TSLP促进扁桃体IgA生成在IgA肾病中的作用机制研究

IgA nephropathy (IgAN) is characterized by an abnormally high level of IgA in the blood and a severe deposition of IgA in the renal mesangium. However, the origin of the IgA remains unclear. Our previous research indicates that the expression level of IgA is significantly increased in the tonsil of IgAN patients, and the upregulated expression of IgA in the tonsil is mainly IgA1, which correlates with serum IgA level and IgA deposited in the renal mesangium. Moreover, the expression of thymic stromal lymphopoietin (TSLP) is significantly up-regulated in the tonsil in IgAN patients, compared with that in non-IgAN, which correlates with enhanced IgA class switching and production detected in the tonsillar germinal center, mainly consisted of follicular dendritic cells (FDCs). FDCs can promote IgA class switching and IgA production. Together, we hypothesize that TSLP on FDC promotes IgA switching and IgA production in the tonsillar germinal center, leading to IgA deposition in the kidney and followed IgA nephropathy. In the present proposed research, we will investigate the effect TSLP on IgA conversion and production in the tonsil, and followed effects on IgAN occurrence. The research will be conducted in IgAN patients at different levels, including examinations on the tonsil, serum, renal tissue, and tonsillar germinal center FDC-associated cluster. The proposed study will shed light on the origin of IgA deposited in the renal mesangium, promoting the prognosis, as well as it may highlight tonsillectomy as a potential treatment for IgAN.

IgA肾病（IgAN）以肾脏IgA沉积及血中IgA水平增高为主要特点，但IgA来源仍不清楚。我们前期发现IgAN扁桃体IgA与血清及肾脏IgA相关；同时首次发现IgAN扁桃体生发中心滤泡树突细胞（FDC）大量表达胸腺基质淋巴细胞生成素（TSLP），后者与扁桃体IgA生成显著正相关。研究证实FDC可调节B细胞IgA类别转换进而影响IgA生成。由此，我们推测：“IgAN扁桃体内高表达的TSLP通过与FDC作用促进IgA类别转换及生成，引起IgAN的发生发展”。我们拟分析TSLP、IgA类别转换调节因子（AID、BAFF等）与扁桃体、血清、肾脏IgA及肾脏病理分级间的关系。同时在扁桃体生发中心细胞中抑制和诱导TSLP的表达，检测IgA类别转换及IgA生成情况，进而探讨TSLP促进扁桃体IgA生成机制。本研究有助于阐明扁桃体TSLP在IgAN发病机制中的作用，为IgAN扁桃体切除治疗提供理论依据。

IgA肾病（IgAN）是全球范围内最常见的一种原发性肾小球肾炎，患者循环系统IgA水平升高是IgAN发生、发展的重要环节，但这些异常IgA起源目前仍不清楚，认清IgA增多机制是解决IgAN治疗的重要瓶颈。近年来研究发现IgAN患者多伴有扁桃体感染症状，同时扁桃体切除对IgAN治疗具有积极意义，扁桃体在IgAN中的作用已成为研究热点。 课题组通过患者切除扁桃体组织、血清、肾活检组织，扁桃体生发中心FDC 相关细胞团模型，探寻IgAN患者体内IgA增多机制，观察IgAN患者及对照组扁桃体IgA类别转换情况，分析其与IgAN患者扁桃体、血清及肾脏IgA水平相关性，并分析其与肾脏病理分级及临床表现的联系。同时在扁桃体生发中心细胞中抑制和诱导TSLP的表达，检测IgA类别转换及IgA生成情况，进而探讨TSLP促进扁桃体IgA生成机制。研究结果发现IgAN患者扁桃体内各型免疫球蛋白比例(IgA:IgG:IgM:IgD:IgE=38.7%:49.0%:7.8%:2.2%:2.4%)较非IgAN慢性扁桃炎患者扁桃体内各型免疫球蛋白比例(26.3%:55.4%:10.8%:3.6%:3.8%)有较大差异。IgAN患者扁桃内IgA1及IgA 比例明显升高，而IgG及IgM比例有所下降。IgAN患者扁桃内IgM+IgD-B细胞向IgA+B细胞的IgA类别转换水平有所提升。扁桃体、血清及肾脏IgA水平与患者尿肌酐、尿酸及CRP水平呈正相关，提示其与肾功能损伤之间的关联性。同时，体外培养生发中心FDC相关细胞团中，TSLP可促进体外培养FDC相关细胞团中IgA分泌量，同时，利用抗TSLPR抗体阻断TSLP通路后，体外培养FDC相关细胞团中IgA分泌量明显减少。表明IgAN患者扁桃体内TSLP可通过FDC作用促进IgA生成。本课题探讨了TSLP促进扁桃体IgA生成在IgA肾病中的作用及机制，为IgAN扁桃体切除治疗提供理论依据，为IgAN治疗提供了新思路。在本基金资助下发表SCI论文12篇（总SCI IF>50）；国家核心期刊2篇，参与编写专家共识4部，获得省级科技奖项2项。