University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, CO.
University of Utah, Salt Lake City, UT.
Hepatology. 2021 May;73(5):1855-1867. doi: 10.1002/hep.31504. Epub 2021 Apr 27.
The etiology of biliary atresia (BA) is not known and is likely multifactorial, including a genetic predisposition, a viral or environmental trigger, an aberrant autoimmune response targeting cholangiocytes, and unique susceptibilities of the neonatal bile ducts to injury. Damaged cholangiocytes may express neo self-antigens and elicit autoreactive T-cell-mediated inflammation and B-cell production of autoantibodies. The aim of this study was to discover autoantibodies in BA that correlated with outcomes.
An autoantigen microarray encompassing approximately 9,500 autoantigens was used to screen for serum immunoglobulin M (IgM) and immunoglobulin G (IgG) autoantibodies in patients with BA or other liver disease controls. Validation of candidate autoantibodies by enzyme-linked immunosorbent assay on a second cohort of subjects (6-12 months following Kasai portoenterostomy) and correlations of autoantibodies with outcomes were performed (serum bilirubin levels and need for liver transplant in first 2 years of life). Mean anti-chitinase 3-like 1 (CHI3L1), anti-delta-like ligand (DLL-4), and antisurfactant protein D (SFTPD) IgM autoantibodies in BA were significantly higher compared with controls, and IgM autoantibody levels positively correlated with worse outcomes. Immunofluorescence revealed cholangiocyte-predominant expression of CHI3L1, DLL-4, and SFTPD. The humoral autoantibody response was associated with C3d complement activation and T-cell autoimmunity, based on detection of cholangiocyte-predominant C3d co-staining and peripheral blood autoreactive T cells specific to CHI3L1, DLL-4 and SFTPD, respectively.
BA is associated with cholangiocyte-predominant IgM autoantibodies in the first year after Kasai portoenterostomy. Anti-CHI3L1, anti-DLL-4, and anti-SFTPD IgM autoantibody correlations with worse outcomes and the detection of C3d on cholangioctyes and antigen-specific autoreactive T cells suggest that autoimmunity plays a role in the ongoing bile duct injury and progression of disease.
胆道闭锁（BA）的病因尚不清楚，可能是多因素的，包括遗传易感性、病毒或环境触发因素、针对胆管细胞的异常自身免疫反应以及新生儿胆管对损伤的独特易感性。受损的胆管细胞可能表达新的自身抗原，并引发自身反应性 T 细胞介导的炎症和 B 细胞产生自身抗体。本研究的目的是发现与结局相关的 BA 自身抗体。
使用包含约 9500 种自身抗原的自身抗原微阵列来筛选 BA 患者或其他肝病对照者的血清免疫球蛋白 M（IgM）和免疫球蛋白 G（IgG）自身抗体。在第二个队列的受试者（Kasai 门腔分流术后 6-12 个月）中通过酶联免疫吸附试验验证候选自身抗体，并进行自身抗体与结局的相关性（血清胆红素水平和生命的前 2 年需要进行肝移植）。BA 患者的抗几丁质酶 3 样 1（CHI3L1）、抗德尔塔样配体（DLL-4）和抗表面活性剂蛋白 D（SFTPD）IgM 自身抗体的平均值明显高于对照组，并且 IgM 自身抗体水平与不良结局呈正相关。免疫荧光显示 CHI3L1、DLL-4 和 SFTPD 主要在胆管细胞上表达。基于胆管细胞上主要的 C3d 共染色和外周血针对 CHI3L1、DLL-4 和 SFTPD 分别具有的自身反应性 T 细胞，发现体液自身抗体反应与 C3d 补体激活和 T 细胞自身免疫有关。
Kasai 门腔分流术后第一年，BA 与胆管细胞上主要的 IgM 自身抗体有关。抗 CHI3L1、抗 DLL-4 和抗 SFTPD IgM 自身抗体与不良结局相关，并且在胆管细胞上检测到 C3d 和针对 CHI3L1、DLL-4 和 SFTPD 的抗原特异性自身反应性 T 细胞表明自身免疫在持续的胆管损伤和疾病进展中起作用。
