Immunology Section, Germans Trias i Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain.
Pediatrics Section, Germans Trias i Pujol University Hospital, Badalona, Spain.
Front Immunol. 2019 Nov 28;10:2811. doi: 10.3389/fimmu.2019.02811. eCollection 2019.
Type 1 diabetes (T1D) is prompted by defective immunological tolerance, an event in which dendritic cells (DCs) are crucial as immune response orchestrators. In fact, they contribute to maintaining tolerance to self-antigens, but they can also prompt an immunogenic response against them, leading to autoimmunity. Countless factors can potentially impact on the proper functionality of the DCs, which range from altered subset distribution, impaired phagocytic function to abnormal gene expression. Moreover, in T1D, metabolic dysregulation could impair DC functions as well. Indeed, since T1D clinical course is likely to be more aggressive in children and adolescents and entails severe dysglycemia, the aim of this study was to analyze circulating DCs subpopulations in pediatric T1D at different stages, as well as to characterize their phagocytosis ability and tolerance induction potential. Thus, pediatric patients newly diagnosed with T1D, with established disease and control subjects were recruited. Firstly, DCs subsets from peripheral blood were found quantitatively altered during the first year of disease, but recovered in the second year of progression. Secondly, to study the tolerogenic functionality of DCs, liposomes with phosphatidylserine (PS) were designed to mimic apoptotic beta cells, which are able to induce tolerance, as previously demonstrated by our group in DCs from adult patients with T1D. In this study, monocyte-derived DCs from pediatric patients with T1D and control subjects were assessed in terms of PS-liposomes capture kinetics, and transcriptional and phenotypic changes. DCs from pediatric patients with T1D were found to phagocyte PS-liposomes more slowly and less efficiently than DCs from control subjects, inversely correlating with disease evolution. Nonetheless, the transcription of PS receptors and immunoregulatory genes, cytokine profile, and membrane expression of immunological markers in DCs was consistent with tolerogenic potential after PS-liposomes phagocytosis. In conclusion, T1D progression in childhood entails altered peripheral blood DCs subsets, as well as impaired DCs phagocytosis, although tolerance induction could still function optimally. Therefore, this study provides useful data for patient follow-up and stratification in immunotherapy clinical trials.
1 型糖尿病（T1D）是由免疫耐受缺陷引起的，树突状细胞（DCs）在免疫反应中起着至关重要的作用。事实上，它们有助于维持对自身抗原的耐受性，但也可以引发针对自身抗原的免疫反应，导致自身免疫。无数因素可能会影响 DCs 的正常功能，包括亚群分布改变、吞噬功能受损到异常基因表达等。此外，在 T1D 中，代谢失调也可能损害 DC 的功能。事实上，由于 T1D 临床病程在儿童和青少年中可能更为激进，并且涉及严重的糖代谢紊乱，因此本研究旨在分析不同阶段儿科 T1D 患者循环 DC 亚群，并对其吞噬能力和诱导耐受的能力进行特征分析。因此，招募了新诊断为 T1D 的儿科患者、疾病已确诊的患者和对照组患者。首先，发现疾病发生后的第一年外周血中的 DC 亚群数量发生了改变，但在病程的第二年恢复正常。其次，为了研究 DC 的耐受功能，设计了含有磷脂酰丝氨酸（PS）的脂质体来模拟凋亡的β细胞，正如我们之前在成人 T1D 患者的 DC 中所证明的那样，凋亡的β细胞能够诱导耐受。在这项研究中，我们评估了来自儿科 T1D 患者和对照组患者的单核细胞来源的 DC 对 PS 脂质体的摄取动力学以及转录和表型变化。与对照组相比，T1D 患儿的 DC 摄取 PS 脂质体的速度较慢且效率较低，与疾病进展呈负相关。尽管如此，PS 受体和免疫调节基因的转录、细胞因子谱以及 DC 表面免疫标志物的表达与 PS 脂质体吞噬后的耐受诱导潜能一致。总之，儿童时期 T1D 的进展导致外周血 DC 亚群改变以及 DC 吞噬功能受损，尽管诱导耐受仍能发挥最佳功能。因此，本研究为免疫治疗临床试验中的患者随访和分层提供了有用的数据。
