The Experts below are selected from a list of 315 Experts worldwide ranked by ideXlab platform
Markku Partinen - One of the best experts on this subject based on the ideXlab platform.
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autoimmunity to hypocretin orexin and molecular mimicry to flu in type 1 narcolepsy 4989
Neurology, 2020Co-Authors: Guo Luo, Markku Partinen, Ling Lin, Aditya Ambati, Holden T Maecker, Emmanuel MignotAbstract:Objective: To investigate the pathophysiology of Type 1 Narcolepsy. Background: Type 1 narcolepsy (T1N) is caused by a hypocretin (HCRT, also called orexin) cell loss. Association with DQB1*06:02/DQA1*01:02 (DQ0602, 98% vs. 25%), T cell receptors (TCR) and other loci indicate autoimmunity. Onset is seasonal and associated with influenza-A, notably pandemic 2009H1N1 (pH1N1) infection and the pH1N1 vaccine Pandemrix. The strong HLA association and unique effects in TCRA and TCRB suggest that autoantigen presentation by DQ0602 to CD4+ T cell is crucial. We surveyed CD4+ T cell binding to autoantigens and flu antigens presented by DQ0602 in narcolepsy versus controls, identifying the immunological basis of narcolepsy. Design/Methods: DQ0602 binding was tested for peptides overlapping RFX4, HCRT and flu HA, NA, PB1and NP sequences. Reactivity to ~100 tetramers was tested in 6 narcolepsy and 4 controls after expansion of cells in 10-day cultures. Higher tetramer-peptide specific CD4+ T cells was found with HCRT54–66-NH2, HCRT86–97-NH2 (HCRTNH2), pHA273–287 and NP17–31, further confirmed for HCRTNH2 and pHA273–287 in 77 T1N and 44 DQ0602 controls. Single cell TCR sequencing after FACS sorting was conducted and public TCR clones transfected into Jurkat76 cells to test for activation after peptide presentation by K562-DQ0602 or RM3-DQ0602 cells. Results: Most commonly used public sequences CDR3β-TRBV4-2-CASSQETQGRNYGYTF, CDR3a-TRAV2-CAVETDSWGKLQF-TRAJ24 and TRAV26-1-CIVRSQGGSYIPTF-TRAJ6 were retrieved using both DQ0602-HCRTNH2 and DQ0602-pHA273–287 but not DQ0602-NP17–31 tetramers. Sharing of clones using TRAJ24 and TRBV4-2 was notable as these exact segments (~0.8% of repertoire) are modulated by rs1154155/rs1483979 and rs1008599, polymorphisms associated with T1N. Jurkat cells transfected with some clones were activated by HCRTNH2 and pHA273–287, suggesting molecular mimicry. As a control, NP17–31 involved different TCRs, notably TRAV8-6_TRAJ34 with TRBV7-9_TRBJ2-3 and was only activated by NP17–31. Conclusions: Our results provide strong evidence for autoimmunity and molecular mimicry with flu antigens modulated by genetic components in the pathophysiology of T1N. Disclosure: Dr. Luo has nothing to disclose. Dr. Ambati has nothing to disclose. Dr. Lin has nothing to disclose. Dr. Partinen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Has participated in advisory boards of AOP Orphan, Bioprojet, UCB, and Umecrine. Dr. Partinen has received research support from Has received research support for clinical trials for Bioprojet, Jazz Pharmaceuticals, MSD, and Umecrine. Dr. Ji has nothing to disclose. Dr. Maecker has nothing to disclose. Dr. Mignot has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Dr Mignot has consulted for Novo Nordisk and Reset Pharmaceuticals, and is on the speakers' bureau for Vox Media.. Dr. Mignot has received research support from Dr. Mignot has received research support from Jazz Pharmaceuticals, Merck, and Glaxo Smith Kline (GSK).
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no evidence of autoimmunity to human ox1 or ox2 orexin receptors in Pandemrix vaccinated narcoleptic children
Journal of translational autoimmunity, 2020Co-Authors: Arja Vuorela, Tobias L Freitag, Markku Partinen, Outi Vaarala, Hanna Nohynek, Krister Melen, Pinja Jalkanen, Jyrki P Kukkonen, Seppo MeriAbstract:Narcolepsy type 1, likely an immune-mediated disease, is characterized by excessive daytime sleepiness and cataplexy. The disease is strongly associated with human leukocyte antigen (HLA) DQB1∗06:02. A significant increase in the incidence of childhood and adolescent narcolepsy was observed after a vaccination campaign with AS03-adjuvanted Pandemrix influenza vaccine in Nordic and several other countries in 2010 and 2011. Previously, it has been suggested that a surface-exposed region of influenza A nucleoprotein, a structural component of the Pandemrix vaccine, shares amino acid residues with the first extracellular domain of the human OX2 orexin/hypocretin receptor eliciting the development of autoantibodies. Here, we analyzed, whether H1N1pdm09 infection or Pandemrix vaccination contributed to the development of autoantibodies to the orexin precursor protein or the OX1 or OX2 receptors. The analysis was based on the presence or absence of autoantibody responses against analyzed proteins. Entire OX1 and OX2 receptors or just their extracellular N-termini were transiently expressed in HuH7 cells to determine specific antibody responses in human sera. Based on our immunofluorescence analysis, none of the 56 Pandemrix-vaccinated narcoleptic patients, 28 patients who suffered from a laboratory-confirmed H1N1pdm09 infection or 19 Pandemrix-vaccinated controls showed specific autoantibody responses to prepro-orexin, orexin receptors or the isolated extracellular N-termini of orexin receptors. We also did not find any evidence for cell-mediated immunity against the N-terminal epitopes of OX2. Our findings do not support the hypothesis that the surface-exposed region of the influenza nucleoprotein A would elicit the development of an immune response against orexin receptors.
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autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Guo Luo, Markku Partinen, Ling Lin, Melodie Bonvalet, Aditya Ambati, Holden T Maecker, Emmanuel MignotAbstract: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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autoimmunity to hypocretin and molecular mimicry to flu antigens in type 1 narcolepsy
bioRxiv, 2018Co-Authors: Guo Luo, Markku Partinen, Ling Lin, Melodie Bonvalet, Aditya Ambati, Holden T Maecker, Emmanuel MignotAbstract:Type 1 narcolepsy (T1N) is caused by hypocretin (HCRT) neuronal loss. Association with the Human Leukocyte Antigen (HLA)-DQB1*06:02/DQA1*01:02 (98% vs 25%) heterodimer (DQ0602), T cell receptor (TCR) and other immune loci suggest autoimmunity but autoantigen(s) are unknown. Onset is seasonal and associated with influenza A, notably pandemic 2009 H1N1 (pH1N1). An extensive unbiased DQ0602 binding peptide screen was performed encompassing peptides derived from Pandemrix X-179-A pH1N1 influenza-A vaccine, a known T1N trigger, other H1N1 strains, and potential human autoantigens HCRT and RFX4, identifying 109 binders. The presence of cognate tetramer-peptide specific CD4+ T cells was studied in 35 narcolepsy cases and 22 DQ0602 controls after expansion of antigen-specific cells in Peripheral Blood Monocytes Cell (PBMC) cultures. Higher reactivity to influenza epitopes pHA273-287 (pH1N1 specific) and PR8 (H1N1 pre 2009)-specific NP17-31 were observed in T1N. Extensive reactivity to C-amidated but not native version of HCRT54-66 and HCRT86-97, which are two highly homologous peptides (HCRTNH2), was observed with higher frequencies of specific T cells in T1N. TCRa/b CDR3 sequences found in pHA273-287, NP17-31 and HCRTNH2 tetramer positive CD4+ cells were also retrieved in single INFg-secreting CD4+ sorted cells stimulated with Pandemrix, confirming immunodominance and functional significance in DQ0602-mediated responses and molecular mimicry. TCRa/b CDR3 motifs of HCRT54-66 and HCRT86-97 tetramers were extensively shared. Particularly notable was sharing across subjects of an CDR3a, CAVETDSWGKLQF (in association with various CDR3bs) that used TRAJ24, a chain modulated by Single Nucleotide Polymorphism (SNPs) rs1154155 and rs1483979 associated with T1N. Sharing of CDR3a CASSQETQGRNYGYTF (in association with various CDR3bs) was also observed with HCRTNH2 and pHA273-287-tetramers across subjects. This segment uses TRBV4-2, a segment modulated by narcolepsy-associated SNP rs1008599. Higher HCRTNH2 positive CD4+ T cell numbers in T1N together with sharing of J24 CAVETDSWGKLQF in HCRTNH2 autoimmune responses, indicates causal DQ0602-mediated CD4+ autoreactivity to HCRT in T1N. 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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Narcolepsy Associated with Pandemrix Vaccine.
Current neurology and neuroscience reports, 2018Co-Authors: Tomi Sarkanen, Anniina Alakuijala, Ilkka Julkunen, Markku PartinenAbstract:After the connection between AS03-adjuvanted pandemic H1N1 vaccine Pandemrix and narcolepsy was recognized in 2010, research on narcolepsy has been more intensive than ever before. The purpose of this review is to provide the reader with current concepts and recent findings on the Pandemrix-associated narcolepsy. After the Pandemrix vaccination campaign in 2009–2010, the risk of narcolepsy was increased 5- to 14-fold in children and adolescents and 2- to 7-fold in adults. According to observational studies, the risk of narcolepsy was elevated for 2 years after the Pandemrix vaccination. Some confounding factors and potential diagnostic biases may influence the observed narcolepsy risk in some studies, but it is unlikely that they would explain the clearly increased incidence in all the countries where Pandemrix was used. An increased risk of narcolepsy after natural H1N1 infection was reported from China, where pandemic influenza vaccination was not used. There is more and more evidence that narcolepsy is an autoimmune disease. All Pandemrix-associated narcolepsy cases have been positive for HLA class II DQB1*06:02 and novel predisposing genetic factors directly linking to the immune system have been identified. Even though recent studies have identified autoantibodies against multiple neuronal structures and other host proteins and peptides, no specific autoantigens that would explain the disease mechanism in narcolepsy have been identified thus far. There was a marked increase in the incidence of narcolepsy after Pandemrix vaccination, especially in adolescents, but also in young adults and younger children. All vaccine-related cases were of narcolepsy type 1 characterized by hypocretin deficiency in the central nervous system. The disease phenotype and the severity of symptoms varied considerably in children and adolescents suffering from Pandemrix-associated narcolepsy, but they were indistinguishable from the symptoms of idiopathic narcolepsy. Narcolepsy type 1 is most likely an autoimmune disease, but the mechanisms have remained elusive.
Emmanuel Mignot - One of the best experts on this subject based on the ideXlab platform.
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autoimmunity to hypocretin orexin and molecular mimicry to flu in type 1 narcolepsy 4989
Neurology, 2020Co-Authors: Guo Luo, Markku Partinen, Ling Lin, Aditya Ambati, Holden T Maecker, Emmanuel MignotAbstract:Objective: To investigate the pathophysiology of Type 1 Narcolepsy. Background: Type 1 narcolepsy (T1N) is caused by a hypocretin (HCRT, also called orexin) cell loss. Association with DQB1*06:02/DQA1*01:02 (DQ0602, 98% vs. 25%), T cell receptors (TCR) and other loci indicate autoimmunity. Onset is seasonal and associated with influenza-A, notably pandemic 2009H1N1 (pH1N1) infection and the pH1N1 vaccine Pandemrix. The strong HLA association and unique effects in TCRA and TCRB suggest that autoantigen presentation by DQ0602 to CD4+ T cell is crucial. We surveyed CD4+ T cell binding to autoantigens and flu antigens presented by DQ0602 in narcolepsy versus controls, identifying the immunological basis of narcolepsy. Design/Methods: DQ0602 binding was tested for peptides overlapping RFX4, HCRT and flu HA, NA, PB1and NP sequences. Reactivity to ~100 tetramers was tested in 6 narcolepsy and 4 controls after expansion of cells in 10-day cultures. Higher tetramer-peptide specific CD4+ T cells was found with HCRT54–66-NH2, HCRT86–97-NH2 (HCRTNH2), pHA273–287 and NP17–31, further confirmed for HCRTNH2 and pHA273–287 in 77 T1N and 44 DQ0602 controls. Single cell TCR sequencing after FACS sorting was conducted and public TCR clones transfected into Jurkat76 cells to test for activation after peptide presentation by K562-DQ0602 or RM3-DQ0602 cells. Results: Most commonly used public sequences CDR3β-TRBV4-2-CASSQETQGRNYGYTF, CDR3a-TRAV2-CAVETDSWGKLQF-TRAJ24 and TRAV26-1-CIVRSQGGSYIPTF-TRAJ6 were retrieved using both DQ0602-HCRTNH2 and DQ0602-pHA273–287 but not DQ0602-NP17–31 tetramers. Sharing of clones using TRAJ24 and TRBV4-2 was notable as these exact segments (~0.8% of repertoire) are modulated by rs1154155/rs1483979 and rs1008599, polymorphisms associated with T1N. Jurkat cells transfected with some clones were activated by HCRTNH2 and pHA273–287, suggesting molecular mimicry. As a control, NP17–31 involved different TCRs, notably TRAV8-6_TRAJ34 with TRBV7-9_TRBJ2-3 and was only activated by NP17–31. Conclusions: Our results provide strong evidence for autoimmunity and molecular mimicry with flu antigens modulated by genetic components in the pathophysiology of T1N. Disclosure: Dr. Luo has nothing to disclose. Dr. Ambati has nothing to disclose. Dr. Lin has nothing to disclose. Dr. Partinen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Has participated in advisory boards of AOP Orphan, Bioprojet, UCB, and Umecrine. Dr. Partinen has received research support from Has received research support for clinical trials for Bioprojet, Jazz Pharmaceuticals, MSD, and Umecrine. Dr. Ji has nothing to disclose. Dr. Maecker has nothing to disclose. Dr. Mignot has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Dr Mignot has consulted for Novo Nordisk and Reset Pharmaceuticals, and is on the speakers' bureau for Vox Media.. Dr. Mignot has received research support from Dr. Mignot has received research support from Jazz Pharmaceuticals, Merck, and Glaxo Smith Kline (GSK).
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meeting report narcolepsy and pandemic influenza vaccination what we know and what we need to know before the next pandemic a report from the 2nd iabs meeting
Biologicals, 2019Co-Authors: Kathryn M Edwards, Emmanuel Mignot, Hanna Nohynek, Elizabeth Miller, Germaine Hanquet, Steve Black, Christopher Jankosky, Tom T Shimabukuro, Pieter NeelsAbstract:A group of scientific and public health experts and key stakeholders convened to discuss the state of knowledge on the relationship between adjuvanted monovalent inactivated 2009 influenza A H1N1 vaccines used during the 2009 influenza pandemic and narcolepsy. There was consensus that an increased risk of narcolepsy was consistently observed after Pandemrix (AS03-adjuvanted) vaccine, but similar associations following Arepanrix (AS03-adjuvanted) or Focetria (MF59-adjuvanted) vaccines were not observed. Whether the differences are due to vaccine composition or other factors such as the timing of large-scale vaccination programs relative to H1N1pdm09 wild-type virus circulation in different geographic regions is not clear. The limitations of retrospective observational methodologies could also be contributing to some of the differences across studies. More basic and epidemiologic research is needed to further elucidate the association between adjuvanted influenza vaccine and narcolepsy and its mechanism and to inform planning and preparation for vaccination programs in advance of the next influenza pandemic.
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autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Guo Luo, Markku Partinen, Ling Lin, Melodie Bonvalet, Aditya Ambati, Holden T Maecker, Emmanuel MignotAbstract: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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autoimmunity to hypocretin and molecular mimicry to flu antigens in type 1 narcolepsy
bioRxiv, 2018Co-Authors: Guo Luo, Markku Partinen, Ling Lin, Melodie Bonvalet, Aditya Ambati, Holden T Maecker, Emmanuel MignotAbstract:Type 1 narcolepsy (T1N) is caused by hypocretin (HCRT) neuronal loss. Association with the Human Leukocyte Antigen (HLA)-DQB1*06:02/DQA1*01:02 (98% vs 25%) heterodimer (DQ0602), T cell receptor (TCR) and other immune loci suggest autoimmunity but autoantigen(s) are unknown. Onset is seasonal and associated with influenza A, notably pandemic 2009 H1N1 (pH1N1). An extensive unbiased DQ0602 binding peptide screen was performed encompassing peptides derived from Pandemrix X-179-A pH1N1 influenza-A vaccine, a known T1N trigger, other H1N1 strains, and potential human autoantigens HCRT and RFX4, identifying 109 binders. The presence of cognate tetramer-peptide specific CD4+ T cells was studied in 35 narcolepsy cases and 22 DQ0602 controls after expansion of antigen-specific cells in Peripheral Blood Monocytes Cell (PBMC) cultures. Higher reactivity to influenza epitopes pHA273-287 (pH1N1 specific) and PR8 (H1N1 pre 2009)-specific NP17-31 were observed in T1N. Extensive reactivity to C-amidated but not native version of HCRT54-66 and HCRT86-97, which are two highly homologous peptides (HCRTNH2), was observed with higher frequencies of specific T cells in T1N. TCRa/b CDR3 sequences found in pHA273-287, NP17-31 and HCRTNH2 tetramer positive CD4+ cells were also retrieved in single INFg-secreting CD4+ sorted cells stimulated with Pandemrix, confirming immunodominance and functional significance in DQ0602-mediated responses and molecular mimicry. TCRa/b CDR3 motifs of HCRT54-66 and HCRT86-97 tetramers were extensively shared. Particularly notable was sharing across subjects of an CDR3a, CAVETDSWGKLQF (in association with various CDR3bs) that used TRAJ24, a chain modulated by Single Nucleotide Polymorphism (SNPs) rs1154155 and rs1483979 associated with T1N. Sharing of CDR3a CASSQETQGRNYGYTF (in association with various CDR3bs) was also observed with HCRTNH2 and pHA273-287-tetramers across subjects. This segment uses TRBV4-2, a segment modulated by narcolepsy-associated SNP rs1008599. Higher HCRTNH2 positive CD4+ T cell numbers in T1N together with sharing of J24 CAVETDSWGKLQF in HCRTNH2 autoimmune responses, indicates causal DQ0602-mediated CD4+ autoreactivity to HCRT in T1N. 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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genetics of vaccination related narcolepsy
bioRxiv, 2017Co-Authors: Hanna M Ollila, Emmanuel Mignot, Markku Partinen, C Hublin, Annika Wennerstrom, Janna Saarela, Turkka Kirjavainen, Logan Schneider, Sarileena Himanen, Outi SaarenpaaheikkilaAbstract:Narcolepsy type 1 is a severe hypersomnia affecting 1/3000 individuals. It is caused by a loss of neurons producing hypocretin/orexin in the hypothalamus. In 2009/2010, an immunization campaign directed towards the new pandemic H1N1 Influenza-A strain was launched and increased risk of narcolepsy reported in Northern European countries following vaccination with Pandemrix, an adjuvanted H1N1 vaccine resulting in ~250 vaccination-related cases in Finland alone. Using whole genome sequencing data of 2000 controls, exome sequencing data of 5000 controls and HumanCoreExome chip genotypes of 81 cases with vaccination-related narcolepsy and 2796 controls, we, built a multilocus genetic risk score with established narcolepsy risk variants. We also analyzed, whether novel risk variants would explain vaccine-related narcolepsy. We found that previously discovered risk variants had strong predictive power (accuracy of 73% and P<2.2*10-16; and ROC curve AUC 0.88) in vaccine-related narcolepsy cases with only 4.9% of cases being assigned to the low risk category. Our findings indicate genetic predisposition to vaccine-triggered narcolepsy, with the possibility of identifying 95% of people at risk.
Seppo Meri - One of the best experts on this subject based on the ideXlab platform.
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no evidence of autoimmunity to human ox1 or ox2 orexin receptors in Pandemrix vaccinated narcoleptic children
Journal of translational autoimmunity, 2020Co-Authors: Arja Vuorela, Tobias L Freitag, Markku Partinen, Outi Vaarala, Hanna Nohynek, Krister Melen, Pinja Jalkanen, Jyrki P Kukkonen, Seppo MeriAbstract:Narcolepsy type 1, likely an immune-mediated disease, is characterized by excessive daytime sleepiness and cataplexy. The disease is strongly associated with human leukocyte antigen (HLA) DQB1∗06:02. A significant increase in the incidence of childhood and adolescent narcolepsy was observed after a vaccination campaign with AS03-adjuvanted Pandemrix influenza vaccine in Nordic and several other countries in 2010 and 2011. Previously, it has been suggested that a surface-exposed region of influenza A nucleoprotein, a structural component of the Pandemrix vaccine, shares amino acid residues with the first extracellular domain of the human OX2 orexin/hypocretin receptor eliciting the development of autoantibodies. Here, we analyzed, whether H1N1pdm09 infection or Pandemrix vaccination contributed to the development of autoantibodies to the orexin precursor protein or the OX1 or OX2 receptors. The analysis was based on the presence or absence of autoantibody responses against analyzed proteins. Entire OX1 and OX2 receptors or just their extracellular N-termini were transiently expressed in HuH7 cells to determine specific antibody responses in human sera. Based on our immunofluorescence analysis, none of the 56 Pandemrix-vaccinated narcoleptic patients, 28 patients who suffered from a laboratory-confirmed H1N1pdm09 infection or 19 Pandemrix-vaccinated controls showed specific autoantibody responses to prepro-orexin, orexin receptors or the isolated extracellular N-termini of orexin receptors. We also did not find any evidence for cell-mediated immunity against the N-terminal epitopes of OX2. Our findings do not support the hypothesis that the surface-exposed region of the influenza nucleoprotein A would elicit the development of an immune response against orexin receptors.
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autoantibodies against ganglioside gm3 are associated with narcolepsy cataplexy developing after Pandemrix vaccination against 2009 pandemic h1n1 type influenza virus
Journal of Autoimmunity, 2015Co-Authors: Annahelena Saariaho, Arja Vuorela, Tobias L Freitag, Fabio Pizza, Giuseppe Plazzi, Markku Partinen, Outi Vaarala, Seppo MeriAbstract:Abstract Following the mass vaccinations against pandemic influenza A/H1N1 virus in 2009, a sudden increase in juvenile onset narcolepsy with cataplexy (NC) was detected in several European countries where AS03-adjuvanted Pandemrix vaccine had been used. NC is a chronic neurological disorder characterized by excessive daytime sleepiness and cataplexy. In human NC, the hypocretin-producing neurons in the hypothalamus or the hypocretin signaling pathway are destroyed by an autoimmune reaction. Both genetic (e.g. HLA-DQB1*0602) and environmental risk factors (e.g. Pandemrix) contribute to the disease development, but the underlying and the mediating immunological mechanisms are largely unknown. Influenza virus hemagglutinin is known to bind gangliosides, which serve as host cell virus receptors. Anti-ganglioside antibodies have previously been linked to various neurological disorders, like the Guillain-Barre syndrome which may develop after infection or vaccination. Because of these links we screened sera of NC patients and controls for IgG anti-ganglioside antibodies against 11 human brain gangliosides (GM1, GM2, GM3, GM4, GD1a, GD1b, GD2, GD3, GT1a, GT1b, GQ1b) and a sulfatide by using a line blot assay. Samples from 173 children and adolescents were analyzed: 48 with Pandemrix-associated NC, 20 with NC without Pandemrix association, 57 Pandemrix-vaccinated and 48 unvaccinated healthy children. We found that patients with Pandemrix-associated NC had more frequently (14.6%) anti-GM3 antibodies than vaccinated healthy controls (3.5%) ( P = 0.047). Anti-GM3 antibodies were significantly associated with HLA-DQB1*0602 ( P = 0.016) both in vaccinated NC patients and controls. In general, anti-ganglioside antibodies were more frequent in vaccinated (18.1%) than in unvaccinated (7.3%) individuals ( P = 0.035). Our data suggest that autoimmunity against GM3 is a feature of Pandemrix-associated NC and that autoantibodies against gangliosides were induced by Pandemrix vaccination.
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autoantibodies against ganglioside gm3 are associated with narcolepsy cataplexy developing after Pandemrix vaccination against 2009 pandemic h1n1 type influenza virus
Journal of Autoimmunity, 2015Co-Authors: Annahelena Saariaho, Arja Vuorela, Tobias L Freitag, Fabio Pizza, Giuseppe Plazzi, Markku Partinen, Outi Vaarala, Seppo MeriAbstract:Following the mass vaccinations against pandemic influenza A/H1N1 virus in 2009, a sudden increase in juvenile onset narcolepsy with cataplexy (NC) was detected in several European countries where AS03-adjuvanted Pandemrix vaccine had been used. NC is a chronic neurological disorder characterized by excessive daytime sleepiness and cataplexy. In human NC, the hypocretin-producing neurons in the hypothalamus or the hypocretin signaling pathway are destroyed by an autoimmune reaction. Both genetic (e.g. HLA-DQB1*0602) and environmental risk factors (e.g. Pandemrix) contribute to the disease development, but the underlying and the mediating immunological mechanisms are largely unknown. Influenza virus hemagglutinin is known to bind gangliosides, which serve as host cell virus receptors. Anti-ganglioside antibodies have previously been linked to various neurological disorders, like the Guillain-Barre syndrome which may develop after infection or vaccination. Because of these links we screened sera of NC patients and controls for IgG anti-ganglioside antibodies against 11 human brain gangliosides (GM1, GM2, GM3, GM4, GD1a, GD1b, GD2, GD3, GT1a, GT1b, GQ1b) and a sulfatide by using a line blot assay. Samples from 173 children and adolescents were analyzed: 48 with Pandemrix-associated NC, 20 with NC without Pandemrix association, 57 Pandemrix-vaccinated and 48 unvaccinated healthy children. We found that patients with Pandemrix-associated NC had more frequently (14.6%) anti-GM3 antibodies than vaccinated healthy controls (3.5%) (P = 0.047). Anti-GM3 antibodies were significantly associated with HLA-DQB1*0602 (P = 0.016) both in vaccinated NC patients and controls. In general, anti-ganglioside antibodies were more frequent in vaccinated (18.1%) than in unvaccinated (7.3%) individuals (P = 0.035). Our data suggest that autoimmunity against GM3 is a feature of Pandemrix-associated NC and that autoantibodies against gangliosides were induced by Pandemrix vaccination.
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antigenic differences between as03 adjuvanted influenza a h1n1 pandemic vaccines implications for Pandemrix associated narcolepsy risk
PLOS ONE, 2014Co-Authors: Outi Vaarala, Arja Vuorela, Tobias L Freitag, Markku Partinen, Seppo Meri, Marc Baumann, Paivi Saavalainen, Matti Jauhiainen, Rabah Soliymani, Turkka KirjavainenAbstract:Background Narcolepsy results from immune-mediated destruction of hypocretin secreting neurons in hypothalamus, however the triggers and disease mechanisms are poorly understood. Vaccine-attributable risk of narcolepsy reported so far with the AS03 adjuvanted H1N1 vaccination Pandemrix has been manifold compared to the AS03 adjuvanted Arepanrix, which contained differently produced H1N1 viral antigen preparation. Hence, antigenic differences and antibody response to these vaccines were investigated. Methods and Findings Increased circulating IgG-antibody levels to Pandemrix H1N1 antigen were found in 47 children with Pandemrix-associated narcolepsy when compared to 57 healthy children vaccinated with Pandemrix. H1N1 antigen of Arepanrix inhibited poorly these antibodies indicating antigenic difference between Arepanrix and Pandemrix. High-resolution gel electrophoresis quantitation and mass spectrometry identification analyses revealed higher amounts of structurally altered viral nucleoprotein (NP) in Pandemrix. Increased antibody levels to hemagglutinin (HA) and NP, particularly to detergent treated NP, was seen in narcolepsy. Higher levels of antibodies to NP were found in children with DQB1*06∶02 risk allele and in DQB1*06∶02 transgenic mice immunized with Pandemrix when compared to controls. Conclusions This work identified 1) higher amounts of structurally altered viral NP in Pandemrix than in Arepanrix, 2) detergent-induced antigenic changes of viral NP, that are recognized by antibodies from children with narcolepsy, and 3) increased antibody response to NP in association of DQB1*06∶02 risk allele of narcolepsy. These findings provide a link between Pandemrix and narcolepsy. Although detailed mechanisms of Pandemrix in narcolepsy remain elusive, our results move the focus from adjuvant(s) onto the H1N1 viral proteins.
Dan Lindholm - One of the best experts on this subject based on the ideXlab platform.
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Prostaglandin D2 Receptor DP1 Antibodies Predict Vaccine-induced and Spontaneous Narcolepsy Type 1: Large-scale Study of Antibody Profiling
EBioMedicine, 2018Co-Authors: Helle Sadam, Anri Kivil, Mariliis Jaago, Priit Adler, Susan Pihelgas, Olli Vapalahti, Toomas Neuman, Arno Pihlak, Jaak Vilo, Dan LindholmAbstract:Background: Neuropathological findings support an autoimmune etiology as an underlying factor for loss of orexin-producing neurons in spontaneous narcolepsy type 1 (narcolepsy with cataplexy; sNT1) as well as in Pandemrix influenza vaccine-induced narcolepsy type 1 (Pdmx-NT1). The precise molecular target or antigens for the immune response have, however, remained elusive. Methods: Here we have performed a comprehensive antigenic repertoire analysis of sera using the next-generation phage display method - mimotope variation analysis (MVA). Samples from 64 children and adolescents were analyzed: 10 with Pdmx-NT1, 6 with sNT1, 16 Pandemrix-vaccinated, 16 H1N1 infected, and 16 unvaccinated healthy individuals. The diagnosis of NT1 was defined by the American Academy of Sleep Medicine international criteria of sleep disorders v3. Findings: Our data showed that although the immunoprofiles toward vaccination were generally similar in study groups, there were also striking differences in immunoprofiles between sNT1 and Pdmx-NT1 groups as compared with controls. Prominent immune response was observed to a peptide epitope derived from prostaglandin D2 receptor (DP1), as well as peptides homologous to B cell lymphoma 6 protein. Further validation confirmed that these can act as true antigenic targets in discriminating NT1 diseased along with a novel epitope of hemagglutinin of H1N1 to delineate exposure to H1N1. Interpretation: We propose that DP1 is a novel molecular target of autoimmune response and presents a potential diagnostic biomarker for NT1. DP1 is involved in the regulation of non-rapid eye movement (NREM) sleep and thus alterations in its functions could contribute to the disturbed sleep regulation in NT1 that warrants further studies. Together our results also show that MVA is a helpful method for finding novel peptide antigens to classify human autoimmune diseases, possibly facilitating the design of better therapies.
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Prostaglandin D2 Receptor DP1 Antibodies Predict Vaccine-induced and Spontaneous Narcolepsy Type 1: Large-scale Study of Antibody Profiling
Elsevier, 2018Co-Authors: Helle Sadam, Anri Kivil, Mariliis Jaago, Priit Adler, Susan Pihelgas, Olli Vapalahti, Toomas Neuman, Arno Pihlak, Jaak Vilo, Dan LindholmAbstract:Background: Neuropathological findings support an autoimmune etiology as an underlying factor for loss of orexin-producing neurons in spontaneous narcolepsy type 1 (narcolepsy with cataplexy; sNT1) as well as in Pandemrix influenza vaccine-induced narcolepsy type 1 (Pdmx-NT1). The precise molecular target or antigens for the immune response have, however, remained elusive. Methods: Here we have performed a comprehensive antigenic repertoire analysis of sera using the next-generation phage display method - mimotope variation analysis (MVA). Samples from 64 children and adolescents were analyzed: 10 with Pdmx-NT1, 6 with sNT1, 16 Pandemrix-vaccinated, 16 H1N1 infected, and 16 unvaccinated healthy individuals. The diagnosis of NT1 was defined by the American Academy of Sleep Medicine international criteria of sleep disorders v3. Findings: Our data showed that although the immunoprofiles toward vaccination were generally similar in study groups, there were also striking differences in immunoprofiles between sNT1 and Pdmx-NT1 groups as compared with controls. Prominent immune response was observed to a peptide epitope derived from prostaglandin D2 receptor (DP1), as well as peptides homologous to B cell lymphoma 6 protein. Further validation confirmed that these can act as true antigenic targets in discriminating NT1 diseased along with a novel epitope of hemagglutinin of H1N1 to delineate exposure to H1N1. Interpretation: We propose that DP1 is a novel molecular target of autoimmune response and presents a potential diagnostic biomarker for NT1. DP1 is involved in the regulation of non-rapid eye movement (NREM) sleep and thus alterations in its functions could contribute to the disturbed sleep regulation in NT1 that warrants further studies. Together our results also show that MVA is a helpful method for finding novel peptide antigens to classify human autoimmune diseases, possibly facilitating the design of better therapies. Keywords: Narcolepsy type 1, H1N1, Pandemrix, Antibody, Prostaglandin, DP
Arja Vuorela - One of the best experts on this subject based on the ideXlab platform.
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enhanced influenza a h1n1 t cell epitope recognition and cross reactivity to protein o mannosyltransferase 1 in Pandemrix associated narcolepsy type 1
Nature Communications, 2021Co-Authors: Arja Vuorela, Tobias L Freitag, Turkka Kirjavainen, Outi Saarenpaaheikkila, Paivi Olsen, Katarzyna Leskinen, H Pessa, Taina Harkonen, I Stracenski, Jorma IlonenAbstract:Narcolepsy type 1 (NT1) is a chronic neurological disorder having a strong association with HLA-DQB1*0602, thereby suggesting an immunological origin. Increased risk of NT1 has been reported among children or adolescents vaccinated with AS03 adjuvant-supplemented pandemic H1N1 influenza A vaccine, Pandemrix. Here we show that pediatric Pandemrix-associated NT1 patients have enhanced T-cell immunity against the viral epitopes, neuraminidase 175-189 (NA175-189) and nucleoprotein 214-228 (NP214-228), but also respond to a NA175-189-mimic, brain self-epitope, protein-O-mannosyltransferase 1 (POMT1675-689). A pathogenic role of influenza virus-specific T-cells and T-cell cross-reactivity in NT1 are supported by the up-regulation of IFN-γ, perforin 1 and granzyme B, and by the converging selection of T-cell receptor TRAV10/TRAJ17 and TRAV10/TRAJ24 clonotypes, in response to stimulation either with peptide NA175-189 or POMT1675-689. Moreover, anti-POMT1 serum autoantibodies are increased in Pandemrix-vaccinated children or adolescents. These results thus identify POMT1 as a potential autoantigen recognized by T- and B-cells in NT1.
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no evidence of autoimmunity to human ox1 or ox2 orexin receptors in Pandemrix vaccinated narcoleptic children
Journal of translational autoimmunity, 2020Co-Authors: Arja Vuorela, Tobias L Freitag, Markku Partinen, Outi Vaarala, Hanna Nohynek, Krister Melen, Pinja Jalkanen, Jyrki P Kukkonen, Seppo MeriAbstract:Narcolepsy type 1, likely an immune-mediated disease, is characterized by excessive daytime sleepiness and cataplexy. The disease is strongly associated with human leukocyte antigen (HLA) DQB1∗06:02. A significant increase in the incidence of childhood and adolescent narcolepsy was observed after a vaccination campaign with AS03-adjuvanted Pandemrix influenza vaccine in Nordic and several other countries in 2010 and 2011. Previously, it has been suggested that a surface-exposed region of influenza A nucleoprotein, a structural component of the Pandemrix vaccine, shares amino acid residues with the first extracellular domain of the human OX2 orexin/hypocretin receptor eliciting the development of autoantibodies. Here, we analyzed, whether H1N1pdm09 infection or Pandemrix vaccination contributed to the development of autoantibodies to the orexin precursor protein or the OX1 or OX2 receptors. The analysis was based on the presence or absence of autoantibody responses against analyzed proteins. Entire OX1 and OX2 receptors or just their extracellular N-termini were transiently expressed in HuH7 cells to determine specific antibody responses in human sera. Based on our immunofluorescence analysis, none of the 56 Pandemrix-vaccinated narcoleptic patients, 28 patients who suffered from a laboratory-confirmed H1N1pdm09 infection or 19 Pandemrix-vaccinated controls showed specific autoantibody responses to prepro-orexin, orexin receptors or the isolated extracellular N-termini of orexin receptors. We also did not find any evidence for cell-mediated immunity against the N-terminal epitopes of OX2. Our findings do not support the hypothesis that the surface-exposed region of the influenza nucleoprotein A would elicit the development of an immune response against orexin receptors.
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autoantibodies against ganglioside gm3 are associated with narcolepsy cataplexy developing after Pandemrix vaccination against 2009 pandemic h1n1 type influenza virus
Journal of Autoimmunity, 2015Co-Authors: Annahelena Saariaho, Arja Vuorela, Tobias L Freitag, Fabio Pizza, Giuseppe Plazzi, Markku Partinen, Outi Vaarala, Seppo MeriAbstract:Abstract Following the mass vaccinations against pandemic influenza A/H1N1 virus in 2009, a sudden increase in juvenile onset narcolepsy with cataplexy (NC) was detected in several European countries where AS03-adjuvanted Pandemrix vaccine had been used. NC is a chronic neurological disorder characterized by excessive daytime sleepiness and cataplexy. In human NC, the hypocretin-producing neurons in the hypothalamus or the hypocretin signaling pathway are destroyed by an autoimmune reaction. Both genetic (e.g. HLA-DQB1*0602) and environmental risk factors (e.g. Pandemrix) contribute to the disease development, but the underlying and the mediating immunological mechanisms are largely unknown. Influenza virus hemagglutinin is known to bind gangliosides, which serve as host cell virus receptors. Anti-ganglioside antibodies have previously been linked to various neurological disorders, like the Guillain-Barre syndrome which may develop after infection or vaccination. Because of these links we screened sera of NC patients and controls for IgG anti-ganglioside antibodies against 11 human brain gangliosides (GM1, GM2, GM3, GM4, GD1a, GD1b, GD2, GD3, GT1a, GT1b, GQ1b) and a sulfatide by using a line blot assay. Samples from 173 children and adolescents were analyzed: 48 with Pandemrix-associated NC, 20 with NC without Pandemrix association, 57 Pandemrix-vaccinated and 48 unvaccinated healthy children. We found that patients with Pandemrix-associated NC had more frequently (14.6%) anti-GM3 antibodies than vaccinated healthy controls (3.5%) ( P = 0.047). Anti-GM3 antibodies were significantly associated with HLA-DQB1*0602 ( P = 0.016) both in vaccinated NC patients and controls. In general, anti-ganglioside antibodies were more frequent in vaccinated (18.1%) than in unvaccinated (7.3%) individuals ( P = 0.035). Our data suggest that autoimmunity against GM3 is a feature of Pandemrix-associated NC and that autoantibodies against gangliosides were induced by Pandemrix vaccination.
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autoantibodies against ganglioside gm3 are associated with narcolepsy cataplexy developing after Pandemrix vaccination against 2009 pandemic h1n1 type influenza virus
Journal of Autoimmunity, 2015Co-Authors: Annahelena Saariaho, Arja Vuorela, Tobias L Freitag, Fabio Pizza, Giuseppe Plazzi, Markku Partinen, Outi Vaarala, Seppo MeriAbstract:Following the mass vaccinations against pandemic influenza A/H1N1 virus in 2009, a sudden increase in juvenile onset narcolepsy with cataplexy (NC) was detected in several European countries where AS03-adjuvanted Pandemrix vaccine had been used. NC is a chronic neurological disorder characterized by excessive daytime sleepiness and cataplexy. In human NC, the hypocretin-producing neurons in the hypothalamus or the hypocretin signaling pathway are destroyed by an autoimmune reaction. Both genetic (e.g. HLA-DQB1*0602) and environmental risk factors (e.g. Pandemrix) contribute to the disease development, but the underlying and the mediating immunological mechanisms are largely unknown. Influenza virus hemagglutinin is known to bind gangliosides, which serve as host cell virus receptors. Anti-ganglioside antibodies have previously been linked to various neurological disorders, like the Guillain-Barre syndrome which may develop after infection or vaccination. Because of these links we screened sera of NC patients and controls for IgG anti-ganglioside antibodies against 11 human brain gangliosides (GM1, GM2, GM3, GM4, GD1a, GD1b, GD2, GD3, GT1a, GT1b, GQ1b) and a sulfatide by using a line blot assay. Samples from 173 children and adolescents were analyzed: 48 with Pandemrix-associated NC, 20 with NC without Pandemrix association, 57 Pandemrix-vaccinated and 48 unvaccinated healthy children. We found that patients with Pandemrix-associated NC had more frequently (14.6%) anti-GM3 antibodies than vaccinated healthy controls (3.5%) (P = 0.047). Anti-GM3 antibodies were significantly associated with HLA-DQB1*0602 (P = 0.016) both in vaccinated NC patients and controls. In general, anti-ganglioside antibodies were more frequent in vaccinated (18.1%) than in unvaccinated (7.3%) individuals (P = 0.035). Our data suggest that autoimmunity against GM3 is a feature of Pandemrix-associated NC and that autoantibodies against gangliosides were induced by Pandemrix vaccination.
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antigenic differences between as03 adjuvanted influenza a h1n1 pandemic vaccines implications for Pandemrix associated narcolepsy risk
PLOS ONE, 2014Co-Authors: Outi Vaarala, Arja Vuorela, Tobias L Freitag, Markku Partinen, Seppo Meri, Marc Baumann, Paivi Saavalainen, Matti Jauhiainen, Rabah Soliymani, Turkka KirjavainenAbstract:Background Narcolepsy results from immune-mediated destruction of hypocretin secreting neurons in hypothalamus, however the triggers and disease mechanisms are poorly understood. Vaccine-attributable risk of narcolepsy reported so far with the AS03 adjuvanted H1N1 vaccination Pandemrix has been manifold compared to the AS03 adjuvanted Arepanrix, which contained differently produced H1N1 viral antigen preparation. Hence, antigenic differences and antibody response to these vaccines were investigated. Methods and Findings Increased circulating IgG-antibody levels to Pandemrix H1N1 antigen were found in 47 children with Pandemrix-associated narcolepsy when compared to 57 healthy children vaccinated with Pandemrix. H1N1 antigen of Arepanrix inhibited poorly these antibodies indicating antigenic difference between Arepanrix and Pandemrix. High-resolution gel electrophoresis quantitation and mass spectrometry identification analyses revealed higher amounts of structurally altered viral nucleoprotein (NP) in Pandemrix. Increased antibody levels to hemagglutinin (HA) and NP, particularly to detergent treated NP, was seen in narcolepsy. Higher levels of antibodies to NP were found in children with DQB1*06∶02 risk allele and in DQB1*06∶02 transgenic mice immunized with Pandemrix when compared to controls. Conclusions This work identified 1) higher amounts of structurally altered viral NP in Pandemrix than in Arepanrix, 2) detergent-induced antigenic changes of viral NP, that are recognized by antibodies from children with narcolepsy, and 3) increased antibody response to NP in association of DQB1*06∶02 risk allele of narcolepsy. These findings provide a link between Pandemrix and narcolepsy. Although detailed mechanisms of Pandemrix in narcolepsy remain elusive, our results move the focus from adjuvant(s) onto the H1N1 viral proteins.
