Stroebel, Philipp and Murumagi, A. and Klein, R. and Luster, M. and Lahti, M. and Krohn, K. and Schalke, B. and Nix, W. and Gold, R. and Rieckmann, P. and Toyka, K. and Burek, C. and Rosenwald, A. and Mueller-Hermelink, H. K. and Pujoll-Borrell, R. and Meager, A. and Willcox, N. and Peterson, P. and Marx, A. (2007) Deficiency of the autoimmune regulator AIRE in thymomas is insufficient to elicit autoimmune polyendocrinopathy syndrome type I (APS-I). JOURNAL OF PATHOLOGY, 211 (5). pp. 563-571. ISSN 0022-3417,
Full text not available from this repository. (Request a copy)Abstract
Thymomas are thymic epithelial neoplasms, associated with a variety of autoimmune disorders (especially myasthenia gravis), that apparently result from aberrant intratumourous 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 lautoirnmune 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 similar to 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 similar to 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 (c) 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CANDIDIASIS-ECTODERMAL DYSTROPHY; PRIMARY BILIARY-CIRRHOSIS; DISEASE TYPE-I; MYASTHENIA-GRAVIS; T-CELLS; NEGATIVE SELECTION; PROTEIN EXPRESSION; MESSENGER-RNA; AUTOANTIBODIES; ANTIBODIES; AIRE; thymomas; polyendocrinopathy syndrome type I |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Neurologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 16 Dec 2020 14:48 |
| Last Modified: | 16 Dec 2020 14:48 |
| URI: | https://pred.uni-regensburg.de/id/eprint/32973 |
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