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Anti-Interferon Autoantibodies in Autoimmune Polyendocrinopathy Syndrome Type 1

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dc.contributor.author Meager, Anthony eng
dc.contributor.author Visvalingam, Kumuthini eng
dc.contributor.author Peterson, Pärt eng
dc.contributor.author Möll, Kaidi eng
dc.contributor.author Murumägi, Astrid eng
dc.contributor.author Krohn, Kai eng
dc.contributor.author Eskelin, Petra eng
dc.contributor.author Perheentupa, Jaakko eng
dc.contributor.author Husebye, Eystein Sverre eng
dc.contributor.author Kadota, Yoshihisa eng
dc.contributor.author Willcox, Nick eng
dc.date.accessioned 2006-11-27T17:58:12Z
dc.date.available 2006-11-27T17:58:12Z
dc.date.issued 2006-06-13 eng
dc.identifier.citation PLoS Med 3(7): e289
dc.identifier.issn 1549-1277 eng
dc.identifier.uri http://hdl.handle.net/1956/1991
dc.description.abstract Background 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.extent 329759 bytes eng
dc.format.mimetype application/pdf eng
dc.language.iso eng eng
dc.publisher Public Library of Science eng
dc.title Anti-Interferon Autoantibodies in Autoimmune Polyendocrinopathy Syndrome Type 1 eng
dc.type Journal article eng
dc.type Peer reviewed eng
dc.subject.nsi VDP::Medisinske Fag: 700 nob
bora.peerreviewed Peer reviewed eng
bora.cristinID 374238 eng
bibo.doi http://dx.doi.org/10.1371/journal.pmed.0030289 eng
dc.identifier.cristinID 374238 eng
dc.identifier.doi http://dx.doi.org/10.1371/journal.pmed.0030289


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