Function of the Th17/Interleukin-17A Immune Response in Murine Lupus Nephritis
Function of the Th17/Interleukin-17A Immune Response in Murine Lupus Nephritis
复制标题
DOI：
10.1002/art.38955
复制
发表时间：
2015-02-01
影响因子：
13.3
通讯作者：
Panzer, Ulf
中科院分区：
文献类型：
--
作者：
Schmidt, Tilman;Paust, Hans-Joachim;Panzer, Ulf
目标。CD4+ T细胞免疫应答在人和实验性狼疮性肾炎的免疫发病机制中起关键作用，但Th17/白细胞介素-17 （IL-17）免疫途径在系统性红斑狼疮（SLE）肾组织损伤中的作用尚不清楚。本研究旨在探讨2种狼疮性肾炎小鼠模型中Th17/IL-17A免疫应答的功能。制备il - 17a缺失的MRL/MPJ-Fas(lpr)/2J （MRL/lpr）小鼠，通过评估尿白蛋白水平、肾组织损伤程度和功能参数来监测肾炎的临床病程。此外，采用抗il - 17a和抗干扰素γ（抗ifn γ）抗体治疗狼疮易感（NZB x NZW）F1 （NZB/NZW）小鼠，观察其对狼疮肾炎临床病程的影响。MRL/lpr和NZB/NZW小鼠肾中产生IL-17A和IFN - γ的T细胞的表征显示CD3+IL-17A+细胞的浸润数量较少。肾IL-17A主要由CD4/CD8双阴性CD3+ T细胞和CD4+ Th17细胞产生。相比之下，随着时间的推移，肾CD3+IFN γ +细胞的数量不断增加，并且主要由典型的CD4+ Th1细胞组成。IL-17A缺乏不影响MRL/lpr狼疮性肾炎小鼠的形态学和功能参数，IL-17A中和也不影响NZB/NZW小鼠肾炎的临床病程，但抗ifn γ +治疗可减轻疾病的严重程度。在MRL/lpr和NZB/NZW小鼠狼疮性肾炎的免疫发病机制中，Th17/IL-17A免疫应答无主要作用。因此，本研究的结果不支持IL-17A靶向治疗SLE患者增殖性狼疮肾炎可能是一种有趣的新治疗方法。
Objective. The CD4+ T cell immune response plays a pivotal role in the immunopathogenesis of human and experimental lupus nephritis, but the contribution of the Th17/interleukin-17 (IL-17) immune pathway to renal tissue injury in systemic lupus erythematosus (SLE) remains to be elucidated. The aim of this study was to characterize the function of the Th17/IL-17A immune response in 2 murine models of lupus nephritis.Methods. IL-17A-deficient MRL/MPJ-Fas(lpr)/2J (MRL/lpr) mice were generated, and the clinical course of nephritis was monitored by assessing the levels of albuminuria, extent of renal tissue injury, and functional parameters. In addition, lupus-prone (NZB x NZW)F1 (NZB/NZW) mice were treated with anti-IL-17A and anti-interferon-gamma (anti-IFN gamma) antibodies, and their effects on the clinical course of lupus nephritis were assessed.Results. Characterization of renal IL-17A-producing and IFN gamma-producing T cells in MRL/lpr and NZB/NZW mice revealed low numbers of infiltrating CD3+IL-17A+ cells. Renal IL-17A was mainly produced by CD4/CD8 double-negative CD3+ T cells and CD4+ Th17 cells. In contrast, the number of renal CD3+IFN gamma+ cells continuously increased over time and largely consisted of typical CD4+ Th1 cells. IL-17A deficiency did not affect the morphologic or functional parameters in MRL/lpr mice with lupus nephritis, nor did IL-17A neutralization affect the clinical course of nephritis in NZB/NZW mice, but anti-IFN gamma+ treatment attenuated the severity of the disease.Conclusion. The Th17/IL-17A immune response plays no major role in the immunopathogenesis of lupus nephritis in MRL/lpr and NZB/NZW mice. Thus, the results of this study do not support the hypothesis that IL-17A targeting could be an intriguing new therapeutic approach for the management of proliferative lupus nephritis in SLE patients.