Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis
Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis
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DOI：
10.1126/sciimmunol.aag3358
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发表时间：
2017-04-01
影响因子：
24.8
通讯作者：
Kaplan, Mariana J.
中科院分区：
文献类型：
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作者：
Carmona-Rivera, Carmelo;Carlucci, Philip M.;Kaplan, Mariana J.
类风湿关节炎(RA)的特征是滑膜关节炎症和对瓜氨酸蛋白产生致病性体液和细胞自身免疫。中性粒细胞胞外陷阱(Net)是瓜氨酸自身抗原的来源之一，并激活RA滑膜成纤维细胞样滑膜细胞(FLS)，这些细胞在关节损伤中起关键作用。我们研究了Net促进FLS致炎表型的分子机制，以及这些相互作用是否会产生致病性的抗瓜氨酸获得性免疫反应。含有瓜氨酸多肽的Net通过RAGE-TLR9途径被FLS内化，促进FLS的炎症表型及其主要组织相容性复合体(MHC)II类的上调。一旦内化，致关节炎的网肽被加载到FLS MHC II类并呈递给抗原特异性T细胞。用携带Net的小鼠FLS免疫的HL A-DRB1*04：01转基因小鼠产生针对瓜氨酸化形式的相关自身抗原的抗体，这些自身抗原与RA的发病机制以及软骨损伤有关。这些结果表明，FLS是RA发病的重要介质，通过内化和呈递网状瓜氨酸肽进入适应性免疫系统，导致病理性自身免疫和软骨损伤。
Rheumatoid arthritis (RA) is characterized by synovial joint inflammation and by development of pathogenic humoral and cellular autoimmunity to citrullinated proteins. Neutrophil extracellular traps (NETs) are a source of citrullinated autoantigens and activate RA synovial fibroblast-like synovlocytes (FLS), cells crucial in joint damage. We investigated the molecular mechanisms by which NETs promote proinflammatory phenotypes in FLS and whether these interactions generate pathogenic anti-citrulline adaptive immune responses. NETs containing citrullinated peptides are internalized by FLS through a RAGE-TLR9 pathway, promoting FLS inflammatory phenotype and their up-regulation of major histocompatibility complex (MHC) class II. Once internalized, arthritogenic NET peptides are loaded into FLS MHC class II and presented to antigen-specific T cells. HLA-DRB1*04:01 transgenic mice immunized with mouse FLS loaded with NETs develop antibodies specific to citrullinated forms of relevant autoantigens implicated in RA pathogenesis as well as cartilage damage. These results implicate FLS as notable mediators in RA pathogenesis, through the internalization and presentation of NET citrullinated peptides to the adaptive immune system, leading to pathogenic autoimmunity and cartilage damage.