Interferon autoantibodies associated with AIRE deficiency decrease the expression of IFN-stimulated genes

Kai Kisand, Maire Link, Anette S. Bøe Wolff, Anthony Meager, Liina Tserel, Tonis Org, Astrid Murumägi, Raivo Uibo, Nick Willcox, Katarina Trebusak Podkrajsek, Tadej Battelino, Anna Lobell, Olle Kämpe, Kari Lima, Antonella Meloni, Berrin Ergun-Longmire, Noel K Maclaren, Jaakko Perheentupa, Kai Krohn, Hamish S ScottEystein S Husebye, Pärt Peterson

    Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

    Sammanfattning

    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-alpha cause highly significant down-regulation of interferon-stimulated gene expression in cells from APECED patients' blood by blocking their highly dilute endogenous IFNs. This downregulation was lost progressively as these APECED cells matured in cultures without neutralizing autoantibodies. Most interestingly, a rare APECED patient with autoantibodies to IFN-omega but not IFN-alpha 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.
    Originalspråkengelska
    TidskriftBlood
    Volym112
    Utgåva7
    Sidor (från-till)2657-2666
    Antal sidor10
    ISSN0006-4971
    DOI
    StatusPublicerad - 2008
    MoE-publikationstypA1 Tidskriftsartikel-refererad

    Citera det här