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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. This Article Full Text Full Text (PDF) Supplemental Tables All Versions of this Article: blood-2008-03-144634v1 112/7/2657    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kisand, K. Articles by Peterson, P. Search for Related Content PubMed PubMed Citation Articles by Kisand, K. Articles by Peterson, P. Related Collections Immunobiology Chemokines, Cytokines, and Interleukins Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CHEMOKINES, CYTOKINES, AND INTERLEUKINS Interferon autoantibodies associated with AIRE deficiency decrease the expression of IFN-stimulated genes Kai Kisand1, Maire Link1, Anette S. B. Wolff2, Anthony Meager3, Liina Tserel1, Tõnis Org1, Astrid Murumägi4, Raivo Uibo1, Nick Willcox5, Katarina Trebuak Podkrajek6, Tadej Battelino6,7, Anna Lobell8, Olle Kämpe8, Kari Lima9, Antonella Meloni10, Berrin Ergun-Longmire11, Noel K. Maclaren12, Jaakko Perheentupa13, Kai J. E. Krohn14, Hamish S. Scott15,16, Eystein S. Husebye2,17, and Pärt Peterson1 1 Institute of General and Molecular Pathology, University of Tartu, Tartu, Estonia; 2 Institute of Medicine, University of Bergen, Bergen, Norway; 3 Biotherapeutics, National Institute for Biological Standards and Control, Potters Bar, United Kingdom; 4 Institute of Medical Technology, University of Tampere, Tampere, Finland; 5 Neurosciences Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom; 6 Centre for Medical Genetics and 7 Department of Pediatric Endocrinology, Diabetes and Metabolism, University Children's Hospital, Ljubljana, Slovenia; 8 Department of Medical Sciences, Uppsala University, Uppsala, Sweden; 9 Section of Endocrinology, Akershus University Hospital, University of Oslo, Oslo, Norway; 10 Pediatric Clinic II, Ospedale Microcitemico and Department of Biomedical and Biotechnological Science, University of Cagliari, Sardinia, Italy; 11 Division of Pediatric Endocrionology, UMDNJ/Robert Wood Johnson Medical School, New Brunswick, NJ; 12 Bioseek Clinics, New York, NY; 13 Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland; 14 Dermagene Oy, Tampere, Finland; 15 Division of Molecular Medicine, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; 16 Division of Molecular Pathology, Institute of Medical and Veterinary Science and the Hanson Institute, School of Medicine at the University of Adelaide, Adelaide, Australia; and 17 Department of Medicine, Haukeland University Hospital, Bergen, Norway Neutralizing autoantibodies to type I, but not type II, interferons (IFNs) 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 a 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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