Ramos Maria I, Perez Samuel Garcia, Aarrass Saida, Helder Boy, Broekstra Pleun, Gerlag Daan M, Reedquist Kris A, Tak Paul Peter, Lebre Maria C
Arthritis Res Ther. 2013;15(6):R209. doi: 10.1186/ar4403.
The FMS-related tyrosine kinase 3 ligand (Flt3L)/CD135 axis plays a fundamental role in proliferation and differentiation of dendritic cells (DCs). As DCs play an important role in rheumatoid arthritis (RA) immunopathology we studied in detail the Flt3L/CD135 axis in RA patients.
The levels of Flt3L in (paired) serum and synovial fluid (SF) were quantified by enzyme-link immunosorbent assay (ELISA). Expression of Flt3L and CD135 in paired peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) was quantified by fluorescence-activated cell sorting (FACS). The expression of Flt3L, CD135 and TNF-Converting Enzyme (TACE) in synovial tissues (STs) and in vitro polarized macrophages and monocyte-derived DCs (Mo-DCs) was assessed by quantitative PCR (qPCR). CD135 ST expression was evaluated by immunohistochemistry and TACE ST expression was assessed by immunofluorescence. Flt3L serum levels were assessed in RA patients treated with oral prednisolone or adalimumab.
Flt3L levels in RA serum, SF and ST were significantly elevated compared to gout patients and healthy individuals (HI). RA SF monocytes, natural killer cells and DCs expressed high levels of Flt3L and CD135 compared to HI. RA ST CD68+ and CD163+ macrophages, CD55+ fibroblast-like synoviocytes (FLS), CD31+ endothelial cells or infiltrating monocytes and CD19+ B cells co-expressed TACE. IFN-γ-differentiated macrophages expressed higher levels of Flt3L compared to other polarized macrophages. Importantly, Flt3L serum levels were reduced by effective therapy.
The Flt3L/CD135 axis is active in RA patients and is responsive to both prednisolone and adalimumab treatment. Conceivably, this ligand receptor pair represents a novel therapeutic target.
FMS相关酪氨酸激酶3配体（Flt3L）/CD135轴在树突状细胞（DC）的增殖和分化中起重要作用。由于DC在类风湿关节炎（RA）免疫病理学中发挥重要作用，我们详细研究了RA患者的Flt3L/CD135轴。
通过酶联免疫吸附测定（ELISA）对（配对的）血清和滑液（SF）中的Flt3L水平进行定量。通过荧光激活细胞分选（FACS）对配对的外周血单核细胞（PBMC）和滑液单核细胞（SFMC）中Flt3L和CD135的表达进行定量。通过定量PCR（qPCR）评估滑膜组织（ST）以及体外极化巨噬细胞和单核细胞衍生DC（Mo-DC）中Flt3L、CD135和肿瘤坏死因子转换酶（TACE）的表达。通过免疫组织化学评估CD135在ST中的表达，并通过免疫荧光评估TACE在ST中的表达。对接受口服泼尼松龙或阿达木单抗治疗的RA患者的Flt3L血清水平进行评估。
与痛风患者和健康个体（HI）相比，RA血清、SF和ST中的Flt3L水平显著升高。与HI相比，RA SF单核细胞、自然杀伤细胞和DC表达高水平的Flt3L和CD135。RA ST CD68 +和CD163 +巨噬细胞、CD55 +成纤维样滑膜细胞（FLS）、CD31 +内皮细胞或浸润单核细胞以及CD19 + B细胞共表达TACE。与其他极化巨噬细胞相比，IFN-γ分化的巨噬细胞表达更高水平的Flt3L。重要的是，有效治疗可降低Flt3L血清水平。
Flt3L/CD135轴在RA患者中具有活性，并且对泼尼松龙和阿达木单抗治疗均有反应。可以想象，这种配体受体对代表了一个新的治疗靶点。
