O10 TNF signalling associated with high risk compared to low risk disease in primary biliary cholangitis: a transcriptomic analysis of peripheral immune cells

• Published in: Gut Vol. 72; no. Suppl 3; pp. A7 - A8
• Main Authors: Mulcahy, Victoria, Jose-Ezequiel, Martin, Hails, Janeane, Sandford, Richard, Jones, David, Hirschfield, Gideon, Mells, George
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group LTD 01.09.2023
• Subjects: Bile ducts; CD4 antigen; CD8 antigen; Cholangitis; Cirrhosis; Factor analysis; Genes; Inflammatory diseases; Liver diseases; Lymphocytes; Lymphocytes B; Lymphocytes T; Monocytes; Peripheral blood mononuclear cells; Risk groups; Signal transduction; Transcriptomics; Ursodeoxycholic acid
• ISSN: 0017-5749; 1468-3288
• DOI: 10.1136/gutjnl-2023-BASL.10

Primary biliary cholangitis (PBC) is an immune-mediated inflammatory disorder of the interlobular bile ducts which leads in many cases to cirrhosis. In patients with PBC, inadequate biochemical response to first-line treatment with ursodeoxycholic acid (UDCA) identifies those at high risk of progressive liver disease. In this study, we used transcriptional profiling of peripheral immune cells to gain insight into the immunobiology of high- vs. low-risk disease.We performed bulk RNA-sequencing of monocytes, NK cells, CD4+ T cells, CD8+ T cells, and B cells isolated from the peripheral blood of 40 treatment-naïve PBC patients; 36 high-risk patients (ALP ≥1.67 times the upper limit of normal [ULN] despite treatment with UDCA); 32 low-risk patients (ALP <1×ULN on UDCA); and 32 matched controls. We used Weighted Gene Co-expression Network Analysis (WGCNA) to identify networks of co-expressed genes (“modules”) associated with high-risk, low-risk or any PBC, and the most highly connected genes (“hub genes”) within them. Finally, we performed Multi-Omics Factor Analysis (MOFA) of WGCNA modules to identify the principal axes of biological variation (“latent factors”) across all immune cell subsets.We identified modules associated with high-risk, low-risk, or any PBC patient (q < 0.05) in each PBMC subset. Hub genes and functional annotations suggested that: (1) CD4+ T cells, CD8+ T cells and monocytes are active in PBC patients irrespective of disease activity, with enrichment of genes involved in TNF, IL-2, IL-6, and INFγ signalling, amongst other pathways; and (2) TNF signalling, implicated in all five cell types studied, is associated with high risk compared to low risk disease. Using MOFA, we identified one latent factor which bridged all cell types; was heavily weighted for modules enriched for TNF signalling; and showed significant difference in high compared to low risk disease (q < 0.05).Using this approach we found evidence of pro-inflammatory signalling in all stages of PBC disease irrespective of high-risk or low-risk disease and we identified TNF signalling as key in high risk compared to low risk disease.Abstract O10 Figure 1Multi-omics latent factor analysis (MOFA) of modules identified by weighted gene co-expression network analysis (WGCNA) for all cell types. Heatmap to show the fitted MOFA model, displaying the percentage of variance explained for each factor (rows) in each cell type. LF1 was associated with all cell types and contained modules enriched for TNF signalling in high risk vs. low risk disease. It also identified latent factors unique to each cell type; for example LF10 was unique to CD4+ T cells[Figure omitted. See PDF]