title: Quantitation of the Rank-Rankl Axis in Primary Biliary Cholangitis.
abstract: There is substantial data that suggests an abnormality of innate immunity in patients with primary biliary cholangitis (PBC) which includes the transcription factor nuclear factor-kB (NF-kB) and well as downstream inflammatory signaling pathways. In addition, ImmunoChip analysis has identified a novel PBC-associated locus near the receptor activator of NF-kB ligand (RANKL) gene. Based on these observations, we investigated the role of the RANKL axis in the liver of patients with PBC compared to controls. We used immunohistochemistry to quantitate liver expression of RANKL, its receptor (RANK), and importantly the decoy receptor osteoprotegerin (OPG), including a total of 122 liver samples (PBC = 37, primary sclerosing cholangitis = 20, autoimmune hepatitis = 26, chronic hepatitis B = 32 and unaffected controls = 7). In addition, we studied RANKL-RANK-OPG co-localization in CD4 and CD8 T cells, B cells, dendritic cells, macrophages, NK, NKT cells, hepatocytes, and cholangiocytes. We report herein that RANK is constitutively expressed by cholangiocytes in both unaffected and diseased liver. However, cholangiocytes from PBC express significantly higher levers of RANK than either the unaffected controls or liver diseased controls. CD4, CD8 and CD19 cells with in the portal areas around bile ducts in PBC express significantly higher levels of RANKL compared to controls. Importantly, the overall hepatic RANKL level and the ratio of hepatic RANKL/OPG correlated with disease severity in PBC. In conclusion, our data indicate a role of RANK-RANKL axis in the innate immune activation in PBC and we hypothesize that the damaged cholangiocytes, which express high levels of RANK, lead to the recruitment of RANKL positive cells and ultimately the classic portal tract infiltrates.
authors.affiliation: Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Ana
authors.initials: A
authors.lastname: Lleo
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Zhaolian
authors.initials: Z
authors.lastname: Bian
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Miao
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Yang
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Yanshen
authors.initials: Y
authors.lastname: Peng
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Chen
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Ruqi
authors.initials: R
authors.lastname: Tang
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Qixia
authors.initials: Q
authors.lastname: Wang
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Dekai
authors.initials: D
authors.lastname: Qiu
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Fang
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Milano Italy.|Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Sobacchi
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Milano Italy.|Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Villa
authors.affiliation: Pathology Unit, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.|Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Di Tommaso
authors.affiliation: Pathology Unit, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.|Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Roncalli
authors.affiliation: Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA, United States of America.
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Ma
authors.affiliation: Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.|Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA, United States of America.|International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Invernizzi
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002761:Cholangitis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D053245:RANK Ligand / Q000378:metabolism*
chemical_list: D053245:RANK Ligand