PDF(Pubmed)
Abstract：
Type 1 diabetes (T1D) is an autoimmune disease in which pancreatic islet β-cells are attacked by the immune system, resulting in insulin deficiency and hyperglycemia. One of the top non-synonymous single-nucleotide polymorphisms (SNP) associated with T1D is in the interferon-induced helicase C domain-containing protein 1 (IFIH1), which encodes an anti-viral cytosolic RNA sensor. This SNP results in an alanine to threonine substitution at amino acid 946 (IFIH1A946T) and confers an increased risk for several autoimmune diseases, including T1D. We hypothesized that the IFIH1A946T risk variant, (IFIH1R) would promote T1D pathogenesis by stimulating type I interferon (IFN I) signaling leading to immune cell alterations. To test this, we developed Ifih1R knock-in mice on the non-obese diabetic (NOD) mouse background, a spontaneous T1D model. Our results revealed a modest increase in diabetes incidence and insulitis in Ifih1R compared to non-risk Ifih1 (Ifih1NR) mice and a significant acceleration of diabetes onset in Ifih1R females. Ifih1R mice exhibited a significantly enhanced interferon stimulated gene (ISG) signature compared to Ifih1NR, indicative of increased IFN I signaling. Ifih1R mice exhibited an increased frequency of plasma cells as well as tissue-dependent changes in the frequency and activation of CD8+ T cells. Our results indicate that IFIH1R may contribute to T1D pathogenesis by altering the frequency and activation of immune cells. These findings advance our knowledge on the connection between the rs1990760 variant and T1D. Further, these data are the first to demonstrate effects of Ifih1R in NOD mice, which will be important to consider for the development of therapeutics for T1D.
摘要：
1型糖尿病（T1D）是一种自身免疫性疾病，其中胰岛β细胞受到免疫系统的攻击，导致胰岛素缺乏和高血糖。与T1D相关的最高非同义单核苷酸多态性（SNP）之一是干扰素诱导的含解旋酶C结构域的蛋白1（IFIH1），它编码抗病毒细胞溶质RNA传感器。该SNP导致丙氨酸在氨基酸946（IFIH1A946T）被替换为苏氨酸，并增加了几种自身免疫性疾病的风险。包括T1D。我们假设IFIH1A946T风险变体，(IFIH1R)将通过刺激导致免疫细胞改变的I型干扰素(IFNI)信号传导来促进T1D发病机理。为了测试这个，我们在非肥胖糖尿病（NOD）小鼠背景下开发了Ifih1R基因敲入小鼠，自发的T1D模型。我们的结果表明，与非风险Ifih1（Ifih1NR）小鼠相比，Ifih1R的糖尿病发病率和胰岛炎略有增加，并且Ifih1R雌性的糖尿病发作显着加速。与Ifih1NR相比，Ifih1R小鼠表现出显着增强的干扰素刺激基因（ISG）特征，表明IFNI信号传导增加。Ifih1R小鼠表现出浆细胞的频率增加以及CD8T细胞的频率和活化的组织依赖性变化。我们的结果表明，IFIH1R可能通过改变免疫细胞的频率和激活来促进T1D的发病。这些发现提高了我们对rs1990760变体和T1D之间联系的认识。Further,这些数据首次证明了Ifih1R在NOD小鼠中的作用，这对于T1D的治疗方法的开发将是重要的。
