Molecular Rheumatology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
The European League Against Rheumatism (EULAR) Centre of Excellence for Rheumatology, Centre for Arthritis and Rheumatic Diseases, St. Vincent's University Hospital, Dublin, Ireland.
Front Immunol. 2021 Oct 7;12:745226. doi: 10.3389/fimmu.2021.745226. eCollection 2021.
To examine the role of synovial CD1cDCs in patients with Inflammatory Arthritis (IA) with a specific focus on the transcriptional and maturation signatures that govern their function.
RNA sequencing was performed on healthy control (HC) peripheral blood (PB), IA PB, and IA synovial fluid (SF) CD1cDCs. Multiparametric flow-cytometry and SPICE analysis were used to examine site [SF and Synovial Tissue (ST) CD1c+DCs] and disease specific characteristics of CD1cDCs, while functional assays such as antigen processing, activation, and MMP production were also performed.
Increased frequency of CD1cDCs (p<0.01) with a concomitant increase in CD80, CCR7 (p<0.01), and CXCR3 (p<0.05) expression was identified in IA PB compared to HC PB. Enrichment of CD1cDCs was identified in IA synovial tissue (ST) (p<0.01) and IA SF (p<0.0001) compared to IA PB, while RNAseq revealed distinct transcriptional variation between PB and SF CD1cDCs. Flow cytometry revealed increased expression of CD83, CD80, PD-L1, and BTLA (all p<0.05) in IA SF CD1cDCs compared to PB, while SPICE identified synovial cells with unique co-expression patterns, expressing multiple DC maturation markers simultaneously. Functionally, synovial CD1cDCs are hyper-responsive to TLR7/8 ligation (p<0.05), have decreased antigen processing capacity (p=0.07), and display dysregulated production of MMPs. Finally, examination of both synovial CD1cDCs and synovial CD141DCs revealed distinct maturation and transcriptomic profiles.
Synovial CD1cDCs accumulate in the inflamed IA synovium in a variety of distinct poly-maturational states, distinguishing them transcriptionally and functionally from CD1cDCs in the periphery and synovial CD141DCs.
研究滑膜 CD1cDC 在炎症性关节炎（IA）患者中的作用，特别关注调控其功能的转录和成熟特征。
对健康对照（HC）外周血（PB）、IA PB 和 IA 滑膜液（SF）CD1cDC 进行 RNA 测序。采用多参数流式细胞术和 SPICE 分析，研究 CD1cDC 在外周和滑膜组织（ST）中位点特异性和疾病特异性特征，同时还进行了抗原加工、激活和 MMP 产生等功能检测。
与 HC PB 相比，IA PB 中 CD1cDC 的频率增加（p<0.01），同时 CD80、CCR7（p<0.01）和 CXCR3（p<0.05）的表达也增加。与 IA PB 相比，IA 滑膜组织（ST）（p<0.01）和 IA SF（p<0.0001）中 CD1cDC 的富集度更高，而 RNAseq 显示 PB 和 SF CD1cDC 之间存在明显的转录差异。流式细胞术显示，与 PB 相比，IA SF CD1cDC 中 CD83、CD80、PD-L1 和 BTLA 的表达增加（均 p<0.05），而 SPICE 则确定了具有独特共表达模式的滑膜细胞，同时表达多个 DC 成熟标志物。功能上，滑膜 CD1cDC 对 TLR7/8 配体的反应更为敏感（p<0.05），抗原加工能力降低（p=0.07），MMPs 的产生失调。最后，对滑膜 CD1cDC 和滑膜 CD141DC 进行检查，发现其具有不同的成熟和转录谱。
在各种不同的多成熟状态下，滑膜 CD1cDC 在炎症性 IA 滑膜中聚集，在转录和功能上与外周的 CD1cDC 和滑膜 CD141DC 区分开来。
