Ueda, H., Howson, . J M., Esposito, L, Heward, J, Snook, H, Chamberlain, G et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423, 506-511

Department of Dental Public Health, University of Helsinki, Helsinki, Uusimaa, Finland
Nature (Impact Factor: 41.46). 06/2003; 423(6939):506-11. DOI: 10.1038/nature01621
Source: PubMed

ABSTRACT Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)--which encodes a vital negative regulatory molecule of the immune system--as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes. In humans, disease susceptibility was mapped to a non-coding 6.1 kb 3' region of CTLA4, the common allelic variation of which was correlated with lower messenger RNA levels of the soluble alternative splice form of CTLA4. In the mouse model of type 1 diabetes, susceptibility was also associated with variation in CTLA-4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as exemplified by our discovery of inherited, quantitative alterations of CTLA4 contributing to autoimmune tissue destruction.

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    • "Negative immune regulators such as Programmed Death-1 (PD-1) and Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) are part of a large network of immune checkpoints that are tightly regulated in order to limit exaggerated immune responses and prevent autoimmunity [1-4]. However, in some instances such as persistent antigenic stimulation during chronic HIV or other viral infections, these negative regulators accumulate progressively on the cell surface of total and Ag-specific T and B cells [5-9]. "
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    ABSTRACT: Background Coexpression of CD160 and PD-1 on HIV-specific CD8+ T-cells defines a highly exhausted T-cell subset. CD160 binds to Herpes Virus Entry Mediator (HVEM) and blocking this interaction with HVEM antibodies reverses T-cell exhaustion. As HVEM binds both inhibitory and activatory receptors, our aim in the current study was to assess the impact of CD160-specific antibodies on the enhancement of T-cell activation.Methods Expression of the two CD160 isoforms; glycosylphosphatidylinositol-anchored (CD160-GPI) and the transmembrane isoforms (CD160-TM) was assessed in CD4 and CD8 primary T-cells by quantitative RT-PCR and Flow-cytometry. Binding of these isoforms to HVEM ligand and the differential capacities of CD160 and HVEM specific antibodies to inhibit this binding were further evaluated using a Time-Resolved Fluorescence assay (TRF). The impact of both CD160 and HVEM specific antibodies on enhancing T-cell functionality upon antigenic stimulation was performed in comparative ex vivo studies using primary cells from HIV-infected subjects stimulated with HIV antigens in the presence or absence of blocking antibodies to the key inhibitory receptor PD-1.ResultsWe first show that both CD160 isoforms, CD160-GPI and CD160-TM, were expressed in human primary CD4+ and CD8+ T-cells. The two isoforms were also recognized by the HVEM ligand, although this binding was less pronounced with the CD160-TM isoform. Mechanistic studies revealed that although HVEM specific antibodies blocked its binding to CD160-GPI, surprisingly, these antibodies enhanced HVEM binding to CD160-TM, suggesting that potential antibody-mediated HVEM multimerization and/or induced conformational changes may be required for optimal CD160-TM binding. Triggering of CD160-GPI over-expressed on Jurkat cells with either bead-bound HVEM-Fc or anti-CD160 monoclonal antibodies enhanced cell activation, consistent with a positive co-stimulatory role for CD160-GPI. However, CD160-TM did not respond to this stimulation, likely due to the lack of optimal HVEM binding. Finally, ex vivo assays using PBMCs from HIV viremic subjects showed that the use of CD160-GPI-specific antibodies combined with blockade of PD-1 synergistically enhanced the proliferation of HIV-1 specific CD8+ T-cells upon antigenic stimulation.Conclusions Antibodies targeting CD160-GPI complement the blockade of PD-1 to enhance HIV-specific T-cell responses and warrant further investigation in the development of novel immunotherapeutic approaches.
    Journal of Translational Medicine 09/2014; 12(1):217. DOI:10.1186/s12967-014-0217-y · 3.93 Impact Factor
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    • "Recent genome-wide association studies (GWAS) have identified a large number of single nucleotide polymorphisms associated with diabetes and obesity [1], but identification of the causal variants in these loci is a formidable challenge. Inbred animal models of diabetes and obesity are therefore invaluable to decipher the complexity of human diabetes and obesity, as evidenced by the identification of common functional variants of a gene involved in type 1 diabetes susceptibility in both humans and mice [2]. "
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    ABSTRACT: BackgroundA susceptibility locus, Nidd2n, for type 2 diabetes has been mapped to mouse chromosome 14 (Chr 14) and confirmed using the consomic strain (C3H-Chr 14NSY) of the Nagoya-Shibata-Yasuda (NSY) mouse, an animal model of spontaneous type 2 diabetes. The aim of this study was to localize and characterize Nidd2n.ResultsWe constructed two novel congenic strains homozygous for different segments of NSY-Chr 14 on the control C3H/HeNcrj (C3H) background: R1 (C3H.NSY-(D14Mit206-D14Mit5)) possesses the proximal and middle segment, and R2 (C3H.NSY-(D14Mit206-D14Mit186)) possesses the most proximal segment of NSY-Chr 14. Diabetes-related phenotypes were studied in comparison with those of consomic C3H-Chr 14NSY (R0) and parental NSY and C3H strains. Congenic R1 and R2 showed significantly higher post-challenge glucose than that in C3H mice. Fasting glucose, in contrast, was significantly lower in R1 and R2 than in C3H mice. Insulin sensitivity was significantly impaired in R1 and R2 compared to C3H mice. R2 showed significantly higher body weight and fat-pad weight than those in C3H and R1. Leptin level was significantly higher in R0, R1 and R2 than in C3H mice, with R2 showing the highest level, similar to that in NSY mice. Serum adiponectin level was significantly lower in R0, R1 and R2 than in C3H mice, while it was significantly higher in NSY than in C3H mice.Conclusions These data indicate that Chr 14 harbors multiple genes for diabetes-related phenotypes. The original Nidd2n, which is located in the middle region of Chr 14, was divided into two segments; Nidd2.1n in proximal Chr 14 and Nidd2.2n in distal Chr 14. Nidd2.1n contributes to post-challenge hyperglycemia, insulin resistance and adiposity. Nidd2.2n contributes to fasting as well as post-challenge hyperglycemia and insulin resistance. Adp1n, which contributes to decreased adiposity and increased insulin sensitivity, rather than a diabetogenic gene, was mapped in the middle segment.
    BMC Genetics 08/2014; 15(1):93. DOI:10.1186/s12863-014-0093-8 · 2.40 Impact Factor
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    • "Cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene is located on chromosome 2q33 and is expressed in activated T cells and inhibits T cell activation by CD28 [[44]]. Over 100 single-nucleotide polymorphisms (SNPs) have been identified in CTLA-4 gene regions, and some of these SNPs were found to be related to immune-mediated diseases including type 1 diabetes mellitus [[45]], multiple sclerosis [[46]], systemic lupus erythematosus (SLE) [[47]], rheumatoid arthritis [[48],[49]], Hashimoto's thyroiditis, and Graves' disease [[45]]. However, some of the studies showed conflicting results in the association of CTLA-4 gene polymorphisms and autoimmune diseases [[50]-[52]]. "
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    ABSTRACT: Vogt-Koyanagi-Harada (VKH) disease is a systemic autoimmune disorder against melanocytes. Recent studies have identified multiple genetic factors that might be associated with the pathogenesis of VKH disease. We performed an electronic database search of PubMed, MEDLINE, and EMBASE, and all relevant papers published up to 13 June 2014 were reviewed. A total of 1,031 publications including articles relevant to the genetics of VKH disease and the references of these articles were reviewed. The review identified a number of genetic factors which might be involved in the pathogenesis of VKH disease, some of which may alter the clinical course of VKH disease. Genes which might be involved in the pathogenesis of VKH disease included genes expressing HLA, complement factor H, interleukins, cytotoxic T-lymphocyte antigen 4 (CTLA-4), killer cell immunoglobulin-like receptors (KIR), programmed cell death 1 (PDCD1), protein tyrosine phosphatase non-receptor 22 (PTPN22), osteopontin, tumor necrosis factor alpha-induced protein 3 (TNFAIP3), macrophage migration inhibitory factor (MIF), and other immune response genes. Further studies to explore the correlation among different genotypes and phenotypes of VKH disease will be useful to shed light on the pathogenesis of uveitis in VKH disease and may facilitate the development of new treatment modalities of uveitis in VKH disease.
    Journal of Ophthalmic Inflammation and Infection 07/2014; 4(1):20. DOI:10.1186/s12348-014-0020-1
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