Tfh通过IL-21–IL-21R/STAT3轴对儿童原发肾病综合征（PNS）B细胞Ig类别转换的影响及机制研究

Primary nephrotic syndrome (PNS) is the most important etiology of children with chronic renal failure in China. Immuno-inflammation is the fundamental pathological processes of PNS in children, which also play an important role in kidney injury and even contribute to the progression of glomerulosclerosis and subsequent chronic renal failure (CRF). .The studies confirmed that CD4+T cell dysfunction in children with PNS including accounted for 80% minimal change nephrotic syndrome (MCNS). Serum IgG levels were significantly reduced and IgE levels were partially increased in children with MCNS. And secondary infection and frequent relapses are common clinical problems in children with PNS, which is closely related to immune dysfunction. . The dysregulation underlying decreased serum IgG and partially increased IgE in PNS patients remains to be established. It does not appear to result from an intrinsic B cell defect that results in decreased switching to IgG and partially enhanced switching to IgE, which may reflect altered production of regulatory cytokines by CD4+ T cells. However, dysregulation of traditional CD4+T cells (Th1/Th2, Th17/Treg cell) immune dysfunction does not fully explain decreased serum IgG and partially increased IgE in PNS patients in MCNS. Studies in recent years found that human B cell differentiation is regulated by cytokines, with produced by T follicular helper cells (Tfh), being key factors in promoting proliferation, isotype switching, plasma cell differentiation, and secretion of Ig isotypes by naive B cells. At the same time, our group found that circulating frequencies of IL-21+ follicular helper CD4+ T cells, IL-21R+ naive B cells and IL-21R+ plasma B cells were decreased in children with PNS than healthy children.. Keep in step with recent research progress and the existing research findings by our study group, we put forward a scientific hypothesis: Tfh mediated dysfunction of naive B cell by pathway of abnormal IL-21–IL-21R/STAT3 is an important in decreased serum IgG and partially increased IgE levels in children with PNS. Thus, IL-21R/STAT3 signaling pathway impaired in naive B cells which results in decreased switching to IgG and enhanced switching to IgE.. In this study, using blood of children with PNS and healthy control , we will reveal a key role for IL-21R/STAT3 signaling in regulating human B cell function, Tfh via the IL-21–IL-21R/STAT3 axis is a key signaling pathway in low serum IgG in children with PNS. B cells respond to IL-21, it may be possible to improve humoral immunity in PNS. it will provide an opportunity to exploit novel therapeutic strategies for immune dysfunction of B cells response, and in order to decrease the risk of recurrence and improve the clinical outcomes of the diseases in children.

原发性肾病综合征(PNS)是我国儿童慢性肾衰竭的重要病因。研究证实CD4+T细胞功能紊乱参与儿童PNS包括占80％的微小病变型肾病(MCNS)的发病。MCNS血浆IgG显著降低，部分IgE增高，与其继发感染与频复发密切相关。传统CD4+T细胞亚群功能紊乱不能完全阐明MCNS低IgG血症。新近本研究组在儿童PNS外周血发现CD4+T细胞新亚群---滤泡性辅助T细胞(Tfh)分泌IL-21受损，IL21R+NaiveB细胞、浆细胞水平降低。紧密结合研究进展及现有发现，我们提出：IL-21–IL-21R/STAT3轴受损是Tfh调控儿童PNS B细胞向IgG类别转换失调的重要机制。本项目拟用PNS和正常体检儿童血标本进行体内外实验，深入阐释Tfh经IL-21–IL-21R/STAT3轴是影响儿童PNS B细胞Ig分泌紊乱的重要通路，最终为临床改善其预后提供新的干预靶点。

原发性肾病综合征(PNS)是我国儿童最常见的肾小球疾病，也是引起慢性肾衰竭的重要病因。儿童PNS中微小病变型肾病(MCNS)占80％的，而临床资料显示MCNS血浆IgG显著降低，部分IgE增高，这与继发感染与频复发密切相关。传统CD4+T细胞亚群功能紊乱不能完全阐明MCNS低IgG血症。研究组在前期发现B细胞亚群紊乱，且IL-21R+naiveB细胞降低的基础上，紧密结合研究进展提出：IL-21–IL-21R/p-STAT3轴受损是介导调控儿童PNS中B细胞类别转换障碍致低IgG血症的重要机制。.本项目采用PNS和正常体检儿童血标本进行体内外实验，得到如下结论：1.在PNS患儿中存在B细胞亚群的紊乱，surface和cytoplasmicCD19+B细胞IgG表达均显著下降，且sIgG+CD19+和cIgG+CD19+细胞比例均与血清IgG水平呈正相关。2.PNS患儿中TFH细胞可能通过CD40/CD40L轴，部分参与低IgG血症发生。3.PNS患儿中naiveB细胞上IL-21R/p-STAT3信号通路受损，可能是介导低IgG血症发生的另一机制。.综上所述，本项目研究发现肾病综合征患儿体内存在B细胞和TFH细胞功能障碍的免疫失衡状态，CD40/CD40L信号通路和IL-21R/p-STAT3信号通路的受损可能是介导B细胞分泌IgG功能障碍致低IgG血症发生的重要机制。本研究为临床防治PNS患儿提供了新的干预靶点。