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dc.contributor.authorSkogberg, Gabriel
dc.contributor.authorLundberg, Vanja
dc.contributor.authorLindgren, Susanne
dc.contributor.authorGudmundsdottir, Judith
dc.contributor.authorSandström, Kerstin
dc.contributor.authorKämpe, Olle
dc.contributor.authorAnnerén, Göran
dc.contributor.authorGustafsson, Jan
dc.contributor.authorSunnegårdh, Jan
dc.contributor.authorvan der Post, Sjoerd
dc.contributor.authorTelemo, Esbjörn
dc.contributor.authorBerglund, Martin
dc.contributor.authorEkwall, Olov
dc.date.accessioned2015-05-12T10:54:44Zen
dc.date.available2015-05-12T10:54:44Zen
dc.date.issued2014-09-01en
dc.date.submitted2015en
dc.identifier.citationJ. Immunol. 2014, 193 (5):2187-95en
dc.identifier.issn1550-6606en
dc.identifier.pmid25038256en
dc.identifier.doi10.4049/jimmunol.1400742en
dc.identifier.urihttp://hdl.handle.net/2336/552655en
dc.descriptionTo access publisher's full text version of this article click on the hyperlink at the bottom of the pageen
dc.description.abstractDown syndrome (DS), caused by trisomy of chromosome 21, is associated with immunological dysfunctions such as increased frequency of infections and autoimmune diseases. Patients with DS share clinical features, such as autoimmune manifestations and specific autoantibodies, with patients affected by autoimmune polyendocrine syndrome type 1. Autoimmune polyendocrine syndrome type 1 is caused by mutations in the autoimmune regulator (AIRE) gene, located on chromosome 21, which regulates the expression of tissue-restricted Ags (TRAs) in thymic epithelial cells. We investigated the expression of AIRE and TRAs in DS and control thymic tissue using quantitative PCR. AIRE mRNA levels were elevated in thymic tissue from DS patients, and trends toward increased expression of the AIRE-controlled genes INSULIN and CHRNA1 were found. Immunohistochemical stainings showed altered cell composition and architecture of the thymic medulla in DS individuals with increased frequencies of AIRE-positive medullary epithelial cells and CD11c-positive dendritic cells as well as enlarged Hassall's corpuscles. In addition, we evaluated the proteomic profile of thymic exosomes in DS individuals and controls. DS exosomes carried a broader protein pool and also a larger pool of unique TRAs compared with control exosomes. In conclusion, the increased AIRE gene dose in DS could contribute to an autoimmune phenotype through multiple AIRE-mediated effects on homeostasis and function of thymic epithelial cells that affect thymic selection processes.
dc.description.sponsorshipSwedish Research Council 80409601 Marianne and Marcus Wallenberg Foundation Region Vastra Gotaland ALFGBG-771712 Arbetsmarknadens Forsakringsaktiebolag 100258 IngaBritt and Arne Lundbergs Research Foundation AnnMari and Per Ahlqvists Foundation Gothenburg Medical Society Wilhelm and Martina Lundgrens Research Foundationen
dc.language.isoenen
dc.publisherAmer Assoc Immunologistsen
dc.relation.urlhttp://dx.doi.org/ 10.4049/jimmunol.1400742en
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135177/en
dc.relation.urlhttp://www.jimmunol.org/content/193/5/2187.full.pdfen
dc.rightsArchived with thanks to Journal of immunology (Baltimore, Md. : 1950)en
dc.subjectDowns heilkennien
dc.subject.meshAntigens, CD11cen
dc.subject.meshChromosomes, Human, Pair 21en
dc.subject.meshDendritic Cellsen
dc.subject.meshDown Syndromeen
dc.subject.meshEpithelial Cellsen
dc.subject.meshExosomesen
dc.subject.meshFemaleen
dc.subject.meshGene Dosageen
dc.subject.meshGene Expression Regulationen
dc.subject.meshHumansen
dc.subject.meshImmunohistochemistryen
dc.subject.meshInfanten
dc.subject.meshInfant, Newbornen
dc.subject.meshInsulinen
dc.subject.meshMaleen
dc.subject.meshPhenotypeen
dc.subject.meshRNA, Messengeren
dc.subject.meshReceptors, Nicotinicen
dc.subject.meshThymus Glanden
dc.subject.meshTranscription Factorsen
dc.titleAltered expression of autoimmune regulator in infant down syndrome thymus, a possible contributor to an autoimmune phenotype.en
dc.typeArticleen
dc.contributor.department[ 1 ] Univ Gothenburg, Dept Rheumatol & Inflammat Res, Inst Med, S-40530 Gothenburg, Sweden [ 2 ] Univ Gothenburg, Inst Clin Sci, Dept Pediat, S-41686 Gothenburg, Sweden [ 3 ] Univ Gothenburg, Sahlgrenska Acad, Dept Pediat Anesthesia & Intens Care, S-41686 Gothenburg, Sweden [ 4 ] Karolinska Inst, Dept Med Solna, Ctr Mol Med, S-17176 Stockholm, Sweden [ 5 ] Uppsala Univ, Sci Life Lab, S-75003 Uppsala, Sweden [ 6 ] Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, S-75185 Uppsala, Sweden [ 7 ] Uppsala Univ, Dept Womens & Childrens Hlth, S-75185 Uppsala, Sweden [ 8 ] Univ Gothenburg, Sahlgrenska Acad, Prote Core Facil, S-41390 Gothenburg, Swedenen
dc.identifier.journalJournal of immunology (Baltimore, Md. : 1950)en
dc.rights.accessLandspitali Access - LSH-aðganguren
html.description.abstractDown syndrome (DS), caused by trisomy of chromosome 21, is associated with immunological dysfunctions such as increased frequency of infections and autoimmune diseases. Patients with DS share clinical features, such as autoimmune manifestations and specific autoantibodies, with patients affected by autoimmune polyendocrine syndrome type 1. Autoimmune polyendocrine syndrome type 1 is caused by mutations in the autoimmune regulator (AIRE) gene, located on chromosome 21, which regulates the expression of tissue-restricted Ags (TRAs) in thymic epithelial cells. We investigated the expression of AIRE and TRAs in DS and control thymic tissue using quantitative PCR. AIRE mRNA levels were elevated in thymic tissue from DS patients, and trends toward increased expression of the AIRE-controlled genes INSULIN and CHRNA1 were found. Immunohistochemical stainings showed altered cell composition and architecture of the thymic medulla in DS individuals with increased frequencies of AIRE-positive medullary epithelial cells and CD11c-positive dendritic cells as well as enlarged Hassall's corpuscles. In addition, we evaluated the proteomic profile of thymic exosomes in DS individuals and controls. DS exosomes carried a broader protein pool and also a larger pool of unique TRAs compared with control exosomes. In conclusion, the increased AIRE gene dose in DS could contribute to an autoimmune phenotype through multiple AIRE-mediated effects on homeostasis and function of thymic epithelial cells that affect thymic selection processes.


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