Kawamura Eiichi, Hisano Satoshi, Nakashima Hitoshi, Takeshita Morishige, Saito Takao
Division of Nephrology and Rheumatology, Department of Internal Medicine, Fukuoka University , Fukuoka , Japan.
Mod Rheumatol. 2015 Jul;25(4):571-8. doi: 10.3109/14397595.2014.1001474. Epub 2015 Feb 11.
Our study aimed to clarify the immunological characteristics and the mechanism of interstitial fibrosis in immunoglobulin G4-related kidney disease (IgG4-RKD) by the immunohistological analysis.
Immunohistological study was performed in the biopsied renal tissues of 16 IgG4-RKD, 16 Sjögren syndrome (SJS), and 17 idiopathic tubulointerstitial nephritis (ITIN) patients using antibodies against IgG; IgG1; IgG4; CD38; CD3; C-X-C chemokine receptor type 3 (CXCR3); chemokine (C-C motif) receptor 4 (CCR4); forkhead box 3 (Foxp3); Type I, Type III, Type IV, and Type VI collagens; and transforming growth factor (TGF)-β1.
Interstitial lymphoplasmacytic and eosinophilic infiltration and the severity of interstitial fibrosis were greater in IgG4-RKD than SJS and ITIN. The ratio of CXCR3+/CD3 + cells was greater in SJS as compared with that in IgG4-RKD and ITIN. The ratio of CCR4+/CD3 + cells was not different among the three diseases. The ratio of interstitial IgG4+/IgG+ plasma cells, Foxp3+/CD3 + cells, and TGF-β1 + cells/total infiltrating cells was higher in IgG4-RKD than SJS and ITIN. There was a positive correlation between the ratio of Foxp3+/CD3 + cells and that of IgG4+/IgG+ plasma cells in IgG4-RKD. Significant correlation was found between the ratio of Foxp3+/CD3 + cells and that of TGF-β1 + cells/total infiltrating cells in IgG4-RKD. Foxp3 + cells and TGF-β1 + cells were colocalized in the interstitium in IgG4-RKD. The significant correlation between the ratio of TGF-β1 + cells/total infiltrating cells and the severity of fibrosis was noticed in IgG4-RKD. The interstitial distribution of type III collagen and type IV collagen was higher in IgG4-RKD than in SJS.
Our results suggest that regulatory T-cells (Tregs) may play a central role in IgG4 production in the interstitium and TGF-β1 induced by Tregs may play a pivotal role in the interstitial fibrosis including type III and type IV collagens in IgG4-RKD.
我们的研究旨在通过免疫组织学分析阐明免疫球蛋白G4相关性肾脏病（IgG4-RKD）的免疫特征及间质纤维化机制。
使用抗IgG、IgG1、IgG4、CD38、CD3、CXC趋化因子受体3（CXCR3）、趋化因子（CC基序）受体4（CCR4）、叉头框蛋白3（Foxp3）、I型、III型、IV型和VI型胶原蛋白以及转化生长因子（TGF）-β1的抗体，对16例IgG4-RKD患者、16例干燥综合征（SJS）患者和17例特发性肾小管间质性肾炎（ITIN）患者的肾活检组织进行免疫组织学研究。
IgG4-RKD的间质淋巴浆细胞和嗜酸性粒细胞浸润以及间质纤维化程度高于SJS和ITIN。与IgG4-RKD和ITIN相比，SJS中CXCR3+/CD3 +细胞的比例更高。三种疾病中CCR4+/CD3 +细胞的比例无差异。IgG4-RKD的间质IgG4+/IgG+浆细胞、Foxp3+/CD3 +细胞和TGF-β1 +细胞/总浸润细胞的比例高于SJS和ITIN。在IgG4-RKD中，Foxp3+/CD3 +细胞的比例与IgG4+/IgG+浆细胞的比例呈正相关。在IgG4-RKD中，发现Foxp3+/CD3 +细胞的比例与TGF-β1 +细胞/总浸润细胞的比例之间存在显著相关性。在IgG4-RKD中，Foxp3 +细胞和TGF-β1 +细胞在间质中共定位。在IgG4-RKD中，注意到TGF-β1 +细胞/总浸润细胞的比例与纤维化程度之间存在显著相关性。IgG4-RKD中III型胶原蛋白和IV型胶原蛋白的间质分布高于SJS。
我们的结果表明，调节性T细胞（Tregs）可能在间质中IgG4的产生中起核心作用，并且Tregs诱导的TGF-β1可能在IgG4-RKD中包括III型和IV型胶原蛋白的间质纤维化中起关键作用。
