title: Altered expression of autoimmune regulator in infant down syndrome thymus, a possible contributor to an autoimmune phenotype.
abstract: Down 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.
authors.affiliation: Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, 405 30 Gothenburg, Sweden; xskoga@gu.se.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Skogberg
authors.affiliation: Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, 405 30 Gothenburg, Sweden;
authors.forename: Vanja
authors.initials: V
authors.lastname: Lundberg
authors.affiliation: Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, 405 30 Gothenburg, Sweden;
authors.forename: Susanne
authors.initials: S
authors.lastname: Lindgren
authors.affiliation: Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, 405 30 Gothenburg, Sweden; Department of Pediatrics at the Institute of Clinical Sciences, University of Gothenburg, 416 86 Gothenburg, Sweden;
authors.forename: Judith
authors.initials: J
authors.lastname: Gudmundsdottir
authors.affiliation: Department of Pediatric Anesthesia and Intensive Care at the Sahlgrenska Academy, University of Gothenburg, 416 86 Gothenburg, Sweden;
authors.forename: Kerstin
authors.initials: K
authors.lastname: Sandström
authors.affiliation: Centre of Molecular Medicine, Department of Medicine (Solna), Karolinska Institutet, 171 76 Stockholm, Sweden; Science for Life Laboratory, Uppsala University, 750 03 Uppsala, Sweden;
authors.forename: Olle
authors.initials: O
authors.lastname: Kämpe
authors.affiliation: Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden;
authors.forename: Göran
authors.initials: G
authors.lastname: Annerén
authors.affiliation: Department of Women's and Children´s Health, Uppsala University, 751 85 Uppsala, Sweden; and.
authors.forename: Jan
authors.initials: J
authors.lastname: Gustafsson
authors.affiliation: Department of Pediatrics at the Institute of Clinical Sciences, University of Gothenburg, 416 86 Gothenburg, Sweden;
authors.forename: Jan
authors.initials: J
authors.lastname: Sunnegårdh
authors.affiliation: Proteomics Core Facility at the Sahlgrenska Academy, University of Gothenburg, 413 90 Gothenburg, Sweden.
authors.forename: Sjoerd
authors.initials: S
authors.lastname: van der Post
authors.affiliation: Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, 405 30 Gothenburg, Sweden;
authors.forename: Esbjörn
authors.initials: E
authors.lastname: Telemo
authors.affiliation: Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, 405 30 Gothenburg, Sweden;
authors.forename: Martin
authors.initials: M
authors.lastname: Berglund
authors.affiliation: Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, 405 30 Gothenburg, Sweden; Department of Pediatrics at the Institute of Clinical Sciences, University of Gothenburg, 416 86 Gothenburg, Sweden;
authors.forename: Olov
authors.initials: O
authors.lastname: Ekwall
mesh_terms: D039521:CD11c Antigen / Q000276:immunology; D002891:Chromosomes, Human, Pair 21 / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D004314:Down Syndrome / Q000276:immunology* / Q000473:pathology; D004847:Epithelial Cells / Q000276:immunology / Q000473:pathology; D055354:Exosomes / Q000276:immunology / Q000473:pathology; D005260:Female; D018628:Gene Dosage / Q000276:immunology*; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D007328:Insulin / Q000276:immunology; D008297:Male; D010641:Phenotype; D012333:RNA, Messenger / Q000276:immunology; D011978:Receptors, Nicotinic / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology* / Q000473:pathology; D014157:Transcription Factors / Q000276:immunology*; D000096927:AIRE Protein
chemical_list: D039521:CD11c Antigen; D007328:Insulin; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D014157:Transcription Factors; D000096927:AIRE Protein; C523021:CHRNA1 protein, human