Jones Albert R, Coleman Emily L, Husni Nicholas R, Deeney Jude T, Raval Forum, Steenkamp Devin, Dooms Hans, Nikolajczyk Barbara S, Corkey Barbara E
Obesity Research Center, Evans Department of Medicine, Boston University School of Medicine, Boston, MA, United States of America.
Yale University School of Medicine, New Haven, CT, United States of America.
PLoS One. 2017 Dec 4;12(12):e0188474. doi: 10.1371/journal.pone.0188474. eCollection 2017.
Triggers of the autoimmune response that leads to type 1 diabetes (T1D) remain poorly understood. A possibility is that parallel changes in both T cells and target cells provoke autoimmune attack. We previously documented greater Ca2+ transients in fibroblasts from T1D subjects than non-T1D after exposure to fatty acids (FA) and tumor necrosis factor α (TNFα). These data indicate that metabolic and signal transduction defects present in T1D can be elicited ex vivo in isolated cells. Changes that precede T1D, including inflammation, may activate atypical responses in people that are genetically predisposed to T1D. To identify such cellular differences in T1D, we quantified a panel of metabolic responses in fibroblasts and peripheral blood cells (PBMCs) from age-matched T1D and non-T1D subjects, as models for non-immune and immune cells, respectively. Fibroblasts from T1D subjects accumulated more lipid, had higher LC-CoA levels and converted more FA to CO2, with less mitochondrial proton leak in response to oleate alone or with TNFα, using the latter as a model of inflammation. T1D-PBMCs contained and also accumulated more lipid following FA exposure. In addition, they formed more peroxidized lipid than controls following FA exposure. We conclude that both immune and non-immune cells in T1D subjects differ from controls in terms of responses to FA and TNFα. Our results suggest a differential sensitivity to inflammatory insults and FA that may precede and contribute to T1D by priming both immune cells and their targets for autoimmune reactions.
导致1型糖尿病（T1D）的自身免疫反应触发因素仍知之甚少。一种可能性是T细胞和靶细胞的平行变化引发自身免疫攻击。我们之前记录到，与非T1D患者的成纤维细胞相比，T1D患者的成纤维细胞在暴露于脂肪酸（FA）和肿瘤坏死因子α（TNFα）后，Ca2+瞬变更大。这些数据表明，T1D中存在的代谢和信号转导缺陷可以在离体的分离细胞中引发。T1D之前的变化，包括炎症，可能会在具有T1D遗传易感性的人群中激活非典型反应。为了识别T1D中的此类细胞差异，我们分别对来自年龄匹配的T1D和非T1D受试者的成纤维细胞和外周血单核细胞（PBMC）中的一组代谢反应进行了量化，分别作为非免疫细胞和免疫细胞的模型。T1D受试者的成纤维细胞积累了更多脂质，具有更高的LC-CoA水平，并将更多的FA转化为CO2，单独使用油酸或与TNFα一起使用时，线粒体质子泄漏更少，后者作为炎症模型。T1D-PBMC在暴露于FA后含有并积累了更多脂质。此外，在暴露于FA后，它们形成的过氧化脂质比对照组更多。我们得出结论，T1D受试者的免疫细胞和非免疫细胞在对FA和TNFα的反应方面与对照组不同。我们的结果表明，对炎症刺激和FA的敏感性差异可能在T1D之前出现，并通过使免疫细胞及其靶标引发自身免疫反应而导致T1D。
