| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Department of Immunology and
Department of Virology, Haartman Institute, University of Helsinki, Helsinki, Finland;
Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland;
Blood Service, Finnish Red Cross, Helsinki, Finland;
¶ Hospital for Children and Adolescents, Helsinki University Central Hospital, Helsinki, Finland; and
|| Department of Immunology, Diagnostics Laboratory, Helsinki University Central Hospital, Helsinki, Finland
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic recessive disease characterized by autoimmunity against multiple tissues, offers a unique possibility to study the breakdown of self-tolerance in humans. It is caused by mutations in the autoimmune regulator gene (AIRE), which encodes a transcriptional regulator. Work using Aire–/– mice suggests that Aire induces ectopic expression of peripheral Ags and promotes their presentation in the thymus. We have explored reasons for the difference between the comparatively mild phenotype of Aire-deficient mice and human APECED patients. We provide evidence that, unlike in the Aire–/– mice, in the patients a key mediator of active tolerance, the CD4+CD25+ regulatory T (Treg) cell subset is impaired. This was shown by significantly decreased expression of FOXP3 mRNA and protein, decreased function, and alterations in TCR repertoire. Also, in the normal human thymus a concentric accumulation of AIRE+ cells was seen around thymic Hassall’s corpuscles, suggesting that in the patients these cells may be involved in the observed Treg cell failure. In Aire–/– mice the expression of FoxP3 was normal and even increased in target tissues in parallel with the lymphocyte infiltration process. Our results suggest that a Treg cell defect is involved in the pathogenesis of APECED and emphasize the importance of active tolerance mechanisms in preventing human autoimmunity.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Academy of Finland, the Ahokas Foundation, the Helsinki University Science Foundation, research funds of the Helsinki University Central Hospital, the Sigrid Juselius Foundation, the Päivikki and Sakari Sohlberg Foundation, the Maud Kuistila Foundation, Finska Läkaresällskapet, and the European Union’s Sixth Framework Programme (European Association of Plastic Surgeons) Project LSHM-CT-2005-005223.
2 Address correspondence and reprint requests to Dr. T. Petteri Arstila, Haartman Institute, Department of Immunology, PB21, 00014 University of Helsinki, Finland. E-mail address: petteri.arstila{at}helsinki.fi
3 Abbreviations used in this paper: APECED, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; AIRE, autoimmune regulator; Treg, regulatory T; MEC, thymic medullary epithelial cell; WT, wild type.
This article has been cited by other articles:
|
|
 |
|
  J. J. DeVoss, A. K. Shum, K. P. A. Johannes, W. Lu, A. K. Krawisz, P. Wang, T. Yang, N. P. LeClair, C. Austin, E. C. Strauss, et al. Effector Mechanisms of the Autoimmune Syndrome in the Murine Model of Autoimmune Polyglandular Syndrome Type 1 J. Immunol., September 15, 2008; 181(6): 4072 - 4079. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F.-X. Hubert, S. A. Kinkel, K. E. Webster, P. Cannon, P. E. Crewther, A. I. Proeitto, L. Wu, W. R. Heath, and H. S. Scott A Specific Anti-Aire Antibody Reveals Aire Expression Is Restricted to Medullary Thymic Epithelial Cells and Not Expressed in Periphery J. Immunol., March 15, 2008; 180(6): 3824 - 3832. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Alimohammadi, P. Bjorklund, A. Hallgren, N. Pontynen, G. Szinnai, N. Shikama, M. P. Keller, O. Ekwall, S. A. Kinkel, E. S. Husebye, et al. Autoimmune Polyendocrine Syndrome Type 1 and NALP5, a Parathyroid Autoantigen N. Engl. J. Med., March 6, 2008; 358(10): 1018 - 1028. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. De Luca, C. Montagnoli, T. Zelante, P. Bonifazi, S. Bozza, S. Moretti, C. D'Angelo, C. Vacca, L. Boon, F. Bistoni, et al. Functional yet Balanced Reactivity to Candida albicans Requires TRIF, MyD88, and IDO-Dependent Inhibition of Rorc J. Immunol., November 1, 2007; 179(9): 5999 - 6008. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
