Available online at www.sciencedirect.com Immunology Letters 114 (2007) 31–37 Graft-versus-host-like disease complicating thymoma: Lack of AIRE expression as a cause of non-hereditary autoimmunity? G. Johan Offerhaus a , Marguerite E.I. Schipper a , Audrey J. Lazenby b , Elizabeth Montgomery c , Folkert H.M. Morsink a , Richard J. Bende e , Alex R. Musler e , Rene A.W. van Lier d , Carel J.M. van Noesel e,∗ a Department of Pathology, University Medical Center Utrecht, The Netherlands b Department of Pathology, The University of Alabama Hospital, Birmingham, AL, USA c Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD, USA d Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands e Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands Received 22 August 2007; accepted 30 August 2007 Available online 29 September 2007 Abstract Three patients with graft-versus-host-like enterocolonopathy are reported. Their history was remarkable for thymoma and other autoimmune manifestations such as thrombocytopenia, red cell aplasia, interface dermatitis, Sjogren sialadenits, vanishing bile ducts and rheumatoid arthritis. In all patients, microsatellite analysis showed the autologous nature of the lymphocytes in the affected organs ruling out GVHD. In search for mechanisms that could mediate loss of tolerance to self-antigens we found in a panel of thymomas, including those of the three patients, a complete lack of autoimmune regulator (AIRE) and minimal expression of the transcription factor FOXP3 in the intra-tumoral T cells. AIRE is a recently discovered transcription factor which plays a key role in the maintenance of central tolerance and is mutated in the autosomal recessive autoimmune polyendocrinopathy syndrome APS-1. Our observations indicate that thymoma-related autoimmunity can potentially be elicited by an incomplete deletion of ‘self’-specific T cells in concert with an insufficient formation of natural Tregs. © 2007 Elsevier B.V. All rights reserved. Keywords: Thymoma; Graft-versus-host-disease; Autoimmunity; Microsatellite; AIRE; FOXP3; T-cell development 1. Introduction In normal thymus, immature T cells are initially positively selected in the cortex on the basis of their capacity to bind MHC–peptide complexes with sufficient affinity [1,2]. Next, upon migration through the medullary epithelium cell (MEC) network, T cells with specificity for ‘self’-antigens are clon- ally deleted. This process of central tolerance induction largely depends on the autoimmune regulator (AIRE) gene, a tran- scription factor that controls the ectopic expression of a wide range of peripheral, organ specific genes in MECs [3,4]. In ∗ Corresponding author at: Department of Pathology, M2-229a, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Tel.: +31 20 5662827; fax: +31 20 6360389. E-mail address: c.j.vannoesel@amc.uva.nl (C.J.M. van Noesel). a transgenic, hen egg lysozyme (HEL)-specific mouse model, HEL-reactive thymocytes failed to be deleted in the absence of AIRE [5]. In accordance with its key role in the negative selection of auto-reactive thymocytes, AIRE has been implicated in the hereditary autoimmune polyendocrinopathy syndrome type 1 (APS-1), also designated as auto-immune polyendocrinopathy- candidiasis-ectodermal dystrophy (APECED) [6,7], as well as in a murine multi-organ autoimmune syndrome [8]. An addi- tional mechanism of tolerance induction in the thymic medulla occurs through generation of regulatory T cells (Tregs) capa- ble of controlling peripheral, self-reactive T cells that escaped negative selection [9]. The generation of these CD4 + CD25 + IL- 7R + Tregs depends on the forkhead transcription factor FOXP3. Loss-of-function mutations in FOXP3 provoke the autoim- mune ‘immunodysregulation, polyendocrinopathy, enteropathy X-linked syndrome’ (IPEX) [10,11]. 0165-2478/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.imlet.2007.08.010