调节性T细胞（Treg）作为免疫耐受的关键性调节组分，参与系统性红斑狼疮（SLE）发病，但在SLE肾脏靶器官受累中的研究少见。趋化因子受体CCR4可以诱导淋巴细胞向靶器官迁移,并可以选择性表达在Treg上。我们的前期研究提示：外周血的Treg总数在SLE患者中无明显变化，但是外周血CCR4+Treg在狼疮肾炎（LN）患者中显著降低。结合文献LN肾脏中CCR4+T细胞沉积，我们推测CCR4趋化引导外周血CCR4+Treg在肾脏异常募集是LN发病的重要潜在机制。.本研究拟应用SLE患者验证外周血CCR4+Treg的下降与LN相关，明确下降的CCR4+Treg异常募集沉积于肾脏，阐明CCR4与配体的结合趋化引导CCR4+Treg在肾脏沉积。通过以上，揭示CCR4,Treg与SLE肾脏靶器官受累的关系，以探索LN发病机制并提供诊治新思路。

Regulatory T cell(Treg), as one of the most critical components for immunologic tolerance, plays an important role in the pathogenesis of SLE.However, studies on the relationships of Treg and SLE target organ involvement are rare. CC chemokine receptor 4(CCR4) can recruit T lymphocyte and migrate into the target organ. Our previous study found that there was no significant change in the percentage of Treg in the peripheral blood of SLE. However, we found an interesting phenomenon that a specific group of T cells, CCR4+Treg significantly decreased in peripheral blood of LN patients. Masato et.al reported selective accumulation of CCR4+ T cells in LN patient’s renal tissue.Thus, we hypothesis that CCR4 binding with its ligands (CCL17/CCL22) may lead CCR4+Tregs from peripheral blood to renal tissue. This procedure might be a logical and important potential pathogenesis of lupus nephritis..We designed a series of studies to verify the hypothesis.We would identify the association of decreased CCR4+Treg with lupus nephritis in the peripheral blood monocyte. Then we would identify the accumulation of CCR4+Treg in the kidney organ. We would further investigate that the collaboration of CCR4 and its ligands was crucial in the recruiting of CCR4+Treg from peripheral blood to kidney.Based on the studies above, we try to reveal the pathogenesis relationship between CCR4+Tregs and LN. This novel potent mechanism might contribute to the early diagnosis pathogenesis of LN.

狼疮肾炎（lupus nephritis, LN）是系统性红斑狼疮（systemic lupus erythematosus, SLE）最重要受累的靶器官，本研究探讨了CCR4 趋化调节性T细胞在系统性红斑狼疮/狼疮肾炎的发病机制中作用。本研究入组10例SLE-LN初治患者，10例SLE无肾炎（no-LN，SLE without lupu nephritis）患者，10例健康对照，从外周血和肾脏组织标本确认CCR4+Treg参与了狼疮肾炎的发病机制。首先：LN患者外周血中CCR4+Treg 数量与SLEDAI 评分呈显著负相关（p<0.01，r= -0.241)；LN患者外周血中CCR4+Treg与SLE病情相关抗体抗dsDNA滴度呈负相关(p<0.01，r= -0.004)；而LN患者外周血中CCR4+Treg与24h尿蛋白定量呈无明确相关（p>0.05），CCR4+Treg数量与LN病理类型无明确相关(p>0.05)。第二：通过研究肾脏病理标本，发现在病变肾小球中CCR4mRNA表达较对照组健康对照显著升高（p<0.05），CCR4蛋白表达亦高于健康对照组（P<0.05），进一步印证了CCR4参与肾脏区域靶器官的受累。第三：通过驱化实验对比SLE-LN, no-LN与健康对照组, 检测外周血中与配体CCL17/CCL22结合的Treg，发现LN患者中与CCL17/CCL22结合的Treg数量显著低于健康对照组（p<0.05），而no-LN与健康对照组之间无显著性差异。通过以上，说明了CCR4+Treg作为一组有趋化作用的调节性T细胞参与系统性红斑狼疮/狼疮肾炎的发病机制。本研究一定程度上确认了CCR4+Treg与SLE-LN相关，可能作为潜在的临床诊治标记物。但尚未能解释降低的CCR4+Treg驱化能力下降的机制，需要在肾脏标本中进一步探索Th2细胞以及Treg在肾脏组织中的表达，本研究为后续深入研究提供了依据。