Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity
- University of Texas Southwestern Medical Center, United States
- Yale School of Medicine, United States
- Oklahoma Medical Research Foundation, United States
- Université catholique de Louvain, Belgium
- Penn State Medical School, United States
- Texas Scottish Rite Hospital for Children, United States
- Cincinnati Children's Hospital Medical Center, United States
- University of Southern California, United States
- University of California, Los Angeles, United States
Abstract
Targeted sequencing of sixteen SLE risk loci among 1349 Caucasian cases and controls produced a comprehensive dataset of the variations causing susceptibility to systemic lupus erythematosus (SLE). Two independent disease association signals in the HLA-D region identified two regulatory regions containing 3562 polymorphisms that modified thirty-seven transcription factor binding sites. These extensive functional variations are a new and potent facet of HLA polymorphism. Variations modifying the consensus binding motifs of IRF4 and CTCF in the XL9 regulatory complex modified the transcription of HLA-DRB1, HLA-DQA1 and HLA-DQB1 in a chromosome-specific manner, resulting in a 2.5-fold increase in the surface expression of HLA-DR and DQ molecules on dendritic cells with SLE risk genotypes, which increases to >4-fold after stimulation. Similar analyses of fifteen other SLE risk loci identified 1206 functional variants tightly linked with disease-associated SNPs and demonstrated that common disease alleles contain multiple causal variants modulating multiple immune system genes.
Article and author information
Author details
Reviewing Editor
- Jonathan Flint, Wellcome Trust Centre for Human Genetics, United Kingdom
Ethics
Human subjects: All the study subjects gave their written informed consent for the study. All the research protocols and methods employed were approved by UT Southwestern Institutional Review Board.
Version history
- Received: October 5, 2015
- Accepted: February 13, 2016
- Accepted Manuscript published: February 15, 2016 (version 1)
- Version of Record published: March 17, 2016 (version 2)
Copyright
© 2016, Raj et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity
eLife 5:e12089.
https://doi.org/10.7554/eLife.12089
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Transposable elements (TEs) are repetitive sequences representing ~45% of the human and mouse genomes and are highly expressed by medullary thymic epithelial cells (mTECs). In this study, we investigated the role of TEs on T-cell development in the thymus. We performed multiomic analyses of TEs in human and mouse thymic cells to elucidate their role in T-cell development. We report that TE expression in the human thymus is high and shows extensive age- and cell lineage-related variations. TE expression correlates with multiple transcription factors in all cell types of the human thymus. Two cell types express particularly broad TE repertoires: mTECs and plasmacytoid dendritic cells (pDCs). In mTECs, transcriptomic data suggest that TEs interact with transcription factors essential for mTEC development and function (e.g., PAX1 and REL), and immunopeptidomic data showed that TEs generate MHC-I-associated peptides implicated in thymocyte education. Notably, AIRE, FEZF2, and CHD4 regulate small yet non-redundant sets of TEs in murine mTECs. Human thymic pDCs homogenously express large numbers of TEs that likely form dsRNA, which can activate innate immune receptors, potentially explaining why thymic pDCs constitutively secrete IFN ɑ/β. This study highlights the diversity of interactions between TEs and the adaptive immune system. TEs are genetic parasites, and the two thymic cell types most affected by TEs (mTEcs and pDCs) are essential to establishing central T-cell tolerance. Therefore, we propose that orchestrating TE expression in thymic cells is critical to prevent autoimmunity in vertebrates.
