Confirmation and Identification of Biomarkers Implicating Environmental Triggers in the Pathogenesis of Type 1 Diabetes.
Confirmation and Identification of Biomarkers Implicating Environmental Triggers in the Pathogenesis of Type 1 Diabetes.
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DOI：
10.3389/fimmu.2020.01922
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发表时间：
2020
影响因子：
7.3
通讯作者：
Sarvetnick N
中科院分区：
文献类型：
--
作者：
Harms RZ;Ostlund KR;Cabrera MS;Edwards E;Fisher M;Sarvetnick N
已经提出了多种环境触发因素来解释1型糖尿病（T1 D）发病率的增加。这些包括病毒感染，微生物组紊乱，代谢紊乱和维生素D缺乏症。在这里，我们使用ELISA检测血浆从青少年T1 D受试者和年龄匹配的控制，丰富的几个循环因子相关的这些假设。我们筛选了血浆sCD 14、甘露糖结合凝集素（MBL）、脂多糖结合蛋白（LBP）、C反应蛋白（CRP）、脂肪酸结合蛋白2（FABP 2）、人生长激素、瘦素、总脂联素、高分子量（HMW）脂联素、总IgG、总IgA、总IgM、内毒素核心抗体（EndoCAb）、25（OH）维生素D、维生素D结合蛋白、IL-7、IL-10、IFN-γ、TNF-α、IL-17 A、IL-18和IL-18 BPa。还检测了受试者靶向腺病毒、副流感病毒1/2/3、柯萨奇病毒、巨细胞病毒、EB病毒病毒衣壳抗原（EBV VCA）、单纯疱疹病毒1型和酿酒酵母的抗体的患病率。最后，筛选所有受试者是否存在靶向胰岛细胞胞质蛋白（伊卡）、谷氨酸脱羧酶2（GAD 65）、锌转运蛋白8（ZNT 8）、胰岛素瘤抗原2（IA-2）、组织转氨酶和甲状腺过氧化物酶的自身抗体及其丰度，同时通过测量C肽水平来衡量β细胞功能。我们观察到对照组和T1 D受试者之间的差异不大。其中，我们发现sCD 14、IL-18 BPa和FABP 2升高，总IgM降低。与对照组相比，女性T1 D受试者的CRP水平显著升高，而男性相似。与对照组相比，T1 D受试者的EBV VCA抗体患病率也显著较低。最后，我们观察到C肽水平与对照组中的瘦素水平显著相关，但这种关系在T1 D受试者中并不显著。另外，脂联素水平与C肽水平在T1 D受试者中显着相关，而对照组显示这两个因素之间没有关系。在T1 D受试者中，最高的C肽水平与最低的脂联素水平相关，脂联素水平是胰岛素抵抗的一个指标。总的来说，从我们的检查中，我们发现有限的数据强烈支持任何研究的假设。相反，我们在T1 D受试者中观察到无法解释的单核细胞/巨噬细胞活化的迹象，这是从sCD 14和IL-18 BPa水平升高判断的。这些观察结果与T1 D受试者中脂肪因子和C肽水平之间的独特关联相结合。
Multiple environmental triggers have been proposed to explain the increased incidence of type 1 diabetes (T1D). These include viral infections, microbiome disturbances, metabolic disorders, and vitamin D deficiency. Here, we used ELISA to examine blood plasma from juvenile T1D subjects and age-matched controls for the abundance of several circulating factors relevant to these hypotheses. We screened plasma for sCD14, mannose binding lectin (MBL), lipopolysaccharide binding protein (LBP), c-reactive protein (CRP), fatty acid binding protein 2 (FABP2), human growth hormone, leptin, total adiponectin, high molecular weight (HMW) adiponectin, total IgG, total IgA, total IgM, endotoxin core antibodies (EndoCAbs), 25(OH) vitamin D, vitamin D binding protein, IL-7, IL-10, IFN-γ, TNF-α, IL-17A, IL-18, and IL-18BPa. Subjects also were tested for prevalence of antibodies targeting adenovirus, parainfluenza 1/2/3, Coxsackievirus, cytomegalovirus, Epstein-Barr virus viral capsid antigen (EBV VCA), herpes simplex virus 1, and Saccharomyces cerevisiae. Finally, all subjects were screened for presence and abundance of autoantibodies targeting islet cell cytoplasmic proteins (ICA), glutamate decarboxylase 2 (GAD65), zinc transporter 8 (ZNT8), insulinoma antigen 2 (IA-2), tissue transglutaminase, and thyroid peroxidase, while β cell function was gauged by measuring c-peptide levels. We observed few differences between control and T1D subjects. Of these, we found elevated sCD14, IL-18BPa, and FABP2, and reduced total IgM. Female T1D subjects were notably elevated in CRP levels compared to control, while males were similar. T1D subjects also had significantly lower prevalence of EBV VCA antibodies compared to control. Lastly, we observed that c-peptide levels were significantly correlated with leptin levels among controls, but this relationship was not significant among T1D subjects. Alternatively, adiponectin levels were significantly correlated with c-peptide levels among T1D subjects, while controls showed no relationship between these two factors. Among T1D subjects, the highest c-peptide levels were associated with the lowest adiponectin levels, an indication of insulin resistance. In total, from our examination we found limited data that strongly support any of the hypotheses investigated. Rather, we observed an indication of unexplained monocyte/macrophage activation in T1D subjects judging from elevated levels of sCD14 and IL-18BPa. These observations were partnered with unique associations between adipokines and c-peptide levels among T1D subjects.
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