Altered Monocyte Responses to Defined TLR Ligands in Patients With Primary Biliary Cirrhosis *
Abstract
The role of the adaptive immune response, with regard to the development of autoantibodies, has been extensively studied in primary biliary cirrhosis (PBC). However, the importance of innate immunity has been noted only recently. Based on the proposed role of microorganisms in the pathogenesis of the disease, we hypothesize that patients with PBC possess a hyper-responsive innate immune system to pathogen-associated stimuli that may facilitate the loss of tolerance. To address this issue, we isolated peripheral blood monocytes from 33 patients with PBC and 26 age-matched healthy controls and stimulated such cells in vitro with defined ligands for toll-like receptor (TLR) 2 (lipoteichoic acid; LTA), TLR3 (polyIC), TLR4 (lipopolysaccharide; LPS), TLR5 (flagellin), and TLR9 (CpG-B). Supernatant fluids from the cultures were analyzed for levels of 5 different pro-inflammatory cytokines, interleukin (IL)-1beta, IL-6, IL-8, IL-12p70, and TNF-alpha. After in vitro challenge with TLR ligands, PBC monocytes produced higher relative levels of pro-inflammatory cytokines, particularly IL-1beta, IL-6, IL-8, and TNF-alpha, compared with controls. In conclusion, monocytes from patients with PBC appear more sensitive to signaling via select TLRs, resulting in secretion of selective pro-inflammatory cytokines integral to the inflammatory response that may be critical in the breakdown of self-tolerance.
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Myeloid cells, i.e., monocytes and macrophages, play an important role in the pathogenesis of primary biliary cholangitis (PBC).
“Myeloid cells, i.e., monocytes and macrophages, represent a key component of innate and adaptive immune systems and play an important role in the pathogenesis of PBC.”
From A regulatory variant at 19p13.3 is associated with primary biliary cholangitis risk and ARID3A expression (2023) · cites this paper as [35]
Monocytes/macrophages from PBC patients are hypersensitive to infectious stimuli and produce cytokines and chemokines that amplify the immune response and further aggravate damage of cholangiocytes.
“Additionally, monocytes/macrophages from PBC patients are hypersensitive to infectious stimuli and produce a variety of cytokines and chemokines that amplify the immune response and further aggravate the damage of cholangiocytes35,36.”
From A regulatory variant at 19p13.3 is associated with primary biliary cholangitis risk and ARID3A expression (2023) · cites this paper as [35]
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- Authors
- Mao, T. K., Lian, Z.-X., Selmi, C., Ichiki, Y., Ashwood, P., Ansari, A. A., Coppel, R. L., Shimoda, S., Ishibashi, H., & Gershwin, E. M.
- Affiliations
- University of California, Davis (US)
- University of Milan (IT)
- Emory University (US)
- Monash University (AU)
- Kyushu University (JP)
- Nagasaki Medical Center (JP)
- Corresponding author
- Gershwin, Eric M.
- ORCID
- Venue
- Hepatology
- Published
- 2005-10
- Volume
- 42
- Issue
- 4
- Pages
- 802-808
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W2119039846
- Cited by
- 185
- References
- 33
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 3 · 2023: 6 · 2022: 8 · 2021: 1 · 2020: 7 · 2019: 6 · 2018: 6 · 2017: 6 · 2016: 5 · 2015: 9 · 2014: 11 · 2013: 13 · 2012: 16
- FWCI
- 6.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Keywords
- primary biliary cirrhosis, monocytes, Toll-like receptors, innate immunity, inflammatory cytokines, lipoteichoic acid, poly(I:C), lipopolysaccharide, flagellin, CpG-B, IL-1β, interleukin-6, interleukin-8, IL-12p70, TNF-α, autoimmunity, loss of self-tolerance
- MeSH terms
- Adult, Aged, Female, Flagellin, Humans, Ligands, Lipopolysaccharides, Liver Cirrhosis, Biliary, Male, Membrane Glycoproteins, Middle Aged, Monocytes, Oligodeoxyribonucleotides, Poly I-C, Receptors, Cell Surface, Teichoic Acids, Cytokines, Lipopolysaccharide Receptors, Toll-Like Receptors, Toll-Like Receptor 2, Toll-Like Receptor 3, Toll-Like Receptor 4, Toll-Like Receptor 5, Toll-Like Receptor 9, In Vitro Techniques
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