Cabrera Susanne M, Henschel Angela M, Hessner Martin J
Max McGee National Research Center for Juvenile Diabetes, Children's Research Institute of Children's Hospital of Wisconsin, Milwaukee, Wis; Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wis.
Max McGee National Research Center for Juvenile Diabetes, Children's Research Institute of Children's Hospital of Wisconsin, Milwaukee, Wis; Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wis.
Transl Res. 2016 Jan;167(1):214-27. doi: 10.1016/j.trsl.2015.04.011. Epub 2015 Apr 29.
Type 1 diabetes mellitus (T1D) is an autoimmune disease often diagnosed in childhood that results in pancreatic β-cell destruction and life-long insulin dependence. T1D susceptibility involves a complex interplay between genetic and environmental factors and has historically been attributed to adaptive immunity, although there is now increasing evidence for a role of innate inflammation. Here, we review studies that define a heightened age-dependent innate inflammatory state in T1D families that is paralleled with high fidelity by the T1D-susceptible biobreeding rat. Innate inflammation may be driven by changes in interactions between the host and environment, such as through an altered microbiome, intestinal hyperpermeability, or viral exposures. Special focus is put on the temporal measurement of plasma-induced transcriptional signatures of recent-onset T1D patients and their siblings as well as in the biobreeding rat as it defines the natural history of innate inflammation. These sensitive and comprehensive analyses have also revealed that those who successfully managed T1D risk develop an age-dependent immunoregulatory state, providing a possible mechanism for the juvenile nature of T1D. Therapeutic targeting of innate inflammation has been proven effective in preventing and delaying T1D in rat models. Clinical trials of agents that suppress innate inflammation have had more modest success, but efficacy may be improved by the addition of combinatorial approaches that target other aspects of T1D pathogenesis. An understanding of innate inflammation and mechanisms by which this susceptibility is both potentiated and mitigated offers important insight into T1D progression and avenues for therapeutic intervention.
1型糖尿病（T1D）是一种常在儿童期被诊断出的自身免疫性疾病，它会导致胰腺β细胞破坏以及终身依赖胰岛素。T1D易感性涉及遗传和环境因素之间的复杂相互作用，并且在历史上一直被归因于适应性免疫，尽管现在越来越多的证据表明先天性炎症也发挥作用。在这里，我们回顾了一些研究，这些研究确定了T1D家族中存在与年龄相关的先天性炎症状态增强，T1D易感的生物繁殖大鼠与之高度一致。先天性炎症可能由宿主与环境之间相互作用的变化驱动，例如通过微生物群改变、肠道通透性增加或病毒暴露。特别关注近期发病的T1D患者及其兄弟姐妹以及生物繁殖大鼠血浆诱导的转录特征的时间测量，因为它定义了先天性炎症的自然史。这些敏感而全面的分析还表明，那些成功控制T1D风险的人会形成与年龄相关的免疫调节状态，这为T1D的青少年发病性质提供了一种可能的机制。在大鼠模型中，针对先天性炎症的治疗已被证明对预防和延缓T1D有效。抑制先天性炎症的药物的临床试验取得的成功较为有限，但通过添加针对T1D发病机制其他方面的联合方法可能会提高疗效。了解先天性炎症以及这种易感性增强和减轻的机制，为T1D的进展和治疗干预途径提供了重要的见解。
