■在脊柱关节炎(SpA)中,增加的3型免疫反应,包括T辅助细胞(Th)17过量,在人类和SpA动物模型中都观察到,例如HLA-B27/人β2-微球蛋白转基因大鼠(B27-rat)。
■为了研究这种无法解释的Th17偏向分化,我们专注于了解B27大鼠幼稚CD4+T细胞(Tn)的免疫生物学。
■我们观察到中性刺激的B27-ratTn甚至在疾病发作之前就发展出增强的Th17轮廓,提示一种内在的促炎倾向。在这个观察的同时,转录组和表观基因组分析表明,B27大鼠Tn表现出干扰素/Th1-表达降低和Th17相关基因表达增加。预测该分子特征与STAT1/STAT3转录因子活性的失衡有关。Stat1mRNA和STAT1蛋白表达在Tn发病前降低,甚至在它们的胸腺前体中,而Stat3/STAT3表达在疾病建立后增加。确认这些结果的相关性,SpA患者的Tn中STAT1mRNA表达也降低,与健康对照组和类风湿关节炎患者相比。最后,用选择性STAT1激活剂刺激B27大鼠Tn消除了这种优先的IL-17A表达,表明B27大鼠中STAT1改变的活性允许Th17分化。
■总之,B27大鼠Tn在疾病发作前存在STAT1缺乏,这可能发生在他们的胸腺分化过程中,其次与持续的Th17偏见相关,在表观基因组水平上有印记。这种早期分子现象可能导致SpA患者CD4+T细胞持续的促炎偏斜,从而为更好地理解和治疗SpA提供了新的线索。
In spondyloarthritis (SpA), an increased type 3 immune response, including T helper cells (Th) 17 excess, is observed in both human and SpA animal models, such as the HLA-B27/human β2-microglobulin transgenic rat (B27-rat).
To investigate this unexplained Th17-biased differentiation, we focused on understanding the immunobiology of B27-rat naive CD4+ T cells (Tn).
We observed that neutrally stimulated B27-rat Tn developed heightened Th17 profile even before disease onset, suggesting an intrinsic proinflammatory predisposition. In parallel with this observation, transcriptomic and epigenomic analyses showed that B27-rat Tn exhibited a decreased expression of Interferon/Th1- and increased expression of Th17-related genes. This molecular signature was predicted to be related to an imbalance of STAT1/STAT3 transcription factors activity. Stat1 mRNA and STAT1 protein expression were decreased before disease onset in Tn, even in their thymic precursors, whereas Stat3/STAT3 expression increased upon disease establishment. Confirming the relevance of these results, STAT1 mRNA expression was also decreased in Tn from SpA patients, as compared with healthy controls and rheumatoid arthritis patients. Finally, stimulation of B27-rat Tn with a selective STAT1 activator abolished this preferential IL-17A expression, suggesting that STAT1-altered activity in B27-rats allows Th17 differentiation.
Altogether, B27-rat Tn harbor a STAT1 deficiency preceding disease onset, which may occur during their thymic differentiation, secondarily associated with a persistent Th17 bias, which is imprinted at the epigenomic level. This early molecular phenomenon might lead to the persistent proinflammatory skew of CD4+ T cells in SpA patients, thus offering new clues to better understand and treat SpA.