Department of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands Department of Experimental Immunology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.
Department of Experimental Immunology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.
Ann Rheum Dis. 2015 Jan;74(1):211-9. doi: 10.1136/annrheumdis-2013-203371. Epub 2013 Sep 24.
Comprehending the mechanisms that regulate activation of autoreactive T cells and B cell antibody production is fundamental for understanding the breakdown in self-tolerance and development of autoimmunity. Here we studied the role of Fms-like tyrosine kinase 3 ligand (Flt3L) signalling in the pathogenesis of collagen-induced arthritis (CIA).
CIA was induced in mice lacking Flt3L (Flt3L(-/-)) and wild-type (WT) littermates (C57/BL6, 8-10 weeks old). Mice were killed in the initial phase (acute phase: experiment 1) and late phase (chronic phase: experiment 2) of the disease. Arthritis severity was assessed using a semiquantitative scoring system (0-4), and histological analysis of cellular infiltration, cartilage destruction and peptidoglycan loss was performed. Phenotypic and functional analysis of T and B cells, FoxP3 expression, activation and lymphocyte costimulatory markers, and cytokine production were performed ex vivo by flow cytometry in lymph nodes. Serum collagen type II (CII)-specific antibodies were measured by ELISA.
Flt3L(-/-) mice showed a marked decrease in clinical arthritis scores and incidence of arthritis in both acute and chronic phases of CIA compared with WT mice. Moreover, decreased synovial inflammation and joint destruction was observed. Both the magnitude and quality of T cell responses were altered in Flt3L(-/-). In the acute phase, the amount of CII-specific IgG2a antibodies was lower in Flt3L(-/-) than WT mice.
These results strongly suggest a role for Flt3L signalling in the development of arthritis.
理解调节自身反应性 T 细胞和 B 细胞抗体产生的机制对于理解自身耐受的破坏和自身免疫的发展至关重要。在这里，我们研究了 Fms 样酪氨酸激酶 3 配体（Flt3L）信号在胶原诱导性关节炎（CIA）发病机制中的作用。
在缺乏 Flt3L（Flt3L（-/-））和野生型（WT）同窝（C57/BL6，8-10 周龄）的小鼠中诱导 CIA。在疾病的初始阶段（急性阶段：实验 1）和晚期阶段（慢性阶段：实验 2）处死小鼠。使用半定量评分系统（0-4）评估关节炎严重程度，并进行细胞浸润、软骨破坏和肽聚糖丢失的组织学分析。通过流式细胞术在淋巴结中进行 T 和 B 细胞的表型和功能分析、FoxP3 表达、激活和淋巴细胞共刺激标志物以及细胞因子产生的分析。通过 ELISA 测量血清胶原类型 II（CII）特异性抗体。
与 WT 小鼠相比，Flt3L（-/-）小鼠在 CIA 的急性和慢性阶段均表现出临床关节炎评分和关节炎发生率的显著降低。此外，观察到滑膜炎症和关节破坏减少。Flt3L（-/-）中 T 细胞反应的幅度和质量均发生改变。在急性阶段，Flt3L（-/-）小鼠的 CII 特异性 IgG2a 抗体量低于 WT 小鼠。
这些结果强烈表明 Flt3L 信号在关节炎的发展中起作用。
