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Functionally impaired plasmacytoid dendritic cells and non-haematopoietic sources of type I interferon characterize human autoimmunity
Nature Communications ( IF 14.7 ) Pub Date : 2020-12-01 , DOI: 10.1038/s41467-020-19918-z
Antonios Psarras 1, 2, 3 , Adewonuola Alase 1 , Agne Antanaviciute 4 , Ian M Carr 4 , Md Yuzaiful Md Yusof 1, 2 , Miriam Wittmann 1, 2 , Paul Emery 1, 2 , George C Tsokos 3 , Edward M Vital 1, 2
Affiliation  

Autoimmune connective tissue diseases arise in a stepwise fashion from asymptomatic preclinical autoimmunity. Type I interferons have a crucial role in the progression to established autoimmune diseases. The cellular source and regulation in disease initiation of these cytokines is not clear, but plasmacytoid dendritic cells have been thought to contribute to excessive type I interferon production. Here, we show that in preclinical autoimmunity and established systemic lupus erythematosus, plasmacytoid dendritic cells are not effector cells, have lost capacity for Toll-like-receptor-mediated cytokine production and do not induce T cell activation, independent of disease activity and the blood interferon signature. In addition, plasmacytoid dendritic cells have a transcriptional signature indicative of cellular stress and senescence accompanied by increased telomere erosion. In preclinical autoimmunity, we show a marked enrichment of an interferon signature in the skin without infiltrating immune cells, but with interferon-κ production by keratinocytes. In conclusion, non-hematopoietic cellular sources, rather than plasmacytoid dendritic cells, are responsible for interferon production prior to clinical autoimmunity.



中文翻译:


功能受损的浆细胞样树突状细胞和 I 型干扰素的非造血来源是人类自身免疫的特征



自身免疫性结缔组织疾病是由无症状的临床前自身免疫逐步产生的。 I 型干扰素在已确定的自身免疫性疾病的进展中发挥着至关重要的作用。这些细胞因子的细胞来源和疾病引发的调节尚不清楚,但浆细胞样树突状细胞被认为导致 I 型干扰素的过度产生。在这里,我们表明,在临床前自身免疫和已建立的系统性红斑狼疮中,浆细胞样树突状细胞不是效应细胞,已经丧失了 Toll 样受体介导的细胞因子产生的能力,并且不诱导 T 细胞激活,与疾病活动和血液无关干扰素签名。此外,浆细胞样树突状细胞具有指示细胞应激和衰老并伴有端粒侵蚀增加的转录特征。在临床前自身免疫中,我们发现皮肤中的干扰素特征显着富集,没有浸润免疫细胞,但角质形成细胞产生干扰素-κ。总之,非造血细胞来源,而不是浆细胞样树突状细胞,负责在临床自身免疫之前产生干扰素。

更新日期:2020-12-01
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