University of Milan, Centro Dino Ferrari, Milan, Italy; Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy.
University of Milan, Centro Dino Ferrari, Milan, Italy.
Cytokine. 2019 Apr;116:115-119. doi: 10.1016/j.cyto.2018.12.024. Epub 2019 Jan 25.
Homozygous mutations in Triggering Receptor Expressed on Myeloid cells 2 gene (TREM2) are one of the major causes of Nasu Hakola Disease (NHD). We analysed Peripheral Blood Mononuclear Cells (PBMC) profile of 164 inflammatory factors in patients with NHD carrying the TREM2 Q33X mutation as compared with heterozygous and wild type individuals. Several molecules related to bone formation and angiogenesis were altered in NHD compared to non-carriers: Bone Morphogenetic Protein (BMP)-1 mRNA levels were significantly increased in PBMC (2.32 fold-increase; P = 0.01), as were Transforming Growth Factor Beta (TGFB)3 levels (1.51 fold-increase; P = 0.02). Conversely, CXCL5 and Pro Platelet Basic Protein (PPBP) were strongly downregulated (-28.26, -9.85 fold-decrease over non-carriers, respectively, P = 0.01), as well as Platelet Factor 4 Variant 1 (PF4V1; -41.44, P = 0.03). Among other inflammatory factors evaluated, Interleukin (IL)-15 and Tumor Necrosis Factor Superfamily Member (TNFSF)4 mRNA levels were decreased in NHD as compared with non-carriers (-2.25 and -3.87 fold-decrease, P = 0.01 and 0.001, respectively). In heterozygous individuals, no significant differences were observed, apart from IL-15 mRNA levels, that were decreased at the same extent as NHD (-2.05 fold-decrease over non-carriers, P = 0.002). We identified a signature in PBMC from patients with NHD consisting of strongly decreased mRNA levels of CXCL5, PPBP, PF4V1, mildly decreased IL-15 and TNFSF4 and mildly increased BMP-1 and TGFB3.
TREM2 基因（Triggering Receptor Expressed on Myeloid cells 2）纯合突变是 Nasu Hakola 病（NHD）的主要病因之一。我们分析了携带 TREM2 Q33X 突变的 NHD 患者外周血单个核细胞（PBMC）中 164 种炎症因子的谱，与杂合子和野生型个体进行比较。与非携带者相比，NHD 中几种与骨形成和血管生成相关的分子发生了改变：BMP-1mRNA 水平在 PBMC 中显著升高（增加 2.32 倍；P=0.01），TGFB3 水平也升高（增加 1.51 倍；P=0.02）。相反，CXCL5 和血小板碱性蛋白基本蛋白（PPBP）强烈下调（与非携带者相比分别下调 28.26、9.85 倍，P=0.01），血小板因子 4 变体 1（PF4V1）也下调（下调 41.44，P=0.03）。在评估的其他炎症因子中，与非携带者相比，白细胞介素（IL）-15 和肿瘤坏死因子超家族成员（TNFSF）4mRNA 水平在 NHD 中降低（分别降低 2.25 和 3.87 倍，P=0.01 和 0.001）。在杂合子个体中，除了 IL-15mRNA 水平同样降低（与非携带者相比降低 2.05 倍，P=0.002）外，没有观察到显著差异。我们在 NHD 患者的 PBMC 中鉴定出一个特征，即 CXCL5、PPBP、PF4V1 的 mRNA 水平强烈降低，IL-15 和 TNFSF4 的 mRNA 水平轻度降低，BMP-1 和 TGFB3 的 mRNA 水平轻度升高。
