Brief Report: Arthritis in KRN T Cell Receptor-Transgenic Mice Does Not Require Interleukin-17 or Th17 Cells.
Brief Report: Arthritis in KRN T Cell Receptor-Transgenic Mice Does Not Require Interleukin-17 or Th17 Cells.
复制标题
DOI：
10.1002/art.39646
复制
发表时间：
2016-08
期刊：
影响因子：
--
通讯作者：
Binstadt BA
中科院分区：
文献类型：
--
作者：
Auger JL;Cowan HM;Engelson BJ;Kashem SW;Prinz I;Binstadt BA
Th17细胞和白介素17细胞因子家族成员参与了许多风湿性疾病的发病机制。大多数对小鼠炎性关节炎模型的研究表明，促炎细胞因子IL-17A及其受体IL-17受体(IL-17R)A/C异二聚体起着关键作用。使用严格的遗传学方法，我们评估了Th17细胞和IL-17在自身抗体依赖的KRN T细胞受体(TCR)转基因小鼠关节炎模型中的作用。我们培育了表达MHCII分子Ag7(K/B/G7)的KRN小鼠，但遗传上缺乏相关的细胞因子IL-17A和IL-17F或其关键受体亚单位IL-17RA。通过骨髓移植，我们产生了K/B/G7造血细胞缺乏关键的Th17分化转录因子Rorγ的小鼠。同时缺乏IL-17A和IL-17F的K/B/G7小鼠产生了正常的致病自身抗体滴度，并正常发生关节炎。同样，在这个模型中，IL-17RA不是疾病发生所必需的，造血细胞也不需要RORγt的表达。尽管先前的报道表明Th17细胞和IL-17A在K/BxN小鼠关节炎的发病机制中起关键作用，但本文提供的结果提供了遗传学证据，表明在K/B/G7模型系统中，IL-17A和IL-17F、IL-17RA和造血细胞Rorγt的表达对于正常的关节炎进展是必不可少的。我们讨论了这两个高度相似的模型系统之间差异的可能解释。这些发现加上其他关节炎小鼠模型的发现，提供了关于为什么针对Th17/IL-17轴的生物疗法对某些人类风湿性疾病有益，而对其他风湿性疾病无效的见解。
Th17 cells and interleukin (IL)-17 cytokine family members are implicated in the pathogenesis of many rheumatic diseases. Most studies of mouse models of inflammatory arthritis have demonstrated a key role for the pro-inflammatory cytokine IL-17A and its receptor, the IL-17 receptor (IL-17R) A/C heterodimer. Using a rigorous genetic approach, we evaluated the contribution of Th17 cells and IL-17 in the autoantibody-dependent, KRN T cell receptor (TCR) transgenic mouse model of arthritis. We bred KRN mice expressing the MHCII molecule Ag7 (K/B/g7) and genetically lacking the related cytokines IL-17A and IL-17F or their critical receptor subunit, IL-17RA. Using bone marrow transplantation, we generated mice in which K/B/g7 hematopoietic donor cells lacked the key Th17-differentiating transcription factor, Rorγt. K/B/g7 mice lacking both IL-17A and IL-17F produced normal titers of pathogenic autoantibodies and developed arthritis normally. Similarly, IL-17RA was not required for disease development in this model, nor was Rorγt expression by hematopoietic cells. Despite prior reports suggesting that Th17 cells and IL-17A are crucially involved in the pathogenesis of arthritis in K/BxN mice, the results presented here provide genetic evidence that IL-17A and IL-17F, IL-17RA, and hematopoietic cell Rorγt expression are dispensable for normal arthritis progression in the K/B/g7 model system. We discuss potential explanations for the discrepancies between these two highly similar model systems. These findings plus those from other mouse models of arthritis provide insight regarding why biologic therapeutics targeting the Th17/IL-17 axis are beneficial in some human rheumatic diseases but not others.