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Animal Models of Autoimmune Liver Diseases: a Comprehensive Review

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Abstract

Autoimmune liver diseases (AILDs) are potentially life-threatening chronic liver diseases which include autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and recently characterized IgG4-related sclerosing cholangitis. They are caused by immune attack on hepatocytes or bile ducts, with different mechanisms and clinical manifestations. The etiologies of AILDs include a susceptible genetic background, environment insults, infections, and changes of commensal microbiota, but remain complicated. Understanding of the underlying mechanisms of AILDs is mandatory for early diagnosis and intervention, which is of great importance for better prognosis. Thus, animal models are developed to mimic the pathogenesis, find biomarkers for early diagnosis, and for therapeutic attempts of AILDs. However, no animal models can fully recapitulate features of certain AILD, especially the late stages of diseases. Certain limitations include different living condition, cell composition, and time frame of disease development and resolution. Moreover, there is no IgG4 in rodents which exists in human. Nevertheless, the understanding and therapy of AILDs have been greatly advanced by the development and mechanistic investigation of animal models. This review will provide a comprehensive overview of traditional and new animal models that recapitulate different features and etiologies of distinct AILDs.

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Abbreviations

ABD:

Autoimmune biliary disease

AE2:

Anion exchanger 2

α-GalCer:

α-Galactosylceramide

AIH:

Autoimmune hepatitis

AILD:

Autoimmune liver disease

ALP:

Alkaline phosphatase

ALT:

Alanine aminotransferase

AMAs:

Antimitochondrial antibodies

ANAs:

Antinuclear antibodies

AU-rich:

Adenylate uridine-rich

BCOADC-E2:

Branched chain 2-oxo acid dehydrogenase complex-E2

BDP:

Bile duct protein

BEC:

Bile duct epithelial cell

BSA:

Bovine serum albumin

ConA:

Concanavalin A

CTLA-4:

Cytotoxic T lymphocyte-associated protein 4

CYP2D6:

Cytochrome P4502D6

dnTGF-βRII:

Dominant-negative TGF-β receptor II

DDC:

3,5-Diethoxycarbonyl-1,4-dihydrocollidine

DSS:

Dextran sulfate sodium

E. coli :

Escherichia coli

FAH:

Fumarylacetoacetate hydrolase

FTCD:

Formiminotransferase cyclodeaminase

GWAS:

Genome-wide association study

HLA:

Human leukocyte antigen

IBD:

Inflammatory bowel disease

Idd:

Insulin-dependent diabetes

iNKT:

Invariant natural killer T

IL-2Rα:

Interleukin-2 receptor α

IgG4-RD:

Immunoglobulin G4–related disease

LCA:

Lithocholic acid

LPS:

Lipopolysaccharide

LSEC:

Liver sinusoidal endothelial cells

LSP:

Liver-specific membrane protein

MHV:

Mouse hepatic virus

NOD:

Non-obese diabetic

N. aromaticivorans :

Novosphingobium aromaticivorans

NTx:

Neonatal thymectomy

OGDC-E2:

2-Oxoglutarate dehydrogenase complex-E2

2-OA:

2-Octyl acid

pANCA:

Perinuclear antineutrophil cytoplasmic antibodies

PBC:

Primary biliary cholangitis

PDC-E2:

Pyruvate dehydrogenase complex-E2

PSC:

Primary sclerosing cholangitis

SLE:

Systemic lupus erythematosus

SMAs:

Smooth muscle antibodies

TNBS:

2,4,6-Trinitrobenzene sulfonic acid

Tregs:

Regulatory T cells

UDCA:

Ursodeoxycholic acid

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Funding

This work is supported by the Program for Guangdong Introducing Innovative and Enterpreneurial Teams (2017ZT07S054), the National Natural Science Foundation of China (81801607, 81873877, 81901652), China Postdoctoral Science Foundation (2018 M643095), and State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases Fund, China (SKL-HIDCA-2018-4).

Author information

Author notes

  1. Shou-Pei Liu and Zhen-Hua Bian contributed equally to this work.

Authors and Affiliations

  1. Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China

    Shou-Pei Liu, Zhen-Hua Bian, Zhi-Bin Zhao, Liang Li & Zhe-Xiong Lian

  2. Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China

    Shou-Pei Liu, Zhen-Hua Bian, Zhi-Bin Zhao, Liang Li & Zhe-Xiong Lian

  3. School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006, Guangdong, China

    Zhen-Hua Bian

  4. College of Environmental Science and Engineering, Yangzhou University, Yangzhou, 225127, Jiangsu, China

    Jinjun Wang

  5. Division of Rheumatology/Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA

    Weici Zhang & Patrick S.C. Leung

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Contributions

Shou-Pei, Zhen-Hua Bian, Zhi-Bin Zhao, Jinjun Wang, and Liang Li wrote the manuscript. Shou-Pei Liu, Zhen-Hua Bian, and Liang Li designed and drew the figures. Weici Zhang, Patrick S.C. Leung, and Zhe-Xiong Lian wrote and edited the manuscript.

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Correspondence to Liang Li or Zhe-Xiong Lian.

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Liu, SP., Bian, ZH., Zhao, ZB. et al. Animal Models of Autoimmune Liver Diseases: a Comprehensive Review. Clinic Rev Allerg Immunol 58, 252–271 (2020). https://doi.org/10.1007/s12016-020-08778-6

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