Published online Dec 28, 2017. doi: 10.3748/wjg.v23.i48.8489
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
To explore the pathogenesis of primary biliary cholangitis (PBC) by identifying candidate autoantibodies in serum samples by proteomics and bioinformatics.
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.
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.
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.
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.