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dc.contributor.authorMeager, Anthonyeng
dc.contributor.authorVisvalingam, Kumuthinieng
dc.contributor.authorPeterson, Pärteng
dc.contributor.authorMöll, Kaidieng
dc.contributor.authorMurumägi, Astrideng
dc.contributor.authorKrohn, Kaieng
dc.contributor.authorEskelin, Petraeng
dc.contributor.authorPerheentupa, Jaakkoeng
dc.contributor.authorHusebye, Eystein Sverreeng
dc.contributor.authorKadota, Yoshihisaeng
dc.contributor.authorWillcox, Nickeng
dc.date.accessioned2006-11-27T17:58:12Z
dc.date.available2006-11-27T17:58:12Z
dc.date.issued2006-06-13eng
dc.identifier.citationPLoS Med 3(7): e289
dc.identifier.issn1549-1277eng
dc.identifier.urihttp://hdl.handle.net/1956/1991
dc.description.abstractBackground The autoimmune regulator (AIRE) gene influences thymic self-tolerance induction. In autoimmune polyendocrinopathy syndrome type 1 (APS1; OMIM 240300), recessive AIRE mutations lead to autoimmunity targetting endocrine and other epithelial tissues, although chronic candidiasis usually appears first. Autoimmunity and chronic candidiasis can associate with thymomas as well. Patients with these tumours frequently also have high titre immunoglobulin G autoantibodies neutralising type I interferon (IFN)–α and IFN-ω, which are secreted signalling proteins of the cytokine superfamily involved in both innate and adaptive immunity. Methods and Findings We tested for serum autoantibodies to type I IFNs and other immunoregulatory cytokines using specific binding and neutralisation assays. Unexpectedly, in 60/60 Finnish and 16/16 Norwegian APS1 patients with both AIRE alleles mutated, we found high titre neutralising immunoglobulin G autoantibodies to most IFN-α subtypes and especially IFN-ω (60% homologous to IFN-α)—mostly in the earliest samples. We found lower titres against IFN-β (30% homologous to IFN-α) in 23% of patients; two-thirds of these (from Finland only) also had low titres against the distantly related “type III IFN” (IFN-λ1; alias interleukin-29). However, autoantibodies to the unrelated type II IFN, IFN-γ, and other immunoregulatory cytokines, such as interleukin-10 and interleukin-12, were much rarer and did not neutralise. Neutralising titres against type I IFNs averaged even higher in patients with APS1 than in patients with thymomas. Anti–type I IFN autoantibodies preceded overt candidiasis (and several of the autoimmune disorders) in the informative patients, and persisted for decades thereafter. They were undetectable in unaffected heterozygous relatives of APS1 probands (except for low titres against IFN-λ1), in APS2 patients, and in isolated cases of the endocrine diseases most typical of APS1, so they appear to be APS1-specific. Looking for potentially autoimmunising cell types, we found numerous IFN-α+ antigen-presenting cells—plus strong evidence of local IFN secretion—in the normal thymic medulla (where AIRE expression is strongest), and also in normal germinal centres, where it could perpetuate these autoantibody responses once initiated. IFN-α2 and IFN-α8 transcripts were also more abundant in antigen-presenting cells cultured from an APS1 patient's blood than from age-matched healthy controls. Conclusions These apparently spontaneous autoantibody responses to IFNs, particularly IFN-α and IFN-ω, segregate like a recessive trait; their high “penetrance” is especially remarkable for such a variable condition. Their apparent restriction to APS1 patients implies practical value in the clinic, e.g., in diagnosing unusual or prodromal AIRE-mutant patients with only single components of APS1, and possibly in prognosis if they prove to predict its onset. These autoantibody responses also raise numerous questions, e.g., about the rarity of other infections in APS1. Moreover, there must also be clues to autoimmunising mechanisms/cell types in the hierarchy of preferences for IFN-ω, IFN-α8, IFN-α2, and IFN-β and IFN-λ1.en
dc.format.extent329759 byteseng
dc.format.mimetypeapplication/pdfeng
dc.language.isoengeng
dc.publisherPublic Library of Scienceeng
dc.titleAnti-Interferon Autoantibodies in Autoimmune Polyendocrinopathy Syndrome Type 1eng
dc.typeJournal articleeng
dc.typePeer reviewedeng
dc.subject.nsiVDP::Medisinske Fag: 700nob
bora.peerreviewedPeer reviewedeng
bora.cristinID374238eng
bibo.doihttp://dx.doi.org/10.1371/journal.pmed.0030289eng
dc.identifier.cristinID374238eng
dc.identifier.doihttp://dx.doi.org/10.1371/journal.pmed.0030289


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