IgA肾病中浆细胞样树突细胞对B细胞合成IgA的调控及其机制

IgA nephropathy (IgAN) is the most common form of glomerulonephritis (GN) globally，however，the exact pathogenic mechanism of IgAN remains unclear. Toll like receptor 9 (TLR9), an important member of the innate immunity, was closely related with IgAN. TLR9 was predominantly expressed in plasmacytoid dendritic cells. Evidence showed that activation of plasmacytoid dendritic cell via TLR9 had an enormous impact on B cell function including proliferation, differentiation and antibody synthesis. Plasmacytoid dendritic cell also manipulated itself or other cells (for example, T cell and B cell) into expressing type I interferon, BAFF, APRIL, TGF-β, IL-10, which augmented the synthesis of IgA. Therefore, we hypothesize that plasmacytyoid dendritic cell modulates B cell function, especially IgA synthesis, through TLR9 activation in IgAN. The result publised on "Nature Genetics" from our lab showed that single nucleotide polymorphrism of APRIL gene (rs3803800) was significantly related with IgAN. We aim to detect the distributional and functional change of plasmacytoid dendritic cells in IgAN patients. We has established an in vitro co-culture system of plasmacytoid dendritic cells and B cell, which will be applied in this research to explore the regulatory role of plasmacytoid dendritic cell on B cell function,including proliferation,differentiation,IgA subcalss secretion,as well asIgA1 glycosylation. We also plan to find out the key regulatory factors within this system by different methods, as well as their potential as new therapeutic targets and new biomarkers. We hope that this research will shed some new light on the mechanism study of IgAN pathogenesis and offer new strategies for the clinical treatment of IgAN.

IgA肾病(IgAN)是目前最常见的原发性肾小球肾病，其发病机制尚不完全清楚。已有研究证实，先天免疫系统的Toll样受体9（TLR9）与IgAN的发病密切相关，TLR9在IgAN病人浆细胞样树突细胞（pDC）中高表达。pDC的TLR9激活后可调控B细胞增殖、分化和抗体合成，并直接或者间接调节I型干扰素、BAFF、APRIL、TGF-β、IL-10等因子促进IgA类别转换；本实验室已经完成的IgAN全基因组关联分析研究也证实APRIL单核苷酸多态性与IgAN显著相关；由此我们推测，IgAN病人中pDC经TLR9激活后调控B细胞分泌IgA的功能。本研究拟检测IgAN病人pDC的分布及TLR9激活功能，并建立体外pDC-B细胞共培养系统，深入探究IgAN中pDC如何调控B细胞合成IgA，并寻找其关键调控因子，验证其作为IgAN干预新靶点的可能性，为IgAN发病机制研究和治疗提供新思路。

IgA肾病中IgA1抗体分子的O-糖基化异常是其主要病理特征，但是发病机制并不清楚。先前研究结果表明Toll样受体（TLR）激活在IgA肾病的发生发展中扮演了重要角色，同时O-糖基转移酶也被认为与IgA肾病密切相关，但是两者之间关联并不清楚。我们研究成果发现来源于IgA肾病病人的外周血单个核细胞（PBMC）在TLR 7/8激活后显著分泌更多的IgA1抗体,同时这些IgA1分子的O-糖基化缺失更严重；而TLR9激活后并不出现上述现象。通过进一步研究发现，TLR7/8而非TLR9激活后IgA肾病病人PBMC中O-糖基转移酶表达比例发生变化，C1GalT1：GalNAcT2相对表达水平在mRNA水平和蛋白水平都显著下降。由于B细胞是IgA表达和O-糖基化修饰的细胞，进一步分析表明TLR7/8激活后导致IgA肾病病人B细胞中C1GalT1表达显著下调而GalNAcT2表达显著上调。