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Altered expression of autoimmune regulator in infant down syndrome thymus, a possible contributor to an autoimmune phenotype.

Journal article
Authors Gabriel Skogberg
Vanja Lundberg
Susanne Lindgren
Judith Gudmundsdottir
Kerstin Sandström
Olle Kämpe
Göran Annerén
Jan Gustafsson
Jan Sunnegårdh
Sjoerd van der Post
Esbjörn Telemo
Martin Berglund
Olov Ekwall
Published in Journal of Immunology
Volume 193
Issue 5
Pages 2187-95
ISSN 0022-1767
Publication year 2014
Published at Institute of Medicine, Department of Rheumatology and Inflammation Research
Core Facilities, Proteomics
Institute of Clinical Sciences, Department of Pediatrics
Pages 2187-95
Language en
Links dx.doi.org/10.4049/jimmunol.1400742
Subject categories Pediatrics

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.

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