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The Immunophysiology and Apoptosis of Biliary Epithelial Cells: Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis

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Abstract

Biliary epithelial cells (BECs) provide the first line of defense against lumenal microbes in the biliary system. BECs express a variety of pathogen recognition receptors and can activate several intracellular signaling cascades to initiate antimicrobial defenses, including production of several anti-microbial peptides, cytokines, chemokines, and adhesion molecules. BECs also secrete immunoglobulin A and interact with other cells through expression and release of adhesion molecules and immune mediators. Recently, several reports suggest a correlation between apoptosis and autoimmunity through ineffective clearance of self-antigens. Primary biliary cirrhosis (PBC) is a slowly progressive, autoimmune cholestatic liver disease characterized by highly specific antimitochondrial antibodies (AMAs) and the specific immune-mediated destruction of BECs. We have demonstrated that the AMA self-antigen, namely the E2 subunit of the pyruvate dehydrogenase complex, is detectable in its antigenically reactive form within apoptotic blebs from human intrahepatic biliary epithelial cells and activates innate immune responses. Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and the presence of concentric fibrosis of intrahepatic and/or extrahepatic bile ducts, eventually leading to cirrhosis. However, apoptosis does not appear to play a central role in PSC. Despite both diseases involving immune-mediated injury to bile ducts, apoptosis occurs more commonly overall in PBC where it likely plays a unique role.

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Abbreviations

AMAs:

Antimitochondrial antibodies

ANA:

Anti-nuclear antibody

BCOADC-E2:

The E2 subunit of the branched chain 2-oxo acid dehydrogenase complex

BECs:

Biliary epithelial cells

BrEPCs:

Human bronchial epithelial cells

CX3CR1:

CX3C chemokine receptor 1

DC:

Dendritic cells

DECR1:

2,4-Dienoyl coenzyme A reductase 1

DR:

Death receptor

FasL:

Fas ligand

gp210:

Glycoprotein 210 kD

hBD:

Human β-defensin

HiBECs:

Human intrahepatic biliary epithelial cells

ICAM-1:

Intercellular adhesion molecule 1

IFN-β1:

Interferon β1

IgA:

Immunoglobulin A

IL-12A:

Interleukin-12A

IL-12RB2:

Interleukin-12 receptor beta2 subunit

IRAK-1:

IL-1 receptor-associated kinase

IRAK-M:

Interleukin-1 receptor-associated kinase M

IRF-3:

Interferon-regulatory factor-3

LFA-1:

Lymphocyte function-associated antigen-1

LFA-3:

Lymphocyte function-associated antigen 3

LPS:

Lipopolysaccharide

MAdCAM1:

Mucosal addressin cell adhesion molecule-1

MaEPCs:

Human mammary epithelial cells

MAPK:

Mitogen-activated protein kinases

MCP-1:

Monocyte chemotactic protein-1

MDA-5:

Melanoma differentiation associated gene 5

MPT:

Mitochondrial membrane permeability transition

MxA:

Myxovirus resistance protein A

MyD88:

Myeloid differentiation factor 88

(NF)–kB:

Nuclear factor

OGDC-E2:

The E2 subunit of the oxo-glutarate dehydrogenase complex

PAMPs:

Pathogen-associated molecular patterns

pANCA:

Perinuclear anti-neutrophil cytoplasmic antibody

PBC:

Primary biliary cirrhosis

PDC-E2:

The E2 subunit of the pyruvate dehydrogenase complex

poly I:C:

Polyinosinic–polycytidylic acid

PSC:

Primary sclerosing cholangitis

Rig-1:

Retinoic acid inducible gene-1

STAT4:

Signal transducer and activator of transcription 4

SSA/Ro:

Sjogren’s syndrome antigen A

TRAIL:

TNF-related apoptosis-inducing ligand

TLRs:

Toll-like receptors

TNF-R1:

TNF-α receptor-1

TUNEL:

TdT-mediated deoxyuridine triphosphate nick-end labeling

UCDA:

Ursodeoxycholic acid

UQCR2:

Ubiquiol cytochrome c reductase complex core protein II

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Authors and Affiliations

  1. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 E. Health Sciences Drive, Suite 6510, Davis, CA, 95616, USA

    Kazuhito Kawata & M. Eric Gershwin

  2. Hepatology Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan

    Kazuhito Kawata & Yoshimasa Kobayashi

  3. Division of Gastroenterology and Hepatology, University of California at Davis School of Medicine, 4150 V Street, PSSB 3500, Sacramento, Davis, CA, 95817, USA

    Christopher L. Bowlus

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  1. Kazuhito Kawata
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  2. Yoshimasa Kobayashi
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  3. M. Eric Gershwin
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  4. Christopher L. Bowlus
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Correspondence to Christopher L. Bowlus.

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Kawata, K., Kobayashi, Y., Gershwin, M.E. et al. The Immunophysiology and Apoptosis of Biliary Epithelial Cells: Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis. Clinic Rev Allerg Immunol 43, 230–241 (2012). https://doi.org/10.1007/s12016-012-8324-0

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  • DOI: https://doi.org/10.1007/s12016-012-8324-0

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