RNAseq

Familial Mediterranean Fever (FMF) is a prototypical periodic fever syndrome caused by genetic variation in MEFV. While it is known that especially IL-1β responses are dysregulated in FMF, its innate immune landscape has not been comprehensively described. Therefore, we extensively characterized the function of monocytes and neutrophils in patients with FMF in between disease attacks, as well as their circulating inflammatory proteome. We found that monocyte IL-1ï¢ and IL-6 production was enhanced following a range of stimulations, in concordance with alterations in the plasma inflammatory proteome. In contrast, neutrophil function in FMF was normal. Additionally, ATAC-seq and RNA-seq analyses revealed important epigenetic and transcriptional reprogramming arguing for monocyte function dysregulation. Interestingly, chromatin-accessibility was down-regulated in genomic regions related to cellular responses. This argues that the primary immune dysregulation in monocytes due to MEFV mutations leads to a chronic inflammatory profile that is subsequently associated with counterregulatory epigenetic and transcriptional changes reminiscent of tolerance (rather than trained immunity) induction. These data increase our understanding of the innate immune changes in FMF, that can be used in the design of novel approaches to manage chronic inflammation of these patients.EGA study EGAS00001007165

家族性地中海热（Familial Mediterranean Fever, FMF）是一种由MEFV基因变异引发的典型周期性发热综合征。目前已知FMF患者体内尤其白细胞介素-1β（IL-1β）的应答存在失调，但尚未对其先天免疫全貌进行全面阐释。为此，本研究对疾病发作间歇期的FMF患者单核细胞与中性粒细胞的功能，及其循环炎症蛋白质组开展了系统性表征。研究发现，在多种刺激条件下，单核细胞的IL-1β与IL-6生成能力均显著增强，这与血浆炎症蛋白质组的改变高度一致。与之相反，FMF患者的中性粒细胞功能未见异常。此外，ATAC测序（ATAC-seq）与RNA测序（RNA-seq）分析结果显示，单核细胞存在重要的表观遗传与转录重编程，印证了其功能失调。值得注意的是，与细胞应答相关的基因组区域的染色质可及性出现下调。这表明，由MEFV突变引发的单核细胞原发性免疫失调，会导致慢性炎症表型，随后伴随与免疫耐受（而非训练免疫）诱导相似的代偿性表观遗传与转录改变。本研究加深了我们对FMF先天免疫改变的认知，可为开发管理此类患者慢性炎症的新型策略提供理论依据。本研究隶属于EGA研究EGAS00001007165。