1. Interferon autoantibodies associated with AIRE deficiency decrease the expression of IFN-stimulated genes
- Author
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Olle Kämpe, Maire Link, Hamish S. Scott, Kai Krohn, Liina Tserel, Berrin Ergun-Longmire, Jaakko Perheentupa, Tõnis Org, Nick Willcox, Eystein S. Husebye, Anna Lobell, Astrid Murumägi, Anette S. B. Wolff, Tadej Battelino, Antonella Meloni, Kari Lima, Kai Kisand, Pärt Peterson, Katarina Trebušak Podkrajšek, Noel K. Maclaren, Raivo Uibo, and Anthony Meager
- Subjects
Male ,medicine.medical_treatment ,Gene mutation ,medicine.disease_cause ,Biochemistry ,Monocytes ,Autoimmunity ,0302 clinical medicine ,Interferon ,Phosphorylation ,Polyendocrinopathies, Autoimmune ,Oligonucleotide Array Sequence Analysis ,Chemokines, Cytokines, and Interleukins ,0303 health sciences ,Hematology ,Autoimmune polyendocrinopathy ,Middle Aged ,3. Good health ,Cytokine ,STAT1 Transcription Factor ,Interferon Type I ,Female ,medicine.drug ,Adult ,animal structures ,Adolescent ,Immunology ,Down-Regulation ,Biology ,Cell Line ,03 medical and health sciences ,Neutralization Tests ,medicine ,Humans ,030304 developmental biology ,Autoantibodies ,Autoimmune disease ,Blood Cells ,Autoantibody ,Models, Immunological ,Cell Biology ,Dendritic Cells ,medicine.disease ,Chemokine CXCL10 ,Case-Control Studies ,Cancer research ,Interferons ,Interferon type I ,030215 immunology ,Transcription Factors - Abstract
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-α 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-ω but not IFN-α 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.
- Published
- 2008