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Cholangiocyte cilia are abnormal in syndromic and non-syndromic biliary atresia.

ABSTRACT: Biliary atresia (BA) is a neonatal disorder characterized by aggressive fibroinflammatory obliteration of the biliary tract. Approximately 20 percent of BA patients demonstrate left-right laterality defects (syndromic BA). Cilia participate in important physiological functions in cholangiocytes, and as some ciliopathies have been associated with both laterality defects and hepatic fibrosis, we hypothesized that patients with syndromic BA exhibit abnormalities of cholangiocyte cilia that disrupt cholangiocyte homeostasis. Nine BA specimens were studied, including pre-Kasai diagnostic biopsies (n=7) and liver explants (n=2). Five specimens were from patients with laterality defects. These were compared with normal pediatric livers, as well as livers affected by primary sclerosing cholangitis, Wilson's disease, and cardiac cirrhosis. Biopsy sections were stained with antibodies against keratin 19 (a cholangiocyte marker) and acetylated ?-tubulin (a cilia marker) and were visualized by confocal microscopy. Computer-assisted relative quantification was used to compare staining of cilia within bile ducts among samples. Surprisingly, cilia in BA specimens were significantly shorter, abnormal in their orientation, and less abundant compared with normal liver and disease controls regardless of the presence of a laterality defect. There are significant abnormalities of cholangiocyte cilia in both syndromic and non-syndromic BA livers compared with normal livers and livers affected by other cholestatic diseases. Although this may result from severe cholestasis or inflammation, it may also reflect common mechanistic pathways in different forms of BA and may have important implications for understanding the progression of the disease.

SUBMITTER: Chu AS

PROVIDER: S-EPMC3341539 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Cholangiocyte cilia are abnormal in syndromic and non-syndromic biliary atresia.

Chu Andrew S AS Russo Pierre A PA Wells Rebecca G RG

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 20120203 5

Biliary atresia (BA) is a neonatal disorder characterized by aggressive fibroinflammatory obliteration of the biliary tract. Approximately 20 percent of BA patients demonstrate left-right laterality defects (syndromic BA). Cilia participate in important physiological functions in cholangiocytes, and as some ciliopathies have been associated with both laterality defects and hepatic fibrosis, we hypothesized that patients with syndromic BA exhibit abnormalities of cholangiocyte cilia that disrupt ...[more]

PMID: 22301700

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Project description:Background and aimsThe 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 resultsAn 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.ConclusionsBA 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.

Project description:Biliary atresia (BA) is a fibroinflammatory obstruction of the extrahepatic biliary tree in neonates. While intrahepatic bile duct proliferation is universal at diagnosis, bile duct paucity develops later. We hypothesized that polarized T helper lymphocyte responses orchestrate progression of intrahepatic biliary injury in this disease. Interleukin 17A (IL-17A)-green fluorescent protein, cluster of differentiation 11c (CD11c)/diphtheria toxin receptor, and IL-17 receptor A-/- mice were used to examine T-lymphocyte polarization, inflammatory leukocyte recruitment, and biliary injury in rhesus rotavirus-induced BA. Multiparameter flow cytometry and automated image analysis of immunostaining were applied to liver tissue samples from infants with BA. In the mouse model, activated CD4+ lymphocytes started to emerge in the liver on day 8 after viral challenge, while innate immune responses were waning. Plasma IL-17A levels rose concomitantly with hepatic accumulation of T helper 17 lymphocytes and myeloid dendritic cells. Targeted depletion of CD11c+ dendritic cells diminished hepatic IL-17A production and ameliorated intrahepatic bile duct injury. Recombinant IL-17A induced expression of chemokine (C-C motif) ligand 2 in neonatal cholangiocytes in vitro, and blockade of the corresponding chemokine (C-C motif) receptor 2 reduced recruitment of inflammatory macrophages to the liver in vivo. Genetic disruption of IL-17A signaling was associated with down-regulation of hepatic Ccl2/Ccr2 messenger RNA expression, reduced infiltration of the liver with inflammatory Ly6Chi macrophages, and improved survival. In the liver of infants with BA, cholangiocytes were found to express IL-17 receptor A, and the prevalence of IL-17A+ cells was positively correlated with the degree of CD68+ macrophage infiltration at diagnosis. Hepatic CD4+ lymphocytes were chief producers of IL-17A in patients with progressive disease undergoing liver transplantation.These findings identify the dendritic cell-T helper 17-macrophage axis as a target for the development of strategies to block progression of intrahepatic bile duct injury in patients with BA. (Hepatology 2017;65:174-188).

Dataset Information

Cholangiocyte cilia are abnormal in syndromic and non-syndromic biliary atresia.

Publications

Cholangiocyte cilia are abnormal in syndromic and non-syndromic biliary atresia.

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