ABSTRACT
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.
Subject(s)
Influenza A Virus, H1N1 Subtype/immunology , Influenza Vaccines/adverse effects , Influenza, Human/prevention & control , Mannosyltransferases/immunology , Narcolepsy/immunology , Adolescent , Animals , Autoantibodies/blood , Autoantibodies/immunology , Autoantigens/immunology , B-Lymphocytes/immunology , CD4 Antigens/genetics , Case-Control Studies , Child , Child, Preschool , Cross Reactions/immunology , Disease Models, Animal , Epitopes, T-Lymphocyte/immunology , Female , HLA-DQ beta-Chains/immunology , Humans , Infant , Influenza Vaccines/immunology , Influenza, Human/immunology , Influenza, Human/virology , Male , Mice, Transgenic , Narcolepsy/blood , Narcolepsy/chemically induced , Neuraminidase/immunology , T-Lymphocytes/immunology , Viral Proteins/immunology , Young AdultABSTRACT
OBJECTIVES: To establish the incidence, current treatment and outcome of adult patients with acute intratemporal and intracranial complications of otitis media (OM). DESIGN: A retrospective chart review with a sent questionnaire. SETTING: Tertiary referral centre, University hospital. PARTICIPANTS: Adult patients treated for acute intratemporal and intracranial complications of OM over the past 15 years (1990-2004) in the study hospital. MAIN OUTCOME MEASURES: Incidence, treatment and outcome of patients with intratemporal and intracranial complications of OM. RESULTS: Fifty patients aged 16-75 years were treated. The annual age-adjusted incidence of acute intratemporal and intracranial complications was 0.32/100 000. Forty-one (82%) of the complications were intratemporal and nine (18%) were intracranial. The ear disease behind the acute complication was acute otitis media (AOM) in 80% (40/50), chronic otitis media (COM) in 12% (6/50) and COM with cholesteatoma in 8% (4/50). Mastoiditis was complicated by subperiosteal abscess, labyrinthitis and facial paresis in 7% (3/41), 15% (6/41) and 32% (13/41) respectively. Mastoidectomy was performed on 56% (28/50) of the patients. Four (44%) of the intracranial complications were intracranial abscesses, four (44%) were meningitis and one (11%) was sinus thrombosis. Permanent hearing loss occurred in 13 (26%) patients and one patient died due to otogenic meningitis. CONCLUSIONS: Severe complications of the OM in adults are rare in Finland. The commonest cause is AOM rather than COM. Operative treatment is predominantly needed for intracranial complications and intratemporal abscesses. Complications of OM are still associated with considerable morbidity, and early recognition is most likely to form the basis for effective treatment.
