Genetic variation at the CD28 locus and its impact on expansion of pro-inflammatory CD28 negative T cells in healthy individuals.
Genetic variation at the CD28 locus and its impact on expansion of pro-inflammatory CD28 negative T cells in healthy individuals.
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DOI：
10.1038/s41598-017-07967-2
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发表时间：
2017-08-09
影响因子：
4.6
通讯作者：
Hirschfield GM
中科院分区：
文献类型：
--
作者：
Liaskou E;Jeffery L;Chanouzas D;Soskic B;Seldin MF;Harper L;Sansom D;Hirschfield GM
CD28位点与多种自身免疫和免疫介导的炎症性疾病的易感性相关，包括原发性硬化性胆管炎（PSC）。此前，我们将CD28途径与PSC疾病病理联系起来，发现维生素D可以维持CD28的表达。在这里，我们评估了psc相关的CD28风险变异A （rs7426056）是否影响健康个体（n = 14 AA, n = 14 AG, n = 14 GG）的CD28表达和T细胞功能。PSC疾病风险等位基因（AA）的纯合子在外周血单个核细胞中的CD28 mRNA表达明显低于GG或AG （p < 0.001）。然而，CD28风险变异本身并不足以解释CD4+ T细胞上CD28蛋白的损失。所有基因型对维生素D的反应都是一样的，这可以通过诱导调节性表型和增加抗炎/促炎细胞因子比例来证明。基因型对tnf - α刺激反应的影响被检测到，维生素d可以抑制这种影响。我们的研究结果表明：(A)易感CD28变体携带者的基因表达改变，(b) CD4+ T细胞的蛋白水平没有差异，(c)炎症条件下CD28变体对CD4+ T细胞的CD28蛋白损失有保护作用。
The CD28 locus is associated with susceptibility to a variety of autoimmune and immune-mediated inflammatory diseases including primary sclerosing cholangitis (PSC). Previously, we linked the CD28 pathway in PSC disease pathology and found that vitamin D could maintain CD28 expression. Here, we assessed whether the PSC-associated CD28 risk variant A (rs7426056) affects CD28 expression and T cell function in healthy individuals (n = 14 AA, n = 14 AG, n = 14 GG). Homozygotes for the PSC disease risk allele (AA) showed significantly lower CD28 mRNA expression ex-vivo than either GG or AG (p < 0.001) in total peripheral blood mononuclear cells. However, the CD28 risk variant alone was not sufficient to explain CD28 protein loss on CD4+ T cells. All genotypes responded equally to vitamin D as indicated by induction of a regulatory phenotype and an increased anti-inflammatory/pro-inflammatory cytokine ratio. A genotypic effect on response to TNFα stimuli was detected, which was inhibited by vitamin D. Together our results show: (a) an altered gene expression in carriers of the susceptible CD28 variant, (b) no differences in protein levels on CD4+ T cells, and (c) a protective effect of the variant upon CD28 protein loss on CD4+ T cells under inflammatory conditions.
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影响因子：
4.4
作者：
Thewissen, Marielle;Somers, Veerle;Stinissen, Piet
通讯作者：
Stinissen, Piet
影响因子：
30.8
作者：
Liu, Jimmy Z.;Hov, Johannes Roksund;Folseraas, Trine;Ellinghaus, Eva;Rushbrook, Simon M.;Doncheva, Nadezhda T.;Andreassen, Ole A.;Weersma, Rinse K.;Weismueller, Tobias J.;Eksteen, Bertus;Invernizzi, Pietro;Hirschfield, Gideon M.;Gotthardt, Daniel Nils;Pares, Albert;Ellinghaus, David;Shah, Tejas;Juran, Brian D.;Milkiewicz, Piotr;Rust, Christian;Schramm, Christoph;Mueller, Tobias;Srivastava, Brijesh;Dalekos, Georgios;Noethen, Markus M.;Herms, Stefan;Winkelmann, Juliane;Mitrovic, Mitja;Braun, Felix;Ponsioen, Cyriel Y.;Croucher, Peter J. P.;Sterneck, Martina;Teufel, Andreas;Mason, Andrew L.;Saarela, Janna;Leppa, Virpi;Dorfman, Ruslan;Alvaro, Domenico;Floreani, Annarosa;Onengut-Gumuscu, Suna;Rich, Stephen S.;Thompson, Wesley K.;Schork, Andrew J.;Naess, Sigrid;Thomsen, Ingo;Mayr, Gabriele;Koenig, Inke R.;Hveem, Kristian;Cleynen, Isabelle;Gutierrez-Achury, Javier;Ricano-Ponce, Isis;van Heel, David;Bjoernsson, Einar;Sandford, Richard N.;Durie, Peter R.;Melum, Espen;Vatn, Morten H.;Silverberg, Mark S.;Duerr, Richard H.;Padyukov, Leonid;Brand, Stephan;Sans, Miquel;Annese, Vito;Achkar, Jean-Paul;Boberg, Kirsten Muri;Marschall, Hanns-Ulrich;Chazouilleres, Olivier;Bowlus, Christopher L.;Wijmenga, Cisca;Schrumpf, Erik;Vermeire, Severine;Albrecht, Mario;Rioux, John D.;Alexander, Graeme;Bergquist, Annika;Cho, Judy;Schreiber, Stefan;Manns, Michael P.;Farkkila, Martti;Dale, Anders M.;Chapman, Roger W.;Lazaridis, Konstantinos N.;Franke, Andre;Anderson, Carl A.;Karlsen, Tom H.
通讯作者：
Karlsen, Tom H.
影响因子：
4
作者：
Lill, Christina M.;Luessi, Felix;Bertram, Lars
通讯作者：
Bertram, Lars
影响因子：
3
作者：
Yuan, JS;Reed, A;Stewart, CN
通讯作者：
Stewart, CN
1,25-二羟基维生素D3和IL-2结合抑制炎性细胞因子的T细胞产生，并促进表达CTLA-4和FOXP3的调节性T细胞的发育。
DOI：
10.4049/jimmunol.0803217
发表时间：
2009-11-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Jeffery LE;Burke F;Mura M;Zheng Y;Qureshi OS;Hewison M;Walker LS;Lammas DA;Raza K;Sansom DM
通讯作者：
Sansom DM