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      Association of Cytotoxic T-Lymphocyte-Associated Protein 4 ( CTLA4) Gene Polymorphisms with Autoimmune Thyroid Disease in Children and Adults: Case-Control Study

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          Abstract

          Autoimmune thyroid disease (AITD), including Graves disease (GD) and Hashimoto disease (HD), is an organ-specific autoimmune disease with a strong genetic component. Although the cytotoxic T-lymphocyte-associated protein 4 ( CTLA4) polymorphism has been reported to be associated with AITD in adults, few studies have focused on children. The aim of our study was to investigate whether the CTLA4 polymorphisms, including -318C/T (rs5742909), +49A/G (rs231775), and CT60 (rs3087243), were associated with GD and HD in Han Chinese adults and children. We studied 289 adult GD, 265 pediatric GD, 229 pediatric HD patients, and 1058 healthy controls and then compared genotype, allele, carrier, and haplotype frequencies between patients and controls. We found that CTLA4 SNPs +49A/G and CT60 were associated with GD in adults and children. Allele G of +49A/G was significantly associated with GD in adults (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.21–1.84; corrected P value [ Pc] < 0.001) and children (OR, 1.42; 95% CI, 1.15–1.77; Pc = 0.002). Allele G of CT60 also significantly increased risk of GD in adults (OR, 1.63; 95% CI, 1.27–2.09; Pc < 0.001) and GD in children (OR, 1.58; 95% CI, 1.22–2.04; Pc < 0.001). Significant linkage disequilibrium was found between +49A/G and CT60 in GD and control subjects (D’ = 0.92). Our results showed that CTLA4 was associated with both GD and HD and played an equivalent role in both adult and pediatric GD in Han Chinese population.

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          Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways.

          Classically, the CD28/cytotoxic T-lymphocyte antigen-4 (CTLA-4) and B7 families of cell surface molecules regulate complex signaling pathways that profoundly affect T-cell responses. The recent identification and characterization of additional CD28 and B7 family members including programmed death-1 (PD-1), programmed death ligand-1 (PD-L1) (B7-H1), and PD-L2 (B7-DC) has added to the complexity and greater appreciation of how surface molecules control T-cell activation and peripheral tolerance. CD28/B7 interactions mediate co-stimulation and significantly enhance peripheral T-cell responses. CTLA-4, in contrast, interacting with the same B7 molecules, results in decreased T-lymphocyte activity and regulates the immune response. Similarly, PD-1 interactions with PD-L1 and PD-L2 downmodulate T-cell immune responses. Despite these similarities, the regulatory roles of the CTLA-4 and PD-1 pathways are distinct. This may be due, at least in part, to the differential expression patterns of the CTLA-4 and PD-1 ligands both temporally and spatially. This article examines the role of CTLA-4 and PD-1 in limiting autoreactivity and establishing peripheral self-tolerance with the hypothesis that CTLA-4 signals are required early in the lymph node during initiation of an immune response and PD-1 pathways act late at the tissue sites to limit T-cell activity.
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            The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry.

            Susceptibility to autoimmune insulin-dependent (type 1) diabetes mellitus is determined by a combination of environmental and genetic factors, which include variation in MHC genes on chromosome 6p21 (IDDM1) and the insulin gene on chromosome 11p15 (IDDM2). However, linkage to IDDM1 and IDDM2 cannot explain the clustering of type 1 diabetes in families, and a role for other genes is inferred. In the present report we describe linkage and association of type 1 diabetes to the CTLA-4 gene (cytotoxic T lymphocyte associated-4) on chromosome 2q33 (designated IDDM12). CTLA-4 is a strong candidate gene for T cell-mediated autoimmune disease because it encodes a T cell receptor that mediates T cell apoptosis and is a vital negative regulator of T cell activation. In addition, we provide supporting evidence that CTLA-4 is associated with susceptibility to Graves' disease, another organ-specific autoimmune disease.
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              Immunogenetics of autoimmune thyroid diseases: A comprehensive review.

              Both environmental and genetic triggers factor into the etiology of autoimmune thyroid disease (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis (HT). Although the exact pathogenesis and causative interaction between environment and genes are unknown, GD and HT share similar immune-mediated mechanisms of disease. They both are characterized by the production of thyroid autoantibodies and by thyroidal lymphocytic infiltration, despite being clinically distinct entities with thyrotoxicosis in GD and hypothyroidism in HT. Family and population studies confirm the strong genetic influence and inheritability in the development of AITD. AITD susceptibility genes can be categorized as either thyroid specific (Tg, TSHR) or immune-modulating (FOXP3, CD25, CD40, CTLA-4, HLA), with HLA-DR3 carrying the highest risk. Of the AITD susceptibility genes, FOXP3 and CD25 play critical roles in the establishment of peripheral tolerance while CD40, CTLA-4, and the HLA genes are pivotal for T lymphocyte activation and antigen presentation. Polymorphisms in these immune-modulating genes, in particular, significantly contribute to the predisposition for GD, HT and, unsurprisingly, other autoimmune diseases. Emerging evidence suggests that single nucleotide polymorphisms (SNPs) in the immunoregulatory genes may functionally hinder the proper development of central and peripheral tolerance and alter T cell interactions with antigen presenting cells (APCs) in the immunological synapse. Thus, susceptibility genes for AITD contribute directly to the key mechanism underlying the development of organ-specific autoimmunity, namely the breakdown in self-tolerance. Here we review the major immune-modulating genes that are associated with AITD and their potential functional effects on thyroidal immune dysregulation.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                25 April 2016
                2016
                : 11
                : 4
                : e0154394
                Affiliations
                [1 ]Department of Pediatrics, MacKay Children’s Hospital, Taipei, Taiwan
                [2 ]Department of Endocrinology and Metabolism, MacKay Memorial Hospital, Taipei, Taiwan
                [3 ]Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
                [4 ]Institute of Mechatronic Engineering, National Taipei University of Technology, Taipei, Taiwan
                [5 ]MacKay Junior College of Medicine, Nursing and Management, New Taipei City, Taiwan
                [6 ]Department of Pediatrics, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan
                [7 ]College of Medicine, Chang Gung University, Tao-Yuan, Taiwan
                [8 ]Department of Medical Research, MacKay Memorial Hospital Tamsui, New Taipei City, Taiwan
                [9 ]Department of Pediatrics, MacKay Memorial Hospital HsinChu, Hsin-Chu, Taiwan
                [10 ]Department of Pediatrics, Chiayi Christian Hospital, Chia-Yi, Taiwan
                [11 ]Department of Pediatrics, Changhua Christian Hospital, Chang-Hua, Taiwan
                [12 ]Department of Pediatrics, Hsinchu Cathay General Hospital, Hsin-Chu, Taiwan
                [13 ]Department of Pediatrics, St. Martin De Porres Hospital, Chia-Yi, Taiwan
                [14 ]Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
                [15 ]Institute of Biomedical Sciences, MacKay Medical College, New Taipei City, Taiwan
                Baylor College of Medicine, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: YJL MNC CHW. Performed the experiments: CLL WSL TYC HWY WFC YPL. Analyzed the data: WHT YJL. Contributed reagents/materials/analysis tools: FSL CYH. Wrote the paper: WHT YJL. Subject recruitment: BWC CHL CCC YLW CMH HJL CIC.

                Article
                PONE-D-15-54025
                10.1371/journal.pone.0154394
                4844099
                27111218
                5bd001a1-e921-4e29-a5da-6b1abe107d6d
                © 2016 Ting et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 13 December 2015
                : 11 April 2016
                Page count
                Figures: 1, Tables: 4, Pages: 13
                Funding
                This study was supported by grants NSC 101-2314-B-715-002-MY3 from the Ministry of Science and Technology, Executive Yuan; MMH E-102-07 from MacKay Memorial Hospital, Taipei; and MMC RD1010045 from MacKay Medical College, New Taipei City, Taiwan.
                Categories
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