title: IL-6-specific autoantibodies among APECED and thymoma patients.
abstract: Both autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) and the rare thymoma patients with chronic mucocutaneous candidiasis (CMC) have neutralizing autoantibodies to Th17 cytokines and significant defects in production of IL-22 and IL-17F by their T cells. The cause of these defects is unknown. We hypothesized that they might result from autoimmunity against upstream cytokines normally responsible for generating and maintaining Th17 cells.
  
  
  
  Luciferase immunoprecipitation (LIPS) was used to screen for autoantibodies to IL-6, IL-1β, TGF-β3, IL-21, and IL-23 in patients with APECED or thymoma. We used Western blotting to assess the conformation-dependence of the IL-6 autoantibodies and flow cytometric analysis of intracellular phospho-STAT3 induction to assess IL-6-neutralizing capacity in IgGs isolated from patient and control sera. We also used Luminex xMAP to measure serum cytokine levels.
  
  
  
  We found autoantibodies binding to conformational epitopes of IL-6 in 19.5% of 41 patients with APECED and 12.5% of 104 with thymoma-especially in those with long disease durations. The autoantibodies were predominantly of IgG1 subclass and failed to neutralize IL-6 activity. Notably, serum levels of the IL-6 and IL-17A cytokines were higher in anti-IL-6 seropositive than-negative APECED patients or healthy controls. We also detected autoantibody binding to IL-23 in 27.9% of thymoma patients, resulting from cross-recognition through the p40 subunit it shares with IL-12.
  
  
  
  IL-6 and IL-17A elevation in these seropositive patients suggests that antibody-binding may protect IL-6 from degradation and prolong its half-life in vivo.
authors.affiliation: Molecular Pathology Research Group, Institute of Biomedicine and Translational Medicine University of Tartu Tartu Estonia.
authors.forename: Jaanika
authors.initials: J
authors.lastname: Kärner
authors.affiliation: Molecular Pathology Research Group, Institute of Biomedicine and Translational Medicine University of Tartu Tartu Estonia.
authors.forename: Maire
authors.initials: M
authors.lastname: Pihlap
authors.affiliation: Department of Dermatology, Allergology and Venereology, Institute of Clinical Medicine, University of Helsinki, and Skin and Allergy Hospital Helsinki University Central Hospital Helsinki Finland.
authors.forename: Annamari
authors.initials: A
authors.lastname: Ranki
authors.affiliation: Clinical Research Institute HUCH Ltd. Helsinki Finland.
authors.forename: Kai
authors.initials: K
authors.lastname: Krohn
authors.affiliation: Unit for Special Laboratory Diagnostics, University Children's HospitalUniversity Medical CentreLjubljanaSlovenia; University of Ljubljana, Medical FacultyLjubljanaSlovenia.
authors.forename: Katarina
authors.initials: K
authors.lastname: Trebusak Podkrajsek
authors.affiliation: Department of Pediatric Endocrinology, Diabetes and Metabolism University Children's Hospital, University Medical Centre Ljubljana Slovenia.
authors.forename: Nina
authors.initials: N
authors.lastname: Bratanic
authors.affiliation: Department of Pediatric Endocrinology, Diabetes and MetabolismUniversity Children's Hospital, University Medical CentreLjubljanaSlovenia; University of Ljubljana, Medical FacultyLjubljanaSlovenia.
authors.forename: Tadej
authors.initials: T
authors.lastname: Battelino
authors.affiliation: Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine University of Oxford Oxford OX3 9DS UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Willcox
authors.affiliation: Molecular Pathology Research Group, Institute of Biomedicine and Translational Medicine University of Tartu Tartu Estonia.
authors.forename: Pärt
authors.initials: P
authors.lastname: Peterson
authors.affiliation: Molecular Pathology Research Group, Institute of Biomedicine and Translational Medicine University of Tartu Tartu Estonia.
authors.forename: Kai
authors.initials: K
authors.lastname: Kisand
mesh_terms: D001323:Autoantibodies; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology*; D016884:Polyendocrinopathies, Autoimmune / Q000276:immunology*; D013945:Thymoma; D013953:Thymus Neoplasms / Q000276:immunology*
chemical_list: D001323:Autoantibodies; C508717:IL17A protein, human; D020381:Interleukin-17; D015850:Interleukin-6
keywords: APECED; Anti‐IL‐6; thymoma