Research Laboratory LR18/SP12 Auto-immunity, Cancer and Immunogenetics, Immunology Department, Habib Bourguiba University Hospital, University of Sfax, Sfax, Tunisia.
Urology Department, Habib Bourguiba Hospital, University of Sfax, Sfax, Tunisia.
Int J Immunogenet. 2021 Jun;48(3):250-259. doi: 10.1111/iji.12531. Epub 2021 Mar 1.
The influence of intracellular Toll-like-receptors (TLR), recognized as nucleic acid sensors, in the immunopathogenesis of systemic lupus erythematosus (SLE) is increasingly explored. Yet, the results of both functional and genetic studies remain conflictual. We evaluated the association between TLR3 and TLR7 genes selected variants and SLE and investigated the possible relationship with clinical and serological parameters. Then, we studied the genetic expression of these receptors, and if the TLR7 gene evades X chromosome inactivation (XCI). Our study covers 106 cases and 200 controls, genotyped using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. TLR3 and TLR7 expression level was assessed by qPCR carried, respectively, on renal tissues and PBMC, and methylation status was evaluated by methylation-specific PCR. Results were statistically analysed using Shesis software, χ , and Mann-Whitney test. Significant associations with SLE susceptibility were found for the TLR3 rs3775291, rs5743305 and rs3775294 polymorphisms. Further subgroup analysis, TLR3 rs3775291 and rs3775294 polymorphisms were significantly associated with lupus nephritis (LN) and even correlate with the presence of auto-antibodies binding RNA molecules. SLE and LN were more common in men with rs3853839-G variant within TLR7 gene versus those carrying the C allele. Moreover, the role of the G allele in the TLR7 expression up-regulation was confirmed. However, gene expression analysis showed no significant differences in TLR3 and TLR7 mRNA levels between LN patient biopsies and healthy tissues (p > .05). When comparing patients and controls, no statistical difference was observed in XCI pattern. Otherwise, notable associations were raised between TLR3 and TLR7 gene variants and clinical and serological lupus features pointing towards the role of genetic background in the physiopathogenesis of the disease.
细胞内 Toll 样受体 (TLR) 作为核酸传感器，其在系统性红斑狼疮 (SLE) 免疫发病机制中的作用正越来越受到关注。然而，功能和遗传研究的结果仍然存在冲突。我们评估了选择的 TLR3 和 TLR7 基因变异与 SLE 的关联，并研究了其与临床和血清学参数的可能关系。然后，我们研究了这些受体的基因表达，以及 TLR7 基因是否逃避 X 染色体失活 (XCI)。我们的研究包括 106 例病例和 200 例对照，使用聚合酶链反应-限制性片段长度多态性 (PCR-RFLP) 技术进行基因分型。通过 qPCR 分别评估 TLR3 和 TLR7 的基因表达水平，通过甲基化特异性 PCR 评估甲基化状态。使用 Shesis 软件进行统计学分析，χ2 和 Mann-Whitney 检验。TLR3 rs3775291、rs5743305 和 rs3775294 多态性与 SLE 易感性显著相关。进一步的亚组分析表明，TLR3 rs3775291 和 rs3775294 多态性与狼疮肾炎 (LN) 显著相关，甚至与自身抗体结合 RNA 分子的存在相关。TLR7 基因中的 rs3853839-G 变体与携带 C 等位基因的个体相比，SLE 和 LN 更常见。此外，证实了 TLR7 基因表达上调中 G 等位基因的作用。然而，TLR3 和 TLR7 mRNA 水平在 LN 患者活检和健康组织之间的基因表达分析没有显示出显著差异（p>.05）。在比较患者和对照组时，XCI 模式没有观察到统计学差异。然而，TLR3 和 TLR7 基因变异与临床和血清学狼疮特征之间存在显著关联，提示遗传背景在疾病的病理生理学中起作用。
