Altered monocyte responses to defined TLR ligands in patients with primary biliary cirrhosis

Authors

  • Tin Ky Mao,

    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA
    2. Statistical Laboratory, University of California, Davis, CA
    Search for more papers by this author
    • T.K.M., Z.-X.L. and C.S. contributed equally to this work.

  • Zhe-Xiong Lian,

    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA
    2. Statistical Laboratory, University of California, Davis, CA
    Search for more papers by this author
    • T.K.M., Z.-X.L. and C.S. contributed equally to this work.

  • Carlo Selmi,

    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA
    2. Division of Internal Medicine, Department of Medicine, Surgery, and Dentistry, San Paolo School of Medicine, University of Milan, Italy
    3. Statistical Laboratory, University of California, Davis, CA
    Search for more papers by this author
    • T.K.M., Z.-X.L. and C.S. contributed equally to this work.

  • Yasunori Ichiki,

    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA
    2. Statistical Laboratory, University of California, Davis, CA
    Search for more papers by this author
  • Paul Ashwood,

    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA
    2. Statistical Laboratory, University of California, Davis, CA
    Search for more papers by this author
  • Aftab A. Ansari,

    1. Department of Pathology, Emory University School of Medicine, Atlanta, GA
    Search for more papers by this author
  • Ross L. Coppel,

    1. Department of Microbiology, Monash University, Clayton, Victoria, Australia
    Search for more papers by this author
  • Shinji Shimoda,

    1. Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
    Search for more papers by this author
  • Hiromi Ishibashi,

    1. National Nagasaki Medical Center, Omura, Japan
    Search for more papers by this author
  • M. Eric Gershwin

    Corresponding author
    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA
    2. Statistical Laboratory, University of California, Davis, CA
    • Division of Rheumatology, Allergy and Clinical Immunology, Genome and Biomedical Sciences Facility, University of California at Davis, 451 E. Health Sciences Drive, Suite 6510, Davis, CA 95616
    Search for more papers by this author
    • fax: 530-752-4669


  • Potential conflict of interest: Nothing to report.

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)-1β, IL-6, IL-8, IL-12p70, and TNF-α. After in vitro challenge with TLR ligands, PBC monocytes produced higher relative levels of pro-inflammatory cytokines, particularly IL-1β, IL-6, IL-8, and TNF-α, 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. (HEPATOLOGY 2005;42:802–808.)

Ancillary