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.
Highlights
Primary biliary cholangitis (PBC) [1], is a chronic liver disease characterized by progressive destruction of intrahepatic bile ducts resulting in cholestasis, portal tract inflammation, and fibrosis that may progress to cirrhosis and end-stage liver disease [2, 3]
In PBC, receptor activator of NF-kB ligand (RANKL) signal was strongly represented in the portal areas around bile ducts (Fig 1A), whereas few RANKL-positive cells were found in portal areas of subjects affected by other chronic liver disease, including autoimmune hepatitis (AIH), chronic hepatitis B (CHB) and primary sclerosing cholangitis (PSC) (Fig 1A)
The number of RANKL positive cells was significantly higher in subjects with PBC (7.36±0.92/high-power field (HPF)), compared with unaffected controls (2.21±0.28/HPF) (p
Summary
Primary biliary cholangitis (PBC) [1], is a chronic liver disease characterized by progressive destruction of intrahepatic bile ducts resulting in cholestasis, portal tract inflammation, and fibrosis that may progress to cirrhosis and end-stage liver disease [2, 3]. Previous work from our group has identified a novel disease-associated locus near the TNFSF11 gene, upstream of the gene encoding the receptor activator of nuclear factor κB (NF-κB) ligand (RANKL) [7] Even though it is inherently difficult for genome wide association studies to identify a specific gene, a large amount of data suggest that RANKL may play a relevant role in PBC. The RANKL/RANK pathway serves a critical role in the immune system and augments the ability of dendritic cells (DC) to stimulate naive T cell proliferation and enhance DC survival [12] It has important regulatory functions in lymph node organogenesis and lymphocyte differentiation [13]. Through the binding of RANKL, OPG inhibits NF-kB, a key regulator of inflammation, innate immunity and immune cell survival and differentiation [9, 14]
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