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The Pathogenesis of Autoimmune Liver Diseases

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Diagnosis and Management of Autoimmune Hepatitis

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Abstract

Autoimmune liver diseases (AILD) are chronic inflammatory and immune-mediated disorders of the liver and biliary tree, the pathogenesis of which involves the attack of the host’s innate and adaptive immune systems against cellular elements of the liver and/or the intra- and/or extra-hepatic biliary tree. The four major forms of AILDs include classic autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and overlap syndromes (OS). In AIH, the principal attack of the immune system is directed at hepatocytes; in PBC, the principal attack is directed at cholangiocytes that line the smaller intrahepatic bile ducts; in PSC, the principal attack is directed at cholangiocytes and perhaps other cells that comprise the larger intra- and/or extrahepatic bile ducts; in OS, there are elements of immune-mediated injury directed at both hepatocytes and cholangiocytes. The pathogenesis of AILD involves the exposure of hosts to infectious agents, such as viruses and bacteria, or to xenobiotics, chemicals that may come from natural sources or that may have been synthesized by humans. In genetically susceptible hosts, these inciting agents lead to the production of neoantigens and/or to substances that exhibit molecular mimicry to endogenous components of hepatocytes and/or cholangiocytes. The neoantigens or mimics elicit innate immune responses, followed by adaptive immune responses, with the formation of autoantibodies, made chiefly by B cells and plasma cells, and by T lymphocytes, including natural killer (NK) T cells, T8 (cytotoxic) and T4 (helper) cells. The latter cells attack and injure and kill hepatocytes and/or cholangiocytes and set in motion proinflammatory and profibrogenic cascades that may eventuate in hepatic necrosis, collapse, fibrosis, cirrhosis, and liver failure.

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Abbreviations

AC:

autoimmune cholangitis

ADCC:

antibody-dependent cytotoxicity

AE:

anion exchanger

AILD:

autoimmune liver diseases

AIH:

autoimmune hepatitis

AMA:

antimitochondrial antibodies

ANA:

antinuclear antibodies

(A)SMA:

(anti-)smooth muscle antibodies

APC:

antigen-presenting cells

ASGPR:

asialoglycoprotein receptor

BEC:

biliary epithelial cells (cholangiocytes)

CD:

cluster of differentiation

(G)CDC:

(glyco)chenodeoxycholic acid

CIRP:

cold-inducible RNA-binding protein

CMV:

cytomegalovirus

CTL:

cytotoxic T lymphocytes

CYP:

cytochrome P-450

CTL:

cytotoxic T lymphocytes

CTLA-4:

CTL antigen A-4

DAMPs:

danger-associated molecular patterns

EBV:

Epstein-Barr virus

GWAS:

genome-wide association study

HAV:

hepatitis A virus

HBV:

hepatitis B virus

HCV:

hepatitis C virus

HDV:

hepatitis D virus

HEV:

hepatitis E virus

HIV:

human immunodeficiency virus

HLA:

human leukocyte antigen

HMGB:

high-mobility group box

HSP:

heat-shock protein

HSV:

herpes simplex virus

IBD:

inflammatory bowel disease

Ig:

immunoglobulins

L:

ligand

LKM:

liver-kidney microsome

LSEC:

liver sinusoidal endothelial cells

LPS:

lipopolysaccharide

LT:

liver transplantation

NLR:

nucleotide binding and leucine-rich repeat

NLRP:

NLR pyrin domain containing

NK (T):

natural killer (T) cells

NO:

nitric oxide

OADC:

organic acid dehydrogenase complexes

OS:

overlap syndromes

PAMPs:

pathogen-associated molecular patterns

pANCA:

perinuclear antineutrophil cytoplasmic antibodies (now called pANNA)

pANNA:

perinuclear antineutrophil nuclear antibodies

PBC:

primary biliary cholangitis

PD:

programmed death

PDC:

pyruvate dehydrogenase complex

PSC:

primary sclerosing cholangitis

SLA:

soluble liver antigen

SLE:

systemic lupus erythematosus

STAT:

signal transducer and activator of translation

TGF:

transforming growth factor

TGR5:

Takeda G protein complex R-5

Th:

T helper cells

TIPS:

transvenous intrahepatic portosystemic shunt

TLR:

Toll-like receptors

TNF:

tumor necrosis factor

TRAIL:

TNF-related apoptosis-inducing ligand

Treg:

regulatory T cells

UC:

ulcerative colitis

UDCA:

ursodeoxycholic acid

UDP:

uridine diphosphate

UGT:

UDP-glucuronosyltransferase(s)

WAF:

water-accommodating fraction

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Acknowledgements

We acknowledge with thanks John M. Vierling, MD for making available to us figures and tables that are featured in this chapter. Supported by awards from NIH/NIDDK U01 DK 065201, U54 DK 083909, and R01 DK 119913 (to HLB).

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Authors and Affiliations

  1. Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Alexander J. Kovalic & Herbert L. Bonkovsky

  2. Section on Gastroenterology & Hepatology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Herbert L. Bonkovsky

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  1. Alexander J. Kovalic
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  2. Herbert L. Bonkovsky
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Correspondence to Herbert L. Bonkovsky .

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  1. Carolinas Medical Center-Atrium Health, University of North Carolina School of Medicine, Charlotte, NC, USA

    Mark W. Russo

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Kovalic, A.J., Bonkovsky, H.L. (2020). The Pathogenesis of Autoimmune Liver Diseases. In: Russo, M. (eds) Diagnosis and Management of Autoimmune Hepatitis. Springer, Cham. https://doi.org/10.1007/978-3-030-33628-8_2

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