Centre for Liver Research and NIHR Birmingham Liver Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
Centre for Rare Diseases, Institute of Translational Medicine, Birmingham Health Partners, University Hospitals Birmingham, Birmingham, UK.
Sci Rep. 2017 Aug 9;7(1):7652. doi: 10.1038/s41598-017-07967-2.
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
CD28 基因座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，我们在 PSC 疾病病理学中发现 CD28 通路与 CD28 相关，并发现维生素 D 可以维持 CD28 的表达。在这里，我们评估了 PSC 相关的 CD28 风险变体 A(rs7426056) 是否会影响健康个体的 CD28 表达和 T 细胞功能（n=14AA，n=14AG，n=14GG）。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 CD28mRNA 表达明显低于 GG 或 AG（p<0.001）。然而，单独的 CD28 风险变体不足以解释 CD4 T 细胞上的 CD28 蛋白丢失。所有基因型对维生素 D 的反应相同，表现为诱导调节表型和增加抗炎/促炎细胞因子比值。还检测到对 TNFα 刺激的基因型效应，该效应被维生素 D 抑制。总之，我们的结果表明：(a) 易感 CD28 变体携带者的基因表达改变；(b) CD4 T 细胞上的蛋白水平无差异；
