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Blood, 1 October 2008, Vol. 112, No. 7, pp. 2657-2666.
Prepublished online as a Blood First Edition Paper on July 7, 2008; DOI 10.1182/blood-2008-03-144634.
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Submitted March 14, 2008
Accepted June 16, 2008
Interferon autoantibodies associated with AIRE-deficiency decrease the expression of IFN-stimulated genes
Kai Kisand*, Maire Link, Anette S. B. Wolff, Anthony Meager, Liina Tserel, Tonis Org, Astrid Murumagi, Raivo Uibo, Nick Willcox, Katarina Trebusak Podkrajsek, Tadej Battelino, Anna Lobell, Olle Kampe, Kari Lima, Antonella Meloni, Berrin Ergun-Longmire, Noel K Maclaren, Jaakko Perheentupa, Kai J. E. Krohn, Hamish S. Scott, Eystein S. Husebye, and Part Peterson
Institute of General and Molecular Pathology, University of Tartu, Tartu, Estonia
Institute of Medicine, University of Bergen, Bergen, Norway
Biotherapeutics, The National Institute for Biological Standards and Control, Herts, United Kingdom
Institute of Medical Technology, University of Tampere, Tampere, Finland
Neurosciences Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
Centre for Medical Genetics, University Children's Hospital, Ljubljana, Slovenia
Department of Pediatric Endocrinology, Diabetes and Metabolism, University Children's Hospital, Ljubljana, Slovenia
Department of Medical Sciences, Uppsala University, Uppsala, Sweden
Section of Endocrinology, Akershus University Hospital, University of Oslo, Oslo, Norway
Pediatric Clinic II, Ospedale Microcitemico, and Department of Biomedical and Biotechnological Science, University of Cagliari, Sardinia, Italy
Division of Pediatric Endocrionology, UMDNJ/Robert Wood Johnson Medical School, New Brunswick, NJ, United States
Bioseek Clinics, New York, NY, United States
The Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland
Dermagene Oy, Tampere, Finland
Division of Molecular Pathology, The Institute of Medical and Veterinary Science and The Hanson Institute, Adelaide, Australia
Department of Medicine, Haukeland University Hospital, Bergen, Norway
* Corresponding author; email: kai.kisand{at}ut.ee.
Neutralizing autoantibodies to type I, but not type II, interferons (IFN) are found at high titers in almost every patient with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), a disease caused by AIRE gene mutations that lead to defects in thymic T cell selection. Combining genome-wide expression array with real time RT-PCR assays, we here demonstrate that antibodies against IFN- cause highly significant down-regulation of interferon-stimulated gene expression in cells from APECED patients' blood by blocking their highly dilute endogenous IFNs. This down-regulation was lost progressively as these APECED cells matured in cultures without neutralizing autoantibodies. Most interestingly, a rare APECED patient with autoantibodies to IFN- but not IFN- showed marked increase in expression of the same interferon-stimulated genes. We also report unexpected increases in serum CXCL10 levels in APECED. Our results argue that the breakdown of tolerance to IFNs in AIRE deficiency is associated with impaired responses to them in thymus, and highlight APECED as another autoimmune disease with associated dysregulation of IFN activity.
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E. Lindh, S. M. Lind, E. Lindmark, S. Hassler, J. Perheentupa, L. Peltonen, O. Winqvist, and M. C. I. Karlsson
AIRE regulates T-cell-independent B-cell responses through BAFF
PNAS,
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[Abstract]
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