cirrhosisCCHcryptogenic chronic hepatitisCDceliac diseaseCDCAchenodeoxycholic acidCIconfidence intervalCNSDCchronic non‐suppurative destructive cholangitisCREBcAMP response element binding proteinCSCesarean sectionCTcomputed tomographyCTDconnective tissue diseaseCTLcytotoxic T lymphocyteCTLAcytotoxic T‐lymphocyte antigenCYPcytochrome PD31,25‐dihydroxyvitamin D3DAGdiacylglycerolDAMPdamage‐associated molecular patternDCdendritic cellDCDdonation after circulatory deathDCregregulatory dendritic cellDDLTdeceased donor liver transplantDILIdrug‐induced liver injuryDOCK1dedicator of cytokinesis 1 (protein)DXAdual‐energy X‐ray absorptiometryEASLEuropean Association for the Study of the LiverEGDesophagogastroduodenoscopyEHAIDextrahepatic autoimmune diseaseELFenhanced liver fibrosis (test)ELISAenzyme‐linked immunosorbent assayELTREuropean Liver Transplant RegistryENAextractable nuclear antigeneQTLexpression quantitative trait locusERCPendoscopic retrograde cholangiopancreatographyeRNAenhancer RNAEULAREuropean League Against RheumatismEUSendoscopic ultrasoundEVLendoscopic variceal ligationFDAFood and Drug AdministrationFISHfluorescence in situ hybridizationFNAfine needle aspirationFoxPforkhead box P3FXRfarnesoid X receptorGEFguanine nucleotide exchange factorGGTgamma‐glutamyltranspeptidase (or gamma‐glutamyltransferase)GLPglucagon‐like peptideGWASgenome‐wide association studiesHAIhepatic/hepatitis activity indexHBRVhuman betaretrovirusHBVhepatitis B virusHCChepatocellular carcinomaHCVhepatitis C virusHDLhigh‐density lipoproteinHLAhuman leukocyte antigenHMG‐CoA3‐hydroxy‐3‐methylglutaryl‐coenzyme AHPFhigh‐power fieldHpSChepatic stem/progenitor cellHRhazard ratioHRQoLhealth‐related quality of lifeHSChepatic stellate cellHSEChepatic sinusoidal endothelial cellHSVherpes simplex virusIACIgG4‐associated cholangitisIAHInternational Autoimmune Hepatitis (score)IAIHGInternational IAH GroupIBDinflammatory bowel diseaseICUintensive care unitIgG4‐RDIgG4‐related diseaseIIFindirect immunofluorescenceILinterleukinINRinternational normalized ratioIPEXimmunodysregulation polyendocrinopathy enteropathy X‐linked (syndrome)IRFinterferon regulatory factorISREinterferon‐stimulated response elementJAKJanus kinaseLAKlymphokine‐activated killer (cell)LC1liver cytosol type 1 (antibody)LDlinkage disequilibriumLDLlow‐density lipoproteinLDLTliving donor liver transplantLElupus erythematosusLFTliver function testLKM1liver kidney microsomal type 1 (antibody)lncRNAlong non‐coding RNALPAlysophosphatidic acidLPSlipopolysaccharideLSECliver sinusoidal endothelial cellLTliver transplantationMAGUKmembrane‐associated guanylate kinaseMAITmucosal invariant T (cell)MAPKmitogen‐activated protein kinaseMDRmultidrug resistanceMELDModel for End‐stage Liver Disease (score)MHCmajor histocompatibility complexMIFmacrophage migration inhibitory factormiRNAmicroRNAMMFmycophenolate mofetil6‐MMP6‐methylmercaptopurineMMTVmouse mammary tumor virus6‐MP6‐mercaptopurinemQTLmethylation quantitative trait locusMRCmagnetic resonance cholangiographyMRCPmagnetic resonance cholangiopancreatographyMRPmultidrug resistance proteinMSmultiple sclerosismTECmedullary thymic epithelial cellNACN‐acetylcysteineNAFLDnon‐alcoholic fatty liver diseaseNANAnuclear anti‐neutrophil antibodyNASHnon‐alcoholic steatohepatitisNETneutrophil extracellular trapNFκBnuclear factor kappa BNICENational Institute for Health and Care Excellence (UK)NICUneonatal intensive care unitNKnatural killer (cell)NKTnatural killer T (cell)NLRP3nucleotide‐binding oligomerization domain (NOD)‐like receptor P3NODnon‐obese diabeticNSAIDnon‐steroidal anti‐inflammatory drugNTCPsodium taurocholate cotransporting polypeptideOATPorganic anion‐transporting polypeptideOCAobeticholic acidOGDC2‐oxoglutarate dehydrogenase complexOPGosteoprotegerinORodds ratioOSoverlap syndromePAMPpathogen‐associated molecular patternpANCAperinuclear anti‐neutrophil cytoplasmic antibodypANNAperinuclear anti‐neutrophil nuclear antibodyPBCprimary biliary cholangitisPBGperibiliary glandPD‐1programmed cell death 1PDCpyruvate dehydrogenase complexPETpositron emission tomographyPKCprotein kinase CP1NPprocollagen type 1 N‐terminal propeptidePPARperoxisome proliferator‐activated receptorPRRpattern recognition receptorPSCprimary sclerosing cholangitisPXRpregnane X receptorQALYquality‐adjusted life‐yearRArheumatoid arthritisRAGrecombination activating generAIHrecurrent autoimmune hepatitisRANKLreceptor activator of nuclear factor kappa‐B ligandRDCreactive ductular cellRFrheumatoid factorRORreceptor‐related orphan receptorrPBCrecurrent primary biliary cholangitisrPSCrecurrent primary sclerosing cholangitisRRrelative riskRTKreceptor tyrosine kinaseRXRretinoid X receptorSASPsenescence‐associated secretory phenotypeSCIDsevere combined immunodeficiencySEsuper enhancerSH2BSH2B adapter protein 3SLAsoluble liver antigenSLEsystemic lupus erythematosusSMAsmooth muscle antibodySNPsingle nucleotide polymorphismSSSjögren syndromeSScsystemic sclerosisSTATsignal transducer and activatorTCRT‐cell receptorT1DMtype 1 diabetes mellitusTFtranscription factorTfhT follicular helper (cell)TGFtransforming growth factor6‐TGN6‐thioguanine nucleotideTIPStransjugular intrahepatic portosystemic shuntTLRToll‐like receptorTLStertiary lymphoid structureTNFtumor necrosis factorTNFAIP3TNF‐induced protein 3TNIP1TNFα‐induced protein 3‐interacting protein 1TORCtransducer of regulated CREB activityTPMTthiopurine S‐methyltransferaseTRAILTNF‐apoptosis‐inducing ligandTregT regulatory cellTRMtissue‐resident memory T (cell)UCulcerative colitisUDCAursodeoxycholic acidUGTuridine diphosphate glucuronosyltransferaseULNupper limit of normalUTIurinary tract infectionVBvariceal bleedingVDRvitamin D receptorWDWilson disease
Introduction The Paradigm and Paradox of Liver Autoimmunity
M. Eric Gershwin
Division of Rheumatology, Allergy and Clinical Immunology, University of California School of Medicine, Davis, CA, USA
From an evolutionary perspective, the immune system was one of the first physiological components of life – even plants have some form of a response against pathogens. The evolution of immunity was of course to protect species from the outside world and this is as much true of people as it is of earthworms. However, on occasion, the immune system attacks one's own tissues, a process known as autoimmunity. Autoimmunity affects a variety of species and clearly increases with inbreeding and genetic diversity. Although we now catalog more than 100 different autoimmune diseases, the etiology of virtually all of autoimmunity remains enigmatic other than the concept, as noted below, of genetic predisposition and one or more environmental stimuli. Indeed, understanding the etiology of autoimmunity, while a major problem, has not deterred effective treatments. In the case of rheumatoid arthritis, we have very effective treatments directed at the mediators of inflammation without knowing what initiates the entire process.
To put this in perspective, it should be re‐emphasized that the immune system is the most pleiotropic and promiscuous physiological component of the human body. Indeed, the potential individual repertoire may include up to 1013 arrangements of the T‐cell receptor (TCR). This magnitude of diversity is a result of evolutionary pressure to protect our species from the outside world and therefore protect us from a myriad of potential pathogens. Interestingly, however, this diversity is not limited to humans. People, dogs, cats, fish and even earthworms exhibit evidence of an immune system, but the pleiotropic nature of immune responses becomes more sophisticated in higher animals.
Ironically, despite the sophistication of the immune system, our recognition of its importance and the multitude of ways in which it can harm the body is a relatively recent development. Although many physicians can be credited with establishing immunology as a science, it is clear that the first giant of immunology was Clemens von Pirquet, born in 1874 in Vienna. Von Pirquet devoted his early work to understanding the immune response to scarlet fever and, in collaboration with multiple coworkers, was among the first to identify precipitants in human sera. He also coined the word “allergy” which essentially means deviation from self. However, it was not until the work of Paul Ehrlich on hemolytic anemia that scientists began to appreciate the possibility that our pleiotropic immune system could attack our own body. Ironically, the first textbook devoted to autoimmunity was not published until 1963, or over 60 years after Ehrlich's initial observations. This book, authored by Mackay and Burnett, was published in a series of monographs entitled American Lectures in Living Chemistry (Charles Thomas Publishers, Springfield, Illinois). This textbook contains 12 chapters devoted to specific autoimmune diseases. The concept of the forbidden clone was discussed and, of particular interest to liver specialists, the terms active chronic and lupoid hepatitis were introduced. Absent from this book was of course the concept of lymphoid subpopulations, the genetics of the immune response,
