新月体肾炎早期Id3通过与E2A作用调控Th17和Treg细胞分化的机制研究

Crescentic glomerulonephritis （CGN）has a rapid onset and leads to rapidly progressive renal injury and poor prognosis. Th17 cell-mediated immune response mainly participates in the early stage of CGN, and regulatory T cells (Treg) alleviates the pathological damages by inhibiting T cell immune response. Th17 and Treg have the same precursor cells and the pathogenesis of CGN can be clarified by investigating the regulation mechanisms of the differentiation between Th17 and Treg. DNA binding inhibition factor 3 (Id3) can regulate the expression of Th17 and Treg characteristic transcription factors (RORγt and Foxp3) at the transcriptional level. This project will study the regulation effect of Treg and Th17 differentiation in the early stage of CGN by using the gene regulation to change the expression of Id3. We further explore that whether Id3 regulates the differentiation of Th17 and Treg through the effect with transcription factor E2A which can be formed non-DNA-binding homodimer to influence the transcription of RORγt and Foxp3 or not. We will study the mechanisms of Th17 and Treg differentiation in the early stage of CGN from the gene regulation, which contributes to the crucial factors in activation of the immune responses in CGN and provides the basis for early intervention in immune responses and the amelioration of pathological damages.

新月体肾炎(CGN)起病急骤，肾功能急剧恶化，预后差。早期以Th17细胞介导的免疫反应为主，调节性T细胞（Treg）则通过抑制T细胞免疫应答减轻病理损害。Th17和Treg具有共同的前体细胞，通过探讨CGN中Th17和Treg的分化调控机制，有助于阐明CGN的发病机理。DNA结合抑制因子3(Id3)可在转录水平调节Th17和Treg特征性转录因子(RORγt和Foxp3)的表达。本课题将利用基因调控技术，重点探讨Id3是否通过与转录因子E2A作用，形成非DNA结合型二聚体，影响RORγt和Foxp3转录，进而调控Th17和Treg细胞分化。通过对CGN早期Th17和Treg分化机制的研究，有助于明确CGN免疫反应活化的关键因素，为早期干预免疫反应，减轻病理损害提供新的理论依据。

在对新月体肾炎（CGN）发病机制的研究中，辅助性T细胞（Th17）和调节性T细胞 (Treg)越来越受到关注且机制各异。本研究在小鼠新月体肾炎模型中发现DNA结合抑制因子 ( Id3）参与病情进展，可能是通过在转录水平影响Th17 和Treg细胞的分化发挥作用的。在本研究中，通过流式细胞学检测技术我们检测了在小鼠新月体肾炎模型不同阶段Th17 和Treg细胞的表达情况，发现在我们观察的时间段内，随着病情的进展，与对照组相比Th17 细胞呈现先升高后下降的趋势且于模型第14天达到峰值，而Treg细胞则呈现渐升高后趋于高值水平的趋势，其相应的转录因子RORγT 和 Foxp3亦呈现该趋势，且与Id3表达相关。同时通过免疫共沉淀的方法我们惊奇的发现，在模型的不同阶段Id3 与 E2a的结合力的变化也与上述相关。在体外，我们将未分化的CD4+T 细胞中加入相应的细胞因子诱导其向Th17 和Treg细胞分化后，检测到诱导的Treg 细胞中Id3的表达明显增加，而Th17细胞则下降。但是在沉默Id3的表达后RORγt 和 Foxp3表达也发生变化。 由此我们得出在新月体肾炎模型组，Id3可能在转录水平通过影响Treg细胞的分化进而影响其病情进展，为新月体肾炎的诊疗提供依据.