A biliary immune landscape map of primary sclerosing cholangitis reveals a dominant network of neutrophils and tissue-resident T cells

Abstract

The human biliary system, a mucosal barrier tissue connecting the liver and intestine, is an organ often affected by serious inflammatory and malignant diseases. Although these diseases are linked to immunological processes, the biliary system represents an unexplored immunological niche. By combining endoscopy-guided sampling of the biliary tree with a high-dimensional analysis approach, comprehensive mapping of the human biliary immunological landscape in patients with primary sclerosing cholangitis (PSC), a severe biliary inflammatory disease, was conducted. Major differences in immune cell composition in bile ducts compared to blood were revealed. Furthermore, biliary inflammation in patients with PSC was characterized by high presence of neutrophils and T cells as compared to control individuals without PSC. The biliary T cells displayed a CD103+CD69+ effector memory phenotype, a combined gut and liver homing profile, and produced interleukin-17 (IL-17) and IL-22. Biliary neutrophil infiltration in PSC associated with CXCL8, possibly produced by resident T cells, and CXCL16 was linked to the enrichment of T cells. This study uncovers the immunological niche of human bile ducts, defines a local immune network between neutrophils and biliary-resident T cells in PSC, and provides a resource for future studies of the immune responses in biliary disorders.

DNA Methylation Profile of Liver Tissue in End-Stage Cholestatic Liver Disease

“…There were also a number of distinct pathways enriched only in PSC, including IL-17 and IL-22 pathways. It has recently been shown that biliary T cells from individuals with PSC display a CD103 + CD69 + effector memory phenotype that secretes both IL-17 and IL-22 [ 57 ]. Taken together, the authors' findings suggest that epigenetic modifications may be partly driving the altered immune landscape in PSC and PBC and could be potential targets for these orphan diseases, particularly PSC, for which there is currently no effective treatment.…”

Role of Immune Cells in Biliary Repair

“…For example, neutrophils can directly interact with cholangiocytes via integrin β1 and elicit cholestasis ( 113 ). Neutrophils were also indicated as central immune cells in the pathogenesis of immune-mediated cholangiopathies such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) ( 114 ). Recently their contribution to tissue repair was also discovered.…”

Neutrophil–T cell crosstalk in inflammatory bowel disease

“…It is evident from studies performed in a non‐IBD context that neutrophils and T cells crosstalk [ 16 ], and their conversation is not one of the lonesome kind: stromal cells in the microenvironment respond to T‐cell‐derived IL‐17 with induction of factors such as IL‐8, G‐CSF or GM‐CSF, crucial for neutrophil recruitment and survival [ 17 , 18 , 19 , 20 ]. Except for Th17 cells that are effector CD4 + T cells named after their ability to produce of IL‐17, also other types of T cells, such as γδT cells, mucosal associated invariant T cells, CD1d‐restricted NKT cells and subsets of CD8 + T cells, are able to produce IL‐17 [ 21 ]. Although neutrophils cannot directly respond to IL‐17 due to the lack of its receptor, Th17 cells can directly interact with human neutrophils through IL‐17‐independent mechanisms via production of GM‐CSF, TNF and IFN‐γ [ 22 ].…”