Center of New Biotechnologies & Precision Medicine.
Joint Rheumatology Program, National and Kapodistrian University of Athens Medical School, Athens.
Rheumatology (Oxford). 2021 Oct 2;60(10):4910-4919. doi: 10.1093/rheumatology/keab052.
Both innate and adaptive immune responses are reportedly increased in Behçet's disease (BD), a chronic, relapsing systemic vasculitis lying at the intersection between autoinflammation and autoimmunity. To further study pathophysiologic molecular mechanisms operating in BD, we searched for transcriptome-wide changes in blood mononuclear cells from these patients.
We performed 3' mRNA next-generation sequencing-based genome-wide transcriptional profiling followed by analysis of differential expression signatures, Kyoto Encyclopedia of Genes and Genomes pathways, GO biological processes and transcription factor signatures.
Differential expression analysis clustered the transcriptomes of 13 patients and one healthy subject separately from those of 10 healthy age/gender-matched controls and one patient. Among the total of 17 591 expressed protein-coding genes, 209 and 31 genes were significantly upregulated and downregulated, respectively, in BD vs controls by at least 2-fold. The most upregulated genes comprised an abundance of CC- and CXC-chemokines. Remarkably, the 5 out of top 10 upregulated biological processes involved leucocyte recruitment to peripheral tissues, especially for neutrophils. Moreover, NF-kB, TNF and IL-1 signalling pathways were prominently enhanced in BD, while transcription factor activity analysis suggested that the NF-kB p65/RELA subunit action underlies the observed differences in the BD transcriptome.
This RNA-sequencing analysis in peripheral blood mononuclear cells derived from patients with BD does not support a major pathogenetic role for adaptive immunity-driven mechanisms, but clearly points to the action of aberrant innate immune responses with a central role played by upregulated neutrophil chemotaxis.
据报道，贝切特病（BD）的先天和适应性免疫反应均增加，BD 是一种慢性、复发性系统性血管炎，位于自身炎症和自身免疫之间的交界处。为了进一步研究 BD 中作用的病理生理分子机制，我们在这些患者的血液单核细胞中寻找转录组范围的变化。
我们进行了基于 3' mRNA 下一代测序的全基因组转录谱分析，然后分析差异表达特征、京都基因与基因组百科全书通路、GO 生物学过程和转录因子特征。
差异表达分析将 13 名患者和 1 名健康受试者的转录组分别与 10 名健康年龄/性别匹配的对照者和 1 名患者的转录组聚类。在总共 17591 个表达的蛋白编码基因中，BD 与对照组相比，分别有 209 个和 31 个基因的表达上调和下调至少 2 倍。上调最明显的基因包括丰富的 CC 和 CXC 趋化因子。值得注意的是，前 10 个上调的生物学过程中有 5 个涉及白细胞向外周组织的募集，特别是中性粒细胞。此外，BD 中 NF-kB、TNF 和 IL-1 信号通路明显增强，而转录因子活性分析表明，NF-kB p65/RELA 亚基的作用是导致 BD 转录组差异的原因。
这项来自 BD 患者外周血单核细胞的 RNA-seq 分析不支持适应性免疫驱动机制的主要致病作用，但清楚地表明异常的先天免疫反应起作用，上调的中性粒细胞趋化作用起着核心作用。
