title: Deficiency of the autoimmune regulator AIRE in thymomas is insufficient to elicit autoimmune polyendocrinopathy syndrome type 1 (APS-1).
abstract: Thymomas are thymic epithelial neoplasms, associated with a variety of autoimmune disorders (especially myasthenia gravis), that apparently result from aberrant intra-tumourous thymopoiesis and export of inefficiently tolerized T-cells to the periphery. The autoimmune regulator (AIRE) drives the expression of self-antigens in the thymic medulla and plays an essential role in 'central' tolerance in both humans and mice. However, while inactivating AIRE mutations result in the 'autoimmune polyendocrinopathy syndrome type 1' (APS-1), its major features are not well reproduced in AIRE-knock-out mice. Therefore, alternative human disease scenarios with concomitant AIRE deficiency may be valuable tools to test conclusions drawn from mouse models. Here we show, in a large series, that approximately 95% of thymoma patients are 'chimeric'; expression of AIRE and major AIRE-related autoantigens (eg insulin) were undetectable in their tumours but maintained in their remnant thymic tissue and lymph nodes. Notably, despite the AIRE-deficient thymopoiesis in thymomas, disorders and autoantibodies typical of APS-1 were distinctly uncommon in these patients. The one striking similarity was in the recently observed neutralizing anti-type I interferon (IFN) antibodies, which are found at diagnosis in 100% of patients with APS-1 and in approximately 60% of patients with thymomas, as we show here. We conclude that APS-1 type autoantigens must be protected from autoimmunity by mechanisms that do not extend to the muscle autoantigens so frequently targeted in thymoma patients but so rarely recognized in APS-1. Thus our findings argue strongly for a tolerogenic function of AIRE beyond its role in negative T-cell selection in human thymopoiesis, and/or for specific autoimmunization against muscle in thymomas.
authors.affiliation: Institute of Pathology, University Medical Centre Mannheim, University of Heidelberg, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Ströbel
authors.affiliation: Institute of Medical Technology, Tampere, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Murumägi
authors.affiliation: Department of Internal Medicine II, University of Tübingen, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Klein
authors.affiliation: Department of Nuclear Medicine, University of Würzburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Luster
authors.affiliation: Institute of Medical Technology, Tampere, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Lahti
authors.affiliation: Institute of Medical Technology, Tampere, Finland.
authors.forename: K
authors.initials: K
authors.lastname: Krohn
authors.affiliation: Department of Neurology, University of Regensburg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Schalke
authors.affiliation: Department of Neurology, University of Mainz, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Nix
authors.affiliation: Department of Neurology, University of Göttingen, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Gold
authors.affiliation: Department of Neurology, University of Würzburg, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Rieckmann
authors.affiliation: Department of Neurology, University of Würzburg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Toyka
authors.affiliation: Institute of Pathology, University of Würzburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Burek
authors.affiliation: Institute of Pathology, University of Würzburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Rosenwald
authors.affiliation: Institute of Pathology, University of Würzburg, Germany.
authors.forename: H K
authors.initials: HK
authors.lastname: Müller-Hermelink
authors.affiliation: Institut Germans Trias i Pujol, Barcelona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Pujoll-Borrell
authors.affiliation: Biotherapeutics, National Institute for Biological Standards and Control, South Mimms, UK.
authors.forename: A
authors.initials: A
authors.lastname: Meager
authors.affiliation: Neurosciences Group, Weatherall Institute of Molecular Medicine, University of Oxford, UK.
authors.forename: N
authors.initials: N
authors.lastname: Willcox
authors.affiliation: Molecular Pathology, University of Tartu, Estonia.
authors.forename: P
authors.initials: P
authors.lastname: Peterson
authors.affiliation: Institute of Pathology, University Medical Centre Mannheim, University of Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Marx
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000912:Antibodies, Neoplasm / Q000276:immunology; D000951:Antigens, Neoplasm / Q000032:analysis; D001323:Autoantibodies / Q000097:blood; D001324:Autoantigens / Q000032:analysis; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000276:immunology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007370:Interferon Type I / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis / Q000276:immunology / Q000378:metabolism; D009363:Neoplasm Proteins / Q000172:deficiency*; D016884:Polyendocrinopathies, Autoimmune / Q000276:immunology*; D013945:Thymoma / Q000737:chemistry*; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism; D013953:Thymus Neoplasms / Q000737:chemistry*; D014157:Transcription Factors / Q000172:deficiency*; D000096927:AIRE Protein
chemical_list: D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D001323:Autoantibodies; D001324:Autoantigens; D016207:Cytokines; D007370:Interferon Type I; D009363:Neoplasm Proteins; D014157:Transcription Factors; D000096927:AIRE Protein