Citrullinated fibrinogen is a target of autoantibodies in interstitial lung disease in mice with collagen-induced arthritis.
- 作者列表："Sato T","Satooka H","Ichioka S","Maruo Y","Hirata T
: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, CD11bhi 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 autoantibodies against citrullinated proteins, which are specific and predictive markers for RA. Protein citrullination was enhanced in the lung of CIA mice compared to naive mice, and citrullinated fibrinogen was primarily targeted by these autoantibodies. The elevation of autoantibodies 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.
间质性肺病 (ILD) 是类风湿关节炎 (RA) 的一种非常常见和致命的并发症，但其发病机制尚不十分清楚，部分原因是由于缺乏足够的动物模型。虽然胶原诱导性关节炎 (CIA) 是 RA 最广泛使用的动物模型，但在该模型中发生的肺受累很少被研究。为了评价 CIA 作为 RA 相关性 ILD (RA-ILD) 模型的适用性，我们用牛 ⅱ 型胶原免疫 DBA/1 小鼠，并在此模型中表征肺部疾病。组织学分析显示，在 CIA 小鼠中，肺周边区域，特别是胸膜下区域的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 中最常见的模式。在肺浸润中，M2 表型的 CD11bhi 巨噬细胞最显著增加。IgG 和 C3 沉积在炎症细胞浸润的胸膜下区域。CIA 小鼠血清中含有抗瓜氨酸蛋白的自身抗体，瓜氨酸蛋白是 RA 的特异性和预测性标志物。与初始小鼠相比，CIA 小鼠肺中的蛋白瓜氨酸化增强，瓜氨酸化纤维蛋白原主要被这些自身抗体靶向。抗瓜氨酸蛋白自身抗体的升高及其在肺内的沉积与斑片状胸膜下优势提示 CIA 可作为研究 RA-ILD 发病机制的模型。
METHODS:OBJECTIVES:To asses the clinical course in RA-related interstitial lung disease (RA-ILD) patients with and without rituximab (RTX). The influence of other variables was also evaluated. METHODS:A longitudinal multicentre study was conducted in RA diagnosed with ILD from 2007 until 2018 in Madrid. Patients were included in a registry [pNEumology RhEumatology Autoinmune diseases (NEREA)] from the time of ILD diagnosis. The main endpoint was functional respiratory impairment (FI), when there was a decline ≥5% in the predicted forced vital capacity compared with the previous one. Pulmonary function was measured at baseline and in follow-up visits every 6-12 months. The independent variable was therapy with RTX. Covariables included sociodemographic, clinical, radiological and other therapies. Survival techniques were used to estimate the incidence rate (IR) and 95% CI of functional impairment, expressed per 100 patient-semesters. Cox multivariate regression models were run to examine the influence of RTX and other covariates on FI. Results were expressed as the hazard ratio (HR) and CI. RESULTS:A total of 68 patients were included. FI occurred in 42 patients [IR 23.5 (95% CI 19, 29.1)] and 50% of them had FI within 1.75 years of an ILD diagnosis. A multivariate analysis showed that RTX exposure resulted in a lower risk of FI compared with non-exposure [HR 0.51 (95% CI 0.31, 0.85)]. Interstitial pneumonia, glucocorticoids, disease activity and duration also influenced FI. CONCLUSION:RA-ILD patients deteriorate over time, with the median time free of impairment being <2 years. Patients exposed to RTX had a higher probability of remaining free of FI compared with other therapies. Other factors have also been identified. Key words: rheumatoid arthritis, interstitial lung disease, observational study, rituximab and prognosis
METHODS:The safety of anti-programmed cell death 1 (PD-1) antibody for patients with preexisting interstitial lung disease (ILD) remains unknown. The aim of this study was to evaluate the dependence of preexisting ILD on anti-PD-1 antibody-induced pneumonitis in non-small cell lung cancer (NSCLC) patients. We retrospectively reviewed the association of preexisting ILD with the incidence, radiographic pattern, and outcome of pneumonitis in NSCLC patients receiving anti-PD-1 antibody. A total of 331 patients were included in this study. Of these patients, 17 had preexisting ILD. The incidence of pneumonitis was higher among the patients with preexisting ILD than among those without preexisting ILD (29% vs. 10%, P = 0.027). The distributions of the CT appearances at the onset of anti-PD-1 antibody-induced pneumonitis were as follows: for the patients with preexisting ILD, two patients (40%) had diffuse alveolar damage (DAD), one patient each with organizing pneumonia-like (OP), hypersensitivity pneumonitis (HP), and other patterns (20% each); for the patients without preexisting ILD, 19 patients (61%) had OP, 8 (26%) had HP, 3 (10%) had DAD, and 1 (3.2%) had other patterns. The median onset time from the initiation of anti-PD-1 antibody treatment until the development of pneumonitis was 1.3 months (range 0.3–2.1 months) for the patients with preexisting ILD and 2.3 months (range 0.2–14.6 months) for the patients without preexisting ILD. Careful attention to the development of pneumonitis is needed, especially within the first 3 months after the start of anti-PD-1 antibody treatment, when using anti-PD-1 antibody to treat patients with preexisting ILD.
METHODS::Bacteria of the Burkholderia cepacia complex (Bcc) are ubiquitous multidrug resistant organisms and opportunistic pathogens capable of causing life threatening lung infections among cystic fibrosis (CF) patients. No effective therapies are currently available to eradicate Bcc bacteria from CF patients, as these organisms are inherently resistant to the majority of clinically available antimicrobials. An immunoproteomics approach was used to identify Bcc proteins that stimulate the humoral immune response of the CF host, using bacterial cells grown under conditions mimicking the CF lung environment and serum samples from CF patients with a clinical record of Bcc infection. 24 proteins of the Bcc strain B. cenocepacia J2315 were identified as immunoreactive, 19 here reported as immunogenic for the first time. Ten proteins were predicted as extracytoplasmic, 9 of them being conserved in Bcc genomes. The immunogenic Bcc extracytoplasmic proteins are potential targets for development of novel therapeutic strategies and diagnostic tools to protect patients against the onset of chronic Bcc lung infections.