Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 28, 2017; 23(48): 8489-8499
Published online Dec 28, 2017. doi: 10.3748/wjg.v23.i48.8489
Exploring pathogenesis of primary biliary cholangitis by proteomics: A pilot study
Chui-Wen Deng, Li Wang, Yun-Yun Fei, Chao-Jun Hu, Yun-Jiao Yang, Lin-Yi Peng, Xiao-Feng Zeng, Feng-Chun Zhang, Yong-Zhe Li
Chui-Wen Deng, Li Wang, Yun-Yun Fei, Chao-Jun Hu, Yun-Jiao Yang, Lin-Yi Peng, Xiao-Feng Zeng, Feng-Chun Zhang, Yong-Zhe Li, Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
Chui-Wen Deng, Li Wang, Yun-Yun Fei, Chao-Jun Hu, Yun-Jiao Yang, Lin-Yi Peng, Xiao-Feng Zeng, Feng-Chun Zhang, Yong-Zhe Li, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing 100730, China.
Author contributions: Deng CW, Wang L, Fei YY and Li YZ designed the study; Deng CW, Wang L and Fei YY performed the study; Hu CJ, Yang YJ and Peng LY collected the samples; Li YZ contributed new reagents and analytic tools; Deng CW analyzed the data and wrote the paper; Zeng XF and Zhang FC proofread the paper.
Supported by the National Natural Science Foundation of China, No. 81302591, No. 81373188, and No. 81671618; the Capital Health Research and Development of Special, No. 2014-1-4011; and the Research Special Fund for Public Welfare Industry of Health, No. 201202004.
Institutional review board statement: The study was reviewed and approved by the Ethics Committee of the Peking Union Medical College Hospital.
Conflict-of-interest statement: The authors declare that no competing interests exist
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Yong-Zhe Li, MD, Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1, Shuaifuyuan, Dongcheng District, Beijing 100730, China. yongzhelipumch@126.com
Telephone: +86-10-69159966 Fax: +86-10-69159966
Received: October 30, 2017
Peer-review started: October 31, 2017
First decision: November 14, 2017
Revised: November 21, 2017
Accepted: November 28, 2017
Article in press: November 28, 2017
Published online: December 28, 2017
Processing time: 57 Days and 22.2 Hours
Abstract
AIM

To explore the pathogenesis of primary biliary cholangitis (PBC) by identifying candidate autoantibodies in serum samples by proteomics and bioinformatics.

METHODS

Nine antimitochondrial antibody (AMA)-positive PBC patients and nine age- and sex-matched AMA-negative PBC patients were recruited. Antigen enrichment technology was applied to capture autoantigens of human intrahepatic biliary epithelial cells (HiBECs) that are recognized by autoantibodies from the sera of PBC patients. Candidate autoantigens were identified by label-free mass spectrometry. Bioinformatics analysis with MaxQuant software (version 1.5.2.8), DAVID platform, and Cytoscape v.3.0 allowed illustration of pathways potentially involved in the pathogenesis of PBC.

RESULTS

In total, 1081 candidate autoantigen proteins were identified from the PBC patient pool. Among them, 371 were determined to be significantly differentially expressed between AMA-positive and -negative PBC patients (P < 0.05). Fisher’s exact test was performed for enrichment analysis of Gene Ontology protein annotations (biological processes, cellular components, and molecular functions) and the Kyoto Encyclopedia of Genes and Genomes pathways. Significantly different protein categories were revealed between AMA-positive and -negative PBC patients. As expected, autoantigens related to mitochondria were highly enriched in AMA-positive PBC patients. However, lower levels of AMA were also detected in AMA-negative PBC patients. In addition, autoantigens of AMA-negative PBC patients were mainly involved in B-cell activation, recognition of phagocytosis, and complement activation.

CONCLUSION

AMA-negative PBC individuals may not exist, but rather, those patients exhibit pathogenesis pathways different from those of AMA-positive PBC. Comprehensive research is needed to confirm these observations.

Keywords: Anti-mitochondrial antibody; Bioinformatics; Pathogenesis; Primary biliary cholangitis; Proteomics

Core tip: The pathogenesis of primary biliary cholangitis (PBC) is still unclear. Related studies have focused on genes, immune cells, and pathology. However, little research has been conducted to establish pathogenesis-related autoantibodies. In this study, we unraveled the pathogenesis of PBC by detecting novel autoantibodies, using proteomics. Our results suggest that the dysfunction of three pathways in human intrahepatic biliary epithelial cells might be causative in the pathogenesis of antimitochondrial antibody (AMA)-negative PBC. More interestingly, we identified AMA-negative pathology as a potential misnomer, as we detected low levels of AMA in sera of AMA-negative patients. Comprehensive research is needed to confirm these observations.