title: Clinical and serologic parallels to APS-I in patients with thymomas and autoantigen transcripts in their tumors.
abstract: Patients with the autoimmune polyendocrine syndrome type I (APS-I), caused by mutations in the autoimmune regulator (AIRE) gene, and myasthenia gravis (MG) with thymoma, show intriguing but unexplained parallels. They include uncommon manifestations like autoimmune adrenal insufficiency (AI), hypoparathyroidism, and chronic mucocutaneous candidiasis plus autoantibodies neutralizing IL-17, IL-22, and type I IFNs. Thymopoiesis in the absence of AIRE is implicated in both syndromes. To test whether these parallels extend further, we screened 247 patients with MG, thymoma, or both for clinical features and organ-specific autoantibodies characteristic of APS-I patients, and we assayed 26 thymoma samples for transcripts for AIRE and 16 peripheral tissue-specific autoantigens (TSAgs) by quantitative PCR. We found APS-I-typical autoantibodies and clinical manifestations, including chronic mucocutaneous candidiasis, AI, and asplenia, respectively, in 49 of 121 (40%) and 10 of 121 (8%) thymoma patients, but clinical features seldom occurred together with the corresponding autoantibodies. Both were rare in other MG subgroups (n = 126). In 38 patients with APS-I, by contrast, we observed neither autoantibodies against muscle Ags nor any neuromuscular disorders. Whereas relative transcript levels for AIRE and 7 of 16 TSAgs showed the expected underexpression in thymomas, levels were increased for four of the five TSAgs most frequently targeted by these patients' autoantibodies. Therefore, the clinical and serologic parallels to APS-I in patients with thymomas are not explained purely by deficient TSAg transcription in these aberrant AIRE-deficient tumors. We therefore propose additional explanations for the unusual autoimmune biases they provoke. Thymoma patients should be monitored for potentially life-threatening APS-I manifestations such as AI and hypoparathyroidism.
authors.affiliation: Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; Anette.boe@k2.uib.no.
authors.forename: Anette S B
authors.initials: AS
authors.lastname: Wolff
authors.affiliation: Molecular Pathology Group, Institute of Biomedicine and Translational Medicine, University of Tartu, 50090 Tartu, Estonia;
authors.forename: Jaanika
authors.initials: J
authors.lastname: Kärner
authors.affiliation: Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway; Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway;
authors.forename: Jone F
authors.initials: JF
authors.lastname: Owe
authors.affiliation: Department of Clinical Science, University of Bergen, 5021 Bergen, Norway;
authors.forename: Bergithe E V
authors.initials: BE
authors.lastname: Oftedal
authors.affiliation: Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway; Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway;
authors.forename: Nils Erik
authors.initials: NE
authors.lastname: Gilhus
authors.affiliation: Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway;
authors.forename: Martina M
authors.initials: MM
authors.lastname: Erichsen
authors.affiliation: Department of Medicine, Solna, Karolinska University Hospital, Karolinska Institutet, SE-171 76 Stockholm, Sweden;
authors.forename: Olle
authors.initials: O
authors.lastname: Kämpe
authors.affiliation: Biotherapeutics Group, The National Institute for Biological Standards and Control, South Mimms, Potters Bar, Hertfordshire EN6 3QG, United Kingdom; and.
authors.forename: Anthony
authors.initials: A
authors.lastname: Meager
authors.affiliation: Molecular Pathology Group, Institute of Biomedicine and Translational Medicine, University of Tartu, 50090 Tartu, Estonia;
authors.forename: Pärt
authors.initials: P
authors.lastname: Peterson
authors.affiliation: Molecular Pathology Group, Institute of Biomedicine and Translational Medicine, University of Tartu, 50090 Tartu, Estonia;
authors.forename: Kai
authors.initials: K
authors.lastname: Kisand
authors.affiliation: Department of Clinical Neurology, Weatherall Institute for Molecular Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom.
authors.forename: Nick
authors.initials: N
authors.lastname: Willcox
authors.affiliation: Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway;
authors.forename: Eystein S
authors.initials: ES
authors.lastname: Husebye
mesh_terms: D000309:Adrenal Insufficiency / Q000276:immunology; D000328:Adult; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D002178:Candidiasis, Chronic Mucocutaneous; D005260:Female; D059446:Heterotaxy Syndrome / Q000276:immunology; D006801:Humans; D007011:Hypoparathyroidism / Q000276:immunology; D007370:Interferon Type I / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D007378:Interleukins / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis / Q000235:genetics / Q000276:immunology; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics / Q000276:immunology*; D013945:Thymoma / Q000235:genetics / Q000276:immunology*; D013953:Thymus Neoplasms / Q000235:genetics / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics*; D000096927:AIRE Protein; D000097043:Interleukin-22
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D007370:Interferon Type I; D020381:Interleukin-17; D007378:Interleukins; D014157:Transcription Factors; D000096927:AIRE Protein; D000097043:Interleukin-22