance[/h] This work shows that the amidated terminal ends of the secreted hypocretin (HCRT) peptides (HCRT[SUB]NH2[/SUB]) 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 HCRT[SUB]NH2[/SUB] 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.
[h=2]Abstract[/h] 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[SUP]+[/SUP] T cells tested in 35 T1N cases and 22 DQ0602 controls. Higher reactivity to influenza pHA[SUB]273?287[/SUB] (pH1N1 specific), PR8 (H1N1 pre-2009 and H2N2)-specific NP[SUB]17?31[/SUB] and C-amidated but not native version of HCRT[SUB]54?66[/SUB] and HCRT[SUB]86?97[/SUB] (HCRT[SUB]NH2[/SUB]) were observed in T1N. Single-cell TCR sequencing revealed sharing of CDR3β TRBV4-2-CASSQETQGRNYGYTF in HCRT[SUB]NH2[/SUB] and pHA[SUB]273?287[/SUB]-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 HCRT[SUB]54?66-NH2[/SUB] and HCRT[SUB]86?97-NH2[/SUB] 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 pHA[SUB]273?287[/SUB], NP[SUB]17?31[/SUB], and HCRT[SUB]NH2[/SUB] tetramer-positive CD4[SUP]+[/SUP] cells were also retrieved in single INF-γ?secreting CD4[SUP]+[/SUP] 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.
full article
https://www.pnas.org/content/115/52/E12323