title: Low doses of CMV induce autoimmune-mediated and inflammatory responses in bile duct epithelia of regulatory T cell-depleted neonatal mice.
abstract: Recent studies have indicated that perinatal infection with cytomegalovirus (CMV) may promote bile duct damage in biliary atresia (BA) and that the decreased regulatory T cell (Treg) percentage associated with BA may further amplify the bile duct damage. Although a majority of BA patients have had previous CMV infections and lower percentages of Tregs, it is unknown whether an initial exposure to a low dose of CMV could induce exaggerated and progressive biliary injury. A Treg-depleted neonatal mouse was infected with low-dose CMV (LD-CMV) as a model to study BA patients. LD-CMV infection in Treg-depleted mice induced extensive inflammation in both the intrahepatic and extrahepatic bile ducts, accompanied with injury to and atresia of intrahepatic bile ducts and partial obstruction of the extrahepatic bile ducts. Serum total and direct bilirubin amounts were also elevated. Evidence for the involvement of cellular and humoral autoimmune responses in LD-CMV-infection of Treg-depleted mice was also obtained through detection of increased percentages of CD3 and CD8 mononuclear cells and serum autoantibodies reactive to bile duct epithelial proteins, one of which was identified as α-enolase. Depletion of Tregs that can lead to the decreased inhibition of aberrantly activated hepatic T-lymphocytes and generation of autoantibodies may lead to further injury. Increased hepatic expression of Th1-related genes (TNF-α), IFN-γ-activated genes (STAT-1) and Th1 cytokines (TNF-α, lymphotactin, IL-12p40 and MIP -1γ) were also identified. In conclusion, autoimmune-mediated and inflammatory responses induced by LD-CMV infection in Treg-depleted mice results in increased intrahepatic and extrahepatic bile duct injury and contributed to disease progression.
authors.affiliation: 1] Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China [2] Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China [3] Shanghai Institute for Pediatric Research, Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Wen
authors.affiliation: 1] Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China [2] Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China [3] Shanghai Institute for Pediatric Research, Shanghai, China.
authors.forename: Yongtao
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Pan
authors.affiliation: Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Key Lab of Medical Molecular Virology, Department of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Guan
authors.affiliation: 1] Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China [2] Shanghai Institute for Pediatric Research, Shanghai, China.
authors.forename: Yingwei
authors.initials: Y
authors.lastname: Chen
authors.affiliation: 1] Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China [2] Shanghai Institute for Pediatric Research, Shanghai, China.
authors.forename: Kejun
authors.initials: K
authors.lastname: Zhou
authors.affiliation: 1] Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China [2] Shanghai Institute for Pediatric Research, Shanghai, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Lab of Medical Molecular Virology, Department of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
authors.forename: Bisheng
authors.initials: B
authors.lastname: Shi
authors.affiliation: Key Lab of Medical Molecular Virology, Department of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Key Lab of Medical Molecular Virology, Department of Pathogen Diagnosis and Biosafety, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: 1] Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China [2] Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China [3] Shanghai Institute for Pediatric Research, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cai
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000097:blood; D001327:Autoimmune Diseases / Q000209:etiology*; D001652:Bile Ducts / Q000473:pathology; D001656:Biliary Atresia / Q000209:etiology* / Q000276:immunology; D001663:Bilirubin / Q000097:blood; D015153:Blotting, Western; D003586:Cytomegalovirus Infections / Q000150:complications* / Q000276:immunology*; D017931:DNA Primers / Q000235:genetics; D018450:Disease Progression; D004848:Epithelium / Q000276:immunology*; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007249:Inflammation / Q000209:etiology / Q000276:immunology*; D051379:Mice; D010751:Phosphopyruvate Hydratase / Q000276:immunology; D060888:Real-Time Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D000906:Antibodies; D017931:DNA Primers; D010751:Phosphopyruvate Hydratase; D001663:Bilirubin