Unique Cholangiocyte‐Targeted IgM Autoantibodies Correlate With Poor Outcome in Biliary Atresia

Background and Aims 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. Approach and Results 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. Conclusions 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.