No conflicts of interest were declared.
Deficiency of the autoimmune regulator AIRE in thymomas is insufficient to elicit autoimmune polyendocrinopathy syndrome type 1 (APS-1)†
Article first published online: 2 MAR 2007
Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Journal of Pathology
Volume 211, Issue 5, pages 563–571, April 2007
How to Cite
Ströbel, P., Murumägi, A., Klein, R., Luster, M., Lahti, M., Krohn, K., Schalke, B., Nix, W., Gold, R., Rieckmann, P., Toyka, K., Burek, C., Rosenwald, A., Müller-Hermelink, H., Pujoll-Borrell, R., Meager, A., Willcox, N., Peterson, P. and Marx, A. (2007), Deficiency of the autoimmune regulator AIRE in thymomas is insufficient to elicit autoimmune polyendocrinopathy syndrome type 1 (APS-1). J. Pathol., 211: 563–571. doi: 10.1002/path.2141
- Issue published online: 8 MAR 2007
- Article first published online: 2 MAR 2007
- Manuscript Accepted: 21 DEC 2006
- Manuscript Revised: 11 NOV 2006
- Manuscript Received: 10 AUG 2006
- European Union (Euro-Thymaide). Grant Number: LSHB-CT-2003-503410
- Deutsche Krebshilfe. Grant Number: 10-1740
- Interdisciplinary Centre for Clinical Research (IZKF), University of Würzburg, Germany
- polyendocrinopathy syndrome type I
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 ∼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 ∼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. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.