髓系抑制细胞通过STAT3通路诱导Th17/Treg失衡促IgA肾病进展的研究

IgA nephropathy (IgAN) is one kind of refractory glomerular diseases. At present, the pathogenesis of IgAN is still unclear. Recent studies have suggested that there is a Th17/Treg imbalance in IgAN, which is one of the pathogenic factors. Myeloid-derived suppressor cells (MDSC) are heterogeneous population of immature cells derived from myeloid progenitors, which are accumulated in a variety of autoimmune diseases and participate in immune responses. Our preliminary data showed that MDSC have the roles of promoting Th17 differentiation and disease progression in SLE patients and humanized SLE mice. Meanwhile, we found MDSC were significantly amplified in IgAN patients, and there is a Th17/Treg imbalance in the blood of IgA patients. STAT3 pathway is the cross point of Th17 and Treg differentiation. Under inflammatory conditions, the pathway can induce the imbalance of Th17/Treg. Therefore, we put forward the following hypothesis: in the inflammatory condition of IgA nephropathy, MDSC can secrete pro-inflammatory cytokines and affect the differentiation of Th17 cells and Treg cells through STAT3 pathway, resulting in imbalance of Th17/Treg cells and promoting renal tissue injury. Based on the above hypothesis, we will investigate the effect of MDSC on Th17 and Treg differentiation by using the Th17 and Treg differentiation system in vitro, clinical samples from IgAN patients and IgAN mouse model. We aim to make clear the effect and the possible mechanism of MDSC in IgAN. This study will provide us new reference for clinical prognosis and new targets for clinical therapy.

IgA肾病（IgAN）是难治性肾小球疾病，发病机制尚未明确。近年研究提示IgAN存在Th17/Treg失衡，是重要致病因素之一。髓系抑制细胞（MDSC）是骨髓来源前体细胞，在多种自身免疫疾病中参与免疫应答。我们前期已证明MDSC在SLE患者及人源化SLE小鼠中有促Th17分化及致病作用。我们近期发现IgAN患者外周血中MDSC显著增多，且存在Th17/Treg失衡。STAT3通路是Th17、Treg分化交叉点，炎性条件下该通路可诱导Th17/Treg失衡。我们推测，IgAN中MDSC分泌炎性因子，通过STAT3通路影响Th17和Treg的分化，诱导Th17/Treg失衡。因此本项目拟利用IgAN患者外周血、IgAN小鼠模型及体外Th17、Treg分化体系，从分子、细胞、动物及患者多方面分析，研究IgAN中MDSC对Th17和Treg分化的影响，确认其作用机制，为临床治疗IgAN提供新靶点。

IgA肾病（immunoglobulin a nephropathy, IgAN）是我国常见的肾小球疾病，约30-40%左右的IgAN患者会在20-30年内发展为终末期肾衰竭，需进行透析或肾脏移植治疗，这对个人及社会造成了极大的经济负担。IgAN发病机制尚未完全明确，因此阐明IgAN发病机制、开发有效的治疗措施具有重要意义。.近年研究提示Th17/Treg失衡及Th17细胞的促炎效应是IgA肾病发病重要的致病因素之一。髓系抑制细胞（MDSC）是骨髓来源前体细胞，参与多种自身免疫疾病中的免疫应答，然而其在肾小球疾病中的作用尚不完全明确。.项目申请者及课题组在前期研究中证明SLE中MDSC有促Th17分化效应及促进疾病进展的作用，并发现IgAN患者外周血中MDSC比例较健康人显著增多。本项目按计划确认MDSC在IgA肾病中的功能及对Th17分化的影响，并确认其作用机制。.本研究结果证明了IgAN患者外周血中MDSC及其M-MDSC、G-MDSC亚群的比例较健康人明显增多；IgAN外周血Th17细胞的表达增加；IgAN肾穿活组织切片发现病变肾小球有IL-17A沉积。IgAN外周血分选的MDSC可分泌Arg-1酶，其分泌的Arg-1酶较正常人增多。体外Th17极化条件下，IgAN患者外周血分选的MDSC可促Th17分化，而精氨酸酶-1（Arg-1）能完全逆转MDSC促Th17分化的效应。基因芯片检查确定了“MDSC-Arg-1-Th17”轴调节的T细胞内相关microRNA和lincRNA。同时，在另一种肾小球疾病膜性肾病中也发现MDSC同样有促进Th17分化从而促进疾病进展的作用，并发现MDSC有抑制Th2细胞分化功能，扩大了MDSC在肾病领域的作用范围。.综上所述，本项目按计划证明了IgA肾病MDSC扩增，并通过其分泌的Arg-1促进Th17细胞的表达而发挥了促炎效应，并进一步确定了相关调节的miRNA和lincRNA，从而丰富了MDSC在肾病领域中的表达及作用的理论依据，为治疗IgA肾病为首的免疫性肾脏疾病提供新思路和新靶点。