Putlyaeva L V, Demin D E, Korneev K V, Kasyanov A S, Tatosyan K A, Kulakovskiy I V, Kuprash D V, Schwartz A M
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia.
Moscow Institute of Physics and Technology, Department of Molecular and Biological Physics, Dolgoprudny, Moscow Region, 141701, Russia.
Biochemistry (Mosc). 2018 Dec;83(12):1534-1542. doi: 10.1134/S0006297918120118.
CD40 receptor is expressed on B lymphocytes and other professional antigen-presenting cells. The binding of CD40 to its ligand CD154 on the surface of T helper cells plays an important role in the activation of B lymphocytes required for production of antibodies, in particular, against autoantigens. Association of several single nucleotide polymorphisms (SNPs) located in the non-coding areas of human CD40 locus with the elevated risk of autoimmune diseases has been demonstrated. The most studied of these SNPs is rs4810485 located in the first intron of the CD40 gene. Expression of the CD40 gene in B lymphocytes of donors homozygous for the common allelic variant of this polymorphism (G) is higher than in B cells from donors carrying the minor (T) variant. We investigated the enhancer activity of this fragment of the CD40 locus in human B cell lines and showed that it is independent on the rs4810485 alleles. However, the minor allelic variants of the rs4810485-linked SNPs rs548231435 and rs115662534 were associated with a significant decrease in the activity of the CD40 promoter due to the impairments in the binding of EBF1 and STAT1 transcription factors, respectively.
CD40受体在B淋巴细胞和其他专职抗原呈递细胞上表达。CD40与其在辅助性T细胞表面的配体CD154结合，在产生抗体（尤其是针对自身抗原的抗体）所需的B淋巴细胞激活过程中发挥重要作用。已证实位于人类CD40基因座非编码区的几个单核苷酸多态性（SNP）与自身免疫性疾病风险升高有关。其中研究最多的SNP是位于CD40基因第一个内含子中的rs4810485。这种多态性常见等位基因变体（G）纯合的供体B淋巴细胞中CD40基因的表达高于携带次要（T）变体的供体B细胞。我们研究了CD40基因座这一片段在人类B细胞系中的增强子活性，结果表明其与rs4810485等位基因无关。然而，与rs4810485连锁的SNP rs548231435和rs115662534的次要等位基因变体，分别由于EBF1和STAT1转录因子结合受损，与CD40启动子活性显著降低有关。
