Deficiency of the autoimmune regulator AIRE in thymomas is insufficient to elicit autoimmune polyendocrinopathy syndrome type 1 (APS-1).
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.
Ströbel
P
P
Institute of Pathology, University Medical Centre Mannheim, University of Heidelberg, Germany.
Murumägi
A
A
Institute of Medical Technology, Tampere, Finland.
Klein
R
R
Department of Internal Medicine II, University of Tübingen, Germany.
Luster
M
M
Department of Nuclear Medicine, University of Würzburg, Germany.
Lahti
M
M
Institute of Medical Technology, Tampere, Finland.
Krohn
K
K
Institute of Medical Technology, Tampere, Finland.
Schalke
B
B
Department of Neurology, University of Regensburg, Germany.
Nix
W
W
Department of Neurology, University of Mainz, Germany.
Gold
R
R
Department of Neurology, University of Göttingen, Germany.
Rieckmann
P
P
Department of Neurology, University of Würzburg, Germany.
Toyka
K
K
Department of Neurology, University of Würzburg, Germany.
Burek
C
C
Institute of Pathology, University of Würzburg, Germany.
Rosenwald
A
A
Institute of Pathology, University of Würzburg, Germany.
Müller-Hermelink
H K
HK
Institute of Pathology, University of Würzburg, Germany.
Pujoll-Borrell
R
R
Institut Germans Trias i Pujol, Barcelona, Spain.
Meager
A
A
Biotherapeutics, National Institute for Biological Standards and Control, South Mimms, UK.
Willcox
N
N
Neurosciences Group, Weatherall Institute of Molecular Medicine, University of Oxford, UK.
Peterson
P
P
Molecular Pathology, University of Tartu, Estonia.
Marx
A
A
Institute of Pathology, University Medical Centre Mannheim, University of Heidelberg, Germany.
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
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