Table2_Transcriptome Analysis of Monocytes and Fibroblasts Provides Insights Into the Molecular Features of Periodontal Ehlers-Danlos Syndrome.DOCX

Periodontal Ehlers–Danlos syndrome (pEDS) is a rare hereditary disorder characterized by severe early-onset periodontitis with premature tooth loss, pretibial hyperpigmentation, and skin fragility. It is caused by mutant variants in the C1R and C1S genes that result in C4 cleavage and local complement cascade activation, as well as other possible consequences. However, the exact functional consequences of this activation remain unclear. To shed light on molecular mechanisms underlying pEDS and to identify novel molecular targets that may expand treatment strategies, we performed transcriptome profiling by RNA sequencing of monocytes and gingival fibroblasts from two patients with pEDS. Compared to normal controls, differential expression of genes was found only in monocytes but not gingival fibroblasts. Most of the significant genes were enriched in biological processes such as neutrophil-mediated immunity, response to bacterium, TNF-α and IL-17 pathway which are related to inflammation response and immune response. In disease ontology enrichment analysis, genes related to periodontal host defense, inflammatory response, skin disease, and vascular development, including MMP9, VEGFA, IL10, IL1A, IL1B, IL2RA, and IL6, were significantly enriched and also validated by qPCR and ELISA. Overall, the present study provides the transcriptomic data of pEDS for the first time and the distinct molecular features in monocytes of pEDS might serve as a tool to better understand the disease.

牙周型埃勒斯-当洛综合征（periodontal Ehlers–Danlos syndrome, pEDS）是一种罕见的遗传性疾病，以重度早发性牙周炎伴牙齿早失、胫前色素沉着及皮肤脆性为典型特征。该病由C1R与C1S基因的突变变异体引发，可导致C4裂解与局部补体级联激活，以及其他潜在后果，但此类激活的确切功能效应迄今仍未明确。
为阐明pEDS的潜在分子机制并鉴定可拓展治疗策略的新型分子靶点，本研究对2例pEDS患者的单核细胞与牙龈成纤维细胞采用RNA测序（RNA sequencing）开展转录组分析。与正常对照组相比，仅在单核细胞中检测到基因差异表达，牙龈成纤维细胞中未出现此类表达变化。多数显著差异表达基因富集于中性粒细胞介导免疫、细菌应答、肿瘤坏死因子-α（TNF-α）及白细胞介素-17（IL-17）通路等与炎症反应和免疫应答相关的生物学过程。
在疾病本体富集分析中，与牙周宿主防御、炎症反应、皮肤疾病及血管发育相关的基因（包括基质金属蛋白酶9（MMP9）、血管内皮生长因子A（VEGFA）、IL10、IL1A、IL1B、IL2RA及IL6）呈现显著富集，且该结果通过定量聚合酶链反应（quantitative polymerase chain reaction, qPCR）与酶联免疫吸附测定（enzyme-linked immunosorbent assay, ELISA）得到验证。
总体而言，本研究首次提供了pEDS的转录组学数据，且pEDS患者单核细胞中独特的分子特征可作为深入理解该疾病的有效研究工具。