Autoantibodies against the plakin family proteins as a novel marker for chronic graft-versus-host disease of the lung
Autoantibodies against the plakin family proteins as a novel marker for chronic graft-versus-host disease of the lung
复制标题
DOI：
10.1038/s41409-021-01335-5
复制
发表时间：
2021-06
影响因子：
4.8
通讯作者：
N. Kawashima;Eri Nishikawa;A. Tsuchisaka;T. Hashimoto;Y. Okuno;M. Hamada;Daisuke Ichikawa;A. Narita;H. Muramatsu;N. Nishio;S. Kojima;Y. Muro;Yoshiyuki Takahashi
中科院分区：
文献类型：
--
作者：
N. Kawashima;Eri Nishikawa;A. Tsuchisaka;T. Hashimoto;Y. Okuno;M. Hamada;Daisuke Ichikawa;A. Narita;H. Muramatsu;N. Nishio;S. Kojima;Y. Muro;Yoshiyuki Takahashi
同种异体造血干细胞移植（HSCT）后闭塞性细支气管炎综合征（BOS）的快速诊断具有挑战性，因为其病理生理学尚未完全阐明，并且尚未建立特异性疾病标志物[1，2]。诊断依赖于在没有其他病因的情况下使用肺功能测试（PFT）证明的肺损伤，但在年轻个体中进行PFT是困难的。BOS的治疗方法最近已经开发出来[3];然而，疾病特异性治疗仍有待建立[2]，一旦BOS进展为终末期呼吸道疾病，就需要进行肺移植。因此，需要更好地了解BOS的病理生理学和生物标志物的鉴定。在非HSCT环境中也观察到BOS [1，4]，其中据报道，20-30%的副肿瘤性天疱疮（PNP）患者（一种以慢性GVHD样水疱性皮肤病变和粘膜炎为特征的罕见自身免疫性皮肤病）发生BOS [5]。PNP可能是由肿瘤诱导的体液和细胞介导的免疫异常引起的;前者的特征是主要针对桥粒芯糖蛋白和斑蛋白家族蛋白的循环自身抗体。考虑到慢性GVHD和PNP具有共同的基础病理生理学，我们假设PNP和慢性GVHD发展为BOS的患者可能具有相同的异常B细胞免疫。在1988年1月至2015年12月期间在儿科接受同种异体HSCT的连续344例0-26岁患者中，名古屋大学医院（21例患者接受了两次同种异体HSCT，1例患者接受了三次），21例患者发生慢性GVHD并纳入本研究。在住院期间每周收集血清，并储存在-80 ℃下直至进一步使用。患者特征见表S1。根据2014年NIH共识[6]重新评价了诊断、器官受累评价和治疗反应。在预处理前和出院前至少进行两次PFT。详细的移植设置在补充方法中描述。根据文献定义BOS（表S2）[6]。对于不理解PFT说明的儿童，BOS定义为进行性低氧血症伴支气管扩张和/或马赛克模式，马赛克模式定义为与高分辨率计算机断层扫描观察到的肺血管口径狭窄相关的节段性低衰减小叶区域。酶联免疫吸附试验（ELISA）和免疫沉淀免疫印迹（IP-IB）分析如下：
Prompt diagnosis of bronchiolitis obliterans syndrome (BOS) is challenging after allogenic hematopoietic stem cell transplant (HSCT) because its pathophysiology is yet to be fully clarified and no specific disease markers have been established [1, 2]. The diagnosis relies upon pulmonary impairment evidenced using pulmonary function test (PFT) in the absence of other etiologies, but performing PFT in young individuals is difficult. Treatments for BOS have been developed recently [3]; however, a disease-specific treatment remains to be established [2], and lung transplantation is needed once BOS progresses to end-stage respiratory disease. Thus, a better understanding of the pathophysiology and identification of biomarkers for BOS is required. BOS is also observed in non-HSCT settings [1, 4], wherein 20–30% of patients with paraneoplastic pemphigus (PNP), a rare autoimmune skin disease characterized by chronic GVHD-like blistering skin lesions and mucositis, reportedly develop BOS [5]. PNP might be caused by neoplasm-induced abnormalities in humoral and cell-mediated immunity; the former is characterized by circulating autoantibodies primarily targeted against desmogleins and plakin family proteins. Considering that chronic GVHD and PNP share a common underlying pathophysiology, we hypothesized that patients with PNP and chronic GVHD developing BOS might have the same aberrant B-cell immunity.Of consecutive 344 patients aged 0–26 years who underwent allogeneic HSCT between January 1988 and December 2015 at the Department of Pediatrics, Nagoya University Hospital (21 patients received allogeneic HSCT twice and 1 patient received it three times), 21 patients developed chronic GVHD and were included in this study. Sera were collected weekly during hospitalization and stored at− 80 C until further use. The patient characteristics are listed in Table S1. Diagnosis, evaluation of organ involvement, and therapeutic response were re-evaluated according to the 2014 NIH consensus [6]. PFT was performed at least twice before preconditioning and before discharge. Detailed transplant settings are described in the Supplementary Methods. BOS was defined according to the literature (Table S2)[6]. For children who did not understand PFT instructions, BOS was defined by progressive hypoxemia with the presence of bronchiectasis and/or a mosaic pattern defined as segmental lobular areas of hypoattenuation that are associated with narrowing of the caliber of the pulmonary vessels which was observed on high-resolution computed tomography. Enzyme-linked immunosorbent assays (ELISA) and immunoprecipitationimmunoblotting(IP-IB) were analyzed following