Interstitial lung disease (ILD) is a very common and lethal complication of rheumatoid arthritis (RA), yet its pathogenesis is not well understood, in part due to the lack of adequate animal models. Although collagen-induced arthritis (CIA) is the most widely used animal model for RA, the lung involvement occurring in this model has scarcely been studied. To evaluate the suitability of CIA as a model for RA-associated ILD (RA-ILD), we immunized DBA/1 mice with bovine type II collagen and characterized lung disease in this model. Histologic analyses revealed patchy interstitial infiltration of inflammatory cells in the peripheral regions of the lung, notably in the subpleural region, in mice with CIA. This pattern resembled usual interstitial pneumonia in humans, which is the most prevalent pattern in RA-ILD. Among infiltrates in the lung, CD11b^hi macrophages of the M2 phenotype were most prominently increased. IgG and C3 were deposited in the subpleural region where inflammatory cells infiltrated. The sera from CIA mice contained auto-antibodies against citrullinated proteins, which are specific and predictive markers for RA. Protein citrullination was enhanced in the lung of CIA mice compared with naive mice, and citrullinated fibrinogen was primarily targeted by these auto-antibodies. The elevation of auto-antibodies against citrullinated proteins and their deposition in the lung with patchy subpleural preponderance suggest that CIA can serve as a model to study the pathogenesis of RA-ILD.

中文翻译：

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瓜氨酸纤维蛋白原是胶原诱导性关节炎小鼠间质性肺病自身抗体的靶标。

间质性肺病 (ILD) 是类风湿性关节炎 (RA) 的一种非常常见且致命的并发症，但其发病机制尚不清楚，部分原因是缺乏足够的动物模型。尽管胶原诱导的关节炎 (CIA) 是最广泛使用的 RA 动物模型，但几乎没有研究过该模型中发生的肺部受累。为了评估 CIA 作为 RA 相关 ILD (RA-ILD) 模型的适用性，我们用牛 II 型胶原免疫 DBA/1 小鼠，并在该模型中表征肺病。组织学分析显示，在 CIA 小鼠的肺外周区域，特别是在胸膜下区域，炎症细胞呈斑片状间质浸润。这种模式类似于人类常见的间质性肺炎，这是 RA-ILD 中最普遍的模式。在肺部浸润中，CD11b^hi M2表型的巨噬细胞最显着地增加。IgG和C3沉积在炎症细胞浸润的胸膜下区域。CIA 小鼠的血清含有针对瓜氨酸蛋白的自身抗体，瓜氨酸蛋白是 RA 的特异性和预测标志物。与幼稚小鼠相比，CIA 小鼠肺中的蛋白质瓜氨酸化增强，这些自身抗体主要靶向瓜氨酸化纤维蛋白原。针对瓜氨酸蛋白的自身抗体的升高及其在肺中以斑片状胸膜下为主的沉积表明 CIA 可以作为研究 RA-ILD 发病机制的模型。