title: Increased β-haemolytic group A streptococcal M6 serotype and streptodornase B-specific cellular immune responses in Swedish narcolepsy cases.
abstract: BACKGROUND
  Type 1 narcolepsy is a neurological disorder characterized by excessive daytime sleepiness and cataplexy associated with the HLA allele DQB1*06:02. Genetic predisposition along with external triggering factors may drive autoimmune responses, ultimately leading to the selective loss of hypocretin-positive neurons.
  
  
  OBJECTIVE
  The aim of this study was to investigate potential aetiological factors in Swedish cases of postvaccination (Pandemrix) narcolepsy defined by interferon-gamma (IFNγ) production from immune cells in response to molecularly defined targets.
  
  
  METHODS
  Cellular reactivity defined by IFNγ production was examined in blood from 38 (HLA-DQB1*06:02(+) ) Pandemrix-vaccinated narcolepsy cases and 76 (23 HLA-DQB1*06:02(+) and 53 HLA-DQB1*06:02(-) ) control subjects, matched for age, sex and exposure, using a variety of different antigens: β-haemolytic group A streptococcal (GAS) antigens (M5, M6 and streptodornase B), influenza (the pandemic A/H1N1/California/7/09 NYMC X-179A and A/H1N1/California/7/09 NYMC X-181 vaccine antigens, previous Flu-A and -B vaccine targets, A/H1N1/Brisbane/59/2007, A/H1N1/Solomon Islands/3/2006, A/H3N2/Uruguay/716/2007, A/H3N2/Wisconsin/67/2005, A/H5N1/Vietnam/1203/2004 and B/Malaysia/2506/2004), noninfluenza viral targets (CMVpp65, EBNA-1 and EBNA-3) and auto-antigens (hypocretin peptide, Tribbles homolog 2 peptide cocktail and extract from rat hypothalamus tissue).
  
  
  RESULTS
  IFN-γ production was significantly increased in whole blood from narcolepsy cases in response to streptococcus serotype M6 (P = 0.0065) and streptodornase B protein (P = 0.0050). T-cell recognition of M6 and streptodornase B was confirmed at the single-cell level by intracellular cytokine (IL-2, IFNγ, tumour necrosis factor-alpha and IL-17) production after stimulation with synthetic M6 or streptodornase B peptides. Significantly, higher (P = 0.02) titres of serum antistreptolysin O were observed in narcolepsy cases, compared to vaccinated controls.
  
  
  CONCLUSIONS
  β-haemolytic GAS may be involved in triggering autoimmune responses in patients who developed narcolepsy symptoms after vaccination with Pandemrix in Sweden, characterized by a Streptococcus pyogenes M-type-specific IFN-γ cellular immune response.
authors: Department of Medicine, Karolinska Institutet, Stockholm, Sweden.|Centre for Allogeneic Stem Cell Transplantation Karolinska University Hospital, Stockholm, Sweden.
authors: A
authors: A
authors: Ambati
authors: Division of Therapeutic Immunology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: T
authors: T
authors: Poiret
authors: Centre for Allogeneic Stem Cell Transplantation Karolinska University Hospital, Stockholm, Sweden.
authors: B-M
authors: BM
authors: Svahn
authors: Centre for Allogeneic Stem Cell Transplantation Karolinska University Hospital, Stockholm, Sweden.
authors: D
authors: D
authors: Valentini
authors: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors: M
authors: M
authors: Khademi
authors: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors: I
authors: I
authors: Kockum
authors: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors: I
authors: I
authors: Lima
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: L
authors: L
authors: Arnheim-Dahlström
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: F
authors: F
authors: Lamb
authors: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors: K
authors: K
authors: Fink
authors: Division of Therapeutic Immunology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: Q
authors: Q
authors: Meng
authors: Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
authors: A
authors: A
authors: Kumar
authors: Division of Therapeutic Immunology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: L
authors: L
authors: Rane
authors: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors: T
authors: T
authors: Olsson
authors: Centre for Allogeneic Stem Cell Transplantation Karolinska University Hospital, Stockholm, Sweden.|Division of Therapeutic Immunology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: M
authors: M
authors: Maeurer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000989:Antistreptolysin / Q000097:blood; D002648:Child; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000097:blood; D008297:Male; D008875:Middle Aged; D009290:Narcolepsy / Q000453:epidemiology / Q000276:immunology*; D010446:Peptide Fragments / Q000096:biosynthesis / Q000097:blood; D012703:Serotyping; D013292:Streptococcus agalactiae / Q000201:enzymology / Q000276:immunology*; D013299:Streptodornase and Streptokinase / Q000276:immunology*; D013548:Sweden / Q000453:epidemiology
chemical_list: D010446:Peptide Fragments; C069261:interferon gamma (1-39); D007371:Interferon-gamma; D000989:Antistreptolysin; D013299:Streptodornase and Streptokinase
keywords: Pandemrix; Streptococcus; T cells; interferon-gamma; narcolepsy; streptolysin