The Max McGee National Research Center for Juvenile Diabetes, Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, WI, USA.
Genes Immun. 2013 Sep;14(6):387-400. doi: 10.1038/gene.2013.31. Epub 2013 Jun 6.
The dilute plasma cytokine milieu associated with type 1 diabetes (T1D), while difficult to measure directly, is sufficient to drive transcription in a bioassay that uses healthy leukocytes as reporters. Previously, we reported disease-associated, partially IL-1 dependent, transcriptional signatures in both T1D patients and the BioBreeding (BB) rat model. Here, we examine temporal signatures in congenic BBDR.lyp/lyp rats that develop spontaneous T1D, and BBDR rats where T1D progresses only after immunological perturbation in young animals. After weaning, the BBDR temporal signature showed early coincident induction of transcription related to innate inflammation as well as IL-10- and TGF-β-mediated regulation. BBDR plasma cytokine levels mirrored the signatures showing early inflammation, followed by induction of a regulated state that correlated with failure of virus to induce T1D in older rats. In contrast, the BBDR.lyp/lyp temporal signature exhibited asynchronous dynamics, with delayed induction of inflammatory transcription and later, weaker induction of regulatory transcription, consistent with their deficiency in regulatory T cells. Through longitudinal analyses of plasma-induced signatures in BB rats and a human T1D progressor, we have identified changes in immunoregulatory processes that attenuate a preexisting innate inflammatory state in BBDR rats, suggesting a mechanism underlying the decline in T1D susceptibility with age.
与 1 型糖尿病（T1D）相关的稀血浆细胞因子环境虽然难以直接测量，但足以在使用健康白细胞作为报告器的生物测定中驱动转录。此前，我们报道了 T1D 患者和生物繁殖（BB）大鼠模型中与疾病相关的、部分依赖于 IL-1 的转录特征。在这里，我们研究了自发发生 T1D 的同基因 BBDR.lyp/lyp 大鼠和仅在年轻动物的免疫干扰后进展为 T1D 的 BBDR 大鼠的时间特征。断奶后，BBDR 的时间特征显示出与先天炎症以及 IL-10 和 TGF-β 介导的调节相关的转录早期同时诱导。BBDR 血浆细胞因子水平与特征相吻合，表现出早期炎症，随后诱导与病毒在老年大鼠中诱导 T1D 失败相关的调节状态。相比之下，BBDR.lyp/lyp 的时间特征表现出异步动态，炎症转录的诱导延迟，随后调节转录的诱导减弱，这与它们缺乏调节性 T 细胞一致。通过对 BB 大鼠和人类 T1D 进展者的血浆诱导特征进行纵向分析，我们已经确定了免疫调节过程的变化，这些变化减弱了 BBDR 大鼠中预先存在的先天炎症状态，这表明了年龄相关 T1D 易感性下降的机制。
