PDF(Pubmed)
Abstract：
A characteristic feature of sarcoidosis is a dysregulated immune response to persistent stimuli, often leading to the formation of non-necrotizing granulomas in various organs. Although genetic susceptibility is an essential factor in disease development, the etiology of sarcoidosis is not fully understood. Specifically, whether autoimmunity contributes to the initiation or progression of the disease is uncertain. In this study, we investigated systemic autoimmunity to vimentin in sarcoidosis. IgG antibodies to human vimentin were measured in sera from sarcoidosis patients and healthy controls. Mice immunized with recombinant murine vimentin were challenged intravenously with vimentin-coated beads to mimic pulmonary sarcoidosis. Lungs from treated mice were studied for cellular infiltration, granuloma formation, and gene expression. Immune cells in the bronchoalveolar lavage fluid were evaluated by flow cytometry. Compared to healthy controls, sarcoidosis patients had a higher frequency and levels of circulating anti-vimentin IgG. Vimentin-immunized mice developed lung granulomas following intravenous challenge with vimentin-coated beads. These sarcoidosis-like granulomas showed the presence of Langhans and foreign body multinucleated giant cells, CD4 T cells, and a heterogeneous collection of MHC II positive and arginase 1-expressing macrophages. The lungs showed upregulated pro-inflammatory gene expression, including Ifng, Il17, and Tnfa, reflecting TH1/TH17 responses typical of sarcoidosis. In addition, genes in the TH2 canonical pathway were also upregulated, congruent with increased numbers of ILC2 in the bronchoalveolar lavage. Overall, these results further validate vimentin as an autoantigen in sarcoidosis and provide evidence for an anti-vimentin immune response in disease pathogenesis. Our study also highlights the possible role of ILC2-driven TH2-like responses in the formation of lung granulomas in sarcoidosis.
摘要：
结节病的特征是对持续刺激的免疫反应失调，通常导致各种器官非坏死性肉芽肿的形成。尽管遗传易感性是疾病发展的重要因素，结节病的病因尚不完全清楚。具体来说,自身免疫是否有助于疾病的开始或进展尚不确定.在这项研究中,我们研究了结节病中波形蛋白的全身性自身免疫。在结节病患者和健康对照的血清中测量人波形蛋白的IgG抗体。用重组鼠波形蛋白免疫的小鼠用波形蛋白包被的珠子静脉内攻击以模拟肺结节病。研究了来自治疗小鼠的肺的细胞浸润，肉芽肿形成,和基因表达。通过流式细胞术评估支气管肺泡灌洗液中的免疫细胞。与健康对照相比，结节病患者循环抗波形蛋白IgG的频率和水平较高。波形蛋白免疫的小鼠在用波形蛋白包被的珠子静脉内攻击后出现肺肉芽肿。这些结节病样肉芽肿显示存在朗汉斯和异物多核巨细胞，CD4T细胞，和MHCII阳性和精氨酸酶1表达的巨噬细胞的异质集合。肺显示促炎基因表达上调，包括Ifng,Il17和Tnfa,反映结节病典型的TH1/TH17反应。此外,TH2经典途径中的基因也被上调，与支气管肺泡灌洗中ILC2数量增加一致。总的来说,这些结果进一步验证了波形蛋白作为结节病的自身抗原,并为疾病发病机制中的抗波形蛋白免疫应答提供了证据.我们的研究还强调了ILC2驱动的TH2样反应在结节病肺肉芽肿形成中的可能作用。
