A/H1N1 antibodies and TRIB2 autoantibodies in narcolepsy patients diagnosed in conjunction with the Pandemrix vaccination campaign in Sweden 2009-2010.
Narcolepsy is a lifelong sleep disorder related to hypocretin deficiency resulting from a specific loss of hypocretin-producing neurons in the lateral hypothalamic area. The disease is thought to be autoimmune due to a strong association with HLA-DQB1*06:02. In 2009 the World Health Organization (WHO) declared the H1N1 2009 flu pandemic (A/H1N1PDM09). In response to this, the Swedish vaccination campaign began in October of the same year, using the influenza vaccine Pandemrix(®). A few months later an excess of narcolepsy cases was observed. It is still unclear to what extent the vaccination campaign affected humoral autoimmunity associated with narcolepsy. We studied 47 patients with narcolepsy (6-69 years of age) and 80 healthy controls (3-61 years of age) selected after the Pandemrix vaccination campaign. The first aim was to determine antibodies against A/H1N1 and autoantibodies to Tribbles homolog 2 (TRIB2), a narcolepsy autoantigen candidate as well as to GAD65 and IA-2 as disease specificity controls. The second aim was to test if levels and frequencies of these antibodies and autoantibodies were associated with HLA-DQB1*06:02. In vitro transcribed and translated [(35)S]-methionine and -cysteine-labeled influenza A virus (A/California/04/2009/(H1N1)) segment 4 hemagglutinin was used to detect antibodies in a radiobinding assay. Autoantibodies to TRIB2, GAD65 and IA-2 were similarly detected in standard radiobinding assays. The narcolepsy patients had higher median levels of A/H1N1 antibodies than the controls (p = 0.006). A/H1N1 antibody levels were higher among the <13 years old (n = 12) compared to patients who were older than 30 years (n = 12, p = 0.014). Being HLA-DQB1*06:02 positive was associated with higher A/H1N1 antibody levels in both patients and controls (p = 0.026). Serum autoantibody levels to TRIB2 were low overall and high binders did not differ between patients and controls. We observed an association between levels of A/H1N1 antibodies and TRIB2 autoantibody levels particularly among the youngest narcolepsy patients (r = 0.819, p < 0.001). In conclusion, following the 2009 influenza pandemic vaccination, A/H1N1 antibody levels were associated with young age-at-onset narcolepsy patients positive for HLA-DQB1*06:02. The possibility that TRIB2 is an autoantigen in narcolepsy remains to be clarified. We could verify autoantibody responses against TRIB2 which needs to be determined in larger patient cohorts and control populations.
Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden. Electronic address: alexander.lind.619@student.lu.se.
Alexander
A
Lind
Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden. Electronic address: Anita.ramelius@med.lu.se.
Anita
A
Ramelius
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. Electronic address: Tomas.olsson@ki.se.
Tomas
T
Olsson
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. Electronic address: Lisen.arnheim.dahlstrom@ki.se.
Lisen
L
Arnheim-Dahlström
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. Electronic address: Favelle.lamb@ki.se.
Favelle
F
Lamb
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. Electronic address: Mohsen.khademi@ki.se.
Mohsen
M
Khademi
Department of Medicine, Karolinska Institutet, Stockholm, Sweden. Electronic address: Aditya.ambati@ki.se.
Aditya
A
Ambati
TIM, LabMed, Karolinska Institutet and CAST, Karolinska Hospital, Stockholm, Sweden. Electronic address: Markus.maeurer@ki.se.
Markus
M
Maeurer
Paediatric Clinic, Östersund Hospital, Östersund, Sweden. Electronic address: Anna-lena.nilsson@jll.se.
Anna-Lena
AL
Nilsson
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. Electronic address: Izaura.lima@ki.se.
Izaura Lima
IL
Bomfim
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. Electronic address: Katarina.fink@ki.se.
Katharina
K
Fink
Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden. Electronic address: Ake.lernmark@med.lu.se.
Åke
Å
Lernmark
D000293:Adolescent; D000328:Adult; D000368:Aged; D000914:Antibodies, Viral / Q000097:blood*; D001323:Autoantibodies / Q000097:blood*; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002648:Child; D002675:Child, Preschool; D005260:Female; D015870:Gene Expression; D005968:Glutamate Decarboxylase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D059866:HLA-DQ beta-Chains / Q000235:genetics / Q000276:immunology; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000009:adverse effects* / Q000276:immunology; D007251:Influenza, Human / Q000276:immunology / Q000517:prevention & control*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009290:Narcolepsy / Q000139:chemically induced* / Q000175:diagnosis / Q000235:genetics / Q000276:immunology; D058873:Pandemics / Q000517:prevention & control; D013548:Sweden; D014611:Vaccination / Q000009:adverse effects
D000914:Antibodies, Viral; D001323:Autoantibodies; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D007252:Influenza Vaccines; D047908:Intracellular Signaling Peptides and Proteins; C556153:pandemrix; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C489044:TRIB2 protein, human; C505804:GAD55, human; D005968:Glutamate Decarboxylase
A/H1N1; Autoantibodies; Autoimmunity; HLA-DQB1*06:02; Narcolepsy; Vaccination