Antigen-driven autoantibody production in lungs of interstitial lung disease with autoimmune disease
Antigen-driven autoantibody production in lungs of interstitial lung disease with autoimmune disease
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伴有自身免疫性疾病的间质性肺病患者肺部抗原驱动的自身抗体产生
DOI：
10.1016/j.jaut.2021.102661
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发表时间：
2021
影响因子：
12.8
通讯作者：
Takeuchi Tsutomu
中科院分区：
文献类型：
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作者：
Takeshita Masaru;Suzuki Katsuya;Nakazawa Maho;Kamata Hirofumi;Ishii Makoto;Oyamada Yoshitaka;Oshima Hisaji;Takeuchi Tsutomu
间质性肺病（ILD）有时会成为系统性自身免疫性疾病的危及生命的并发症;然而，对肺部病变的免疫反应知之甚少。我们的目的是研究与类风湿性关节炎（RA），干燥综合征（SjS）和混合性结缔组织病（MCTD）相关的ILD的体液免疫，使用支气管肺泡液（BALF）和血清样本从15例自身免疫性疾病相关的ILD。我们首先发现，BALF中含有比血清更高滴度的疾病相关自身抗体，这表明在肺中产生自身抗体的可能性。接下来，我们从BALF中的抗体分泌细胞产生了326个单克隆抗体，并分析了反应性及其回复突变体，其中体细胞超突变回复到种系。在123种来自RA-ILD的抗体中，鉴定了16种疾病相关抗体（抗修饰蛋白抗体和类风湿因子），其中一种抗体具有两种性质。回复突变抗体以复杂的方式改变其靶修饰，表明抗体针对肺中的各种修饰而被选择。在来自SjS-ILD和/或MCTD-ILD的146种抗体中，鉴定出7种抗SSA/Ro 60抗体和15种抗RNP抗体。一些抗RNP抗体同时识别多种RNP组成蛋白，表明表位扩散可能在肺中进行。我们的研究结果显示，存在一个积极的自身免疫性疾病相关的ILD肺。
Interstitial lung disease (ILD) sometimes becomes a life-threatening complication of systemic autoimmune diseases; however, little is known about the immune response in lung lesions. We aimed to investigate humoural immunity in ILD associated with rheumatoid arthritis (RA), sjögren's syndrome (SjS), and mixed connective tissue disease (MCTD), using bronchoalveolar fluid (BALF) and serum samples from 15 patients with autoimmune disease associated-ILD. We first showed that BALF contained higher titers of disease-related autoantibodies than serum, suggesting the possibility of autoantibody production in lungs. Next, we produced 326 monoclonal antibodies from antibody-secreting cells in BALF, and the reactivity and their revertants, in which somatic hypermutations were reverted to germline, were analyzed. Among 123 antibodies from RA-ILD, 16 disease-related antibodies (anti-modified protein antibodies and rheumatoid factors) were identified, of which one antibody had both properties. The revertant antibodies changed their target modification in a complicated manner, suggesting that the antibodies were selected against various modifications in lungs. Among 146 antibodies from SjS-ILD and/or MCTD-ILD, seven anti-SSA/Ro60 antibodies and 15 anti-RNP antibodies were identified. Some of the anti-RNP antibodies recognized multiple RNP constituent proteins simultaneously, indicating that epitope spreading may progress in lungs. Our results revealed the existence of an active autoimmunity in the lungs of autoimmune disease associated-ILD.