Copyright ©The Author(s) 2019.
World J Gastroenterol. Dec 7, 2019; 25(45): 6579-6606
Published online Dec 7, 2019. doi: 10.3748/wjg.v25.i45.6579
Table 1 Factors affecting susceptibility to autoimmune hepatitis
FactorsFeaturesPathogenic Implications in AIH
Genetic predispositionsDRB1*03:01 and DRB1*04:01 in white European and North American patients[16,18,47]DRB1*03:01 associated with young age, severity, cirrhosis, and poor outcome[18,47]
DRB1*04:01 associated with elderly, concurrent immune diseases, treatment response[16,18,373]
DRB1*04:04 and DRB1*04:05 in Asian and Mexican patients[49,51,52,55,367]
DRB1*13:01 in South American children in and DRB1*04:05 in adults[50,53,58,368]
DRB1*13:01 distinguishes South American children from adults[58,368]
DQB1*0201, DRB1*07 and DRB1*03 in patients (mainly children) with anti-LKM1[369]
DQB1*02:01 and DRB1*07 associated with type 2 (anti-LKM1-positive) AIH[369,374,375] Genetics explain 51%-55% of risk-burden[23,25,47,65]
Polymorphisms of TNFα, Fas, CTLA4, and SH2B3 variably involved[48,56,60-62,65,370-372]
Polymorphisms may be discovered by GWAS[23]
Epigenetic changesAlter structure of nucleosomes[25,26]miR-21 and miR-122 increased in AIH[103]
Affect transcriptional activity of genes[67,69]Hypomethylation of gene promoters in SLE and PBC may promote autoimmunity[82-85]
Responsive to environmental cues[26,67]
Changes may be inherited[26,67]Histone acetylation can increase Tregs or expression of pro-inflammatory genes[88,89]
DNA methylation represses gene activity[70] DNA hypomethylation activates gene[77-81]
Histone changes can weaken self-tolerance[71,93]
Histone acetylation, phosphorylation, methylation, and ubiquitination can activate or repress gene activity[72,86,87,92]
May explain population risk differences[25,26]
Contributes to risk burden of AIH[23,25]
MiRNAs silence genes[73,94-96]Epigenetics in AIH under-evaluated[25]
Escaped autoreactive lymphocytesSelf-reactive thymocytes normally eliminated (negative selection)[27-29]Escaped self-reactive CD4+ T cells may promote autoimmunity[112-114]
Thymocytes recognizing foreign antigens normally retained (positive selection)[27-29]
PD-1 expression on thymocytes and lymphocytes may be impaired[109,112,116]
Escaped self-reactive CD4+ T cells become self-tolerant, autoreactive, or Tregs depending on PD-1 and FoxP3 expression[112-114]
PD-1 expression in AIH unassessed[22]
Regulatory role of sPD-1 unknown in AIH[22]
Table 2 Possible triggering events for autoimmune hepatitis
FactorsFeaturesPathogenic Implications in AIH
Microbial triggersInfections with multiple viruses temporally associated with onset of AIH[120,126-128,133]Low frequency of viral markers in AIH[136,147]
Undiscovered viral agents possible[151]
Rarity of AIH contrasts with ubiquity of viruses and supports host-related predisposing factors[147]
Multiple viral antigens discovered in serum and liver tissue of patients with AIH[139,142-144]
Microbial infection as direct cause unlikely[147]
SuperantigensInduced by viruses and bacteria[158,159]Superantigens implicated in model of MS and patients with RA[165-167]
No MHC-restricted antigen presentation[158]
Associated with nearly monoclonal single type Vβ T cells in RA[166]
Bind to class II MHC molecule on APC and Vβ region of TCR[160]
Microbial basis inferred in RA[159,166,167]
Generate polyclonal T cell response[161]
Can induce T cell exhaustion[376,377]
Superantigens unassessed in AIH[158,159]
Drug exposureMetabolites can interact with self-proteins to promote loss of tolerance[176,178,179]Idiosyncratic drug-induced liver injury can resemble AIH[168,169]
Immune checkpoint inhibitors enhance reactivity against neo-antigens[182,184]Immune-mediated hepatitis associated with blockade of immune inhibitors[190-194]
Immune checkpoint inhibitors induce diverse autoimmune diseases[186,187]Hepatitis may occur months after cessation of immune checkpoint inhibitor[189]
Drugs can cause DNA demethylation[199-203]DNA demethylating drugs induce lupus-like reactions in animal models[202]
Environmental pressuresDiet, drug or alcohol abuse, pollutants, sanitation, polypharmacy, and socioeconomic status are potential but unevaluated risk factors for AIH[25]Vitamin D deficiency in refractory AIH[209,210]
Vitamin D response element in genes[378,379]
Gene expressions affected by vitamin D deficiency[35,85,207,208,211]
Environment can affect antigen exposures, gene expression, and immune responses[25]
Polymorphisms of VDR associated with occurrence of AIH[212,213]
Other environmental factors unexplored in AIH
Table 3 Factors affecting maintenance or escalation of autoimmune hepatitis
FactorsFeaturesPathogenic implications in AIH
Molecular mimicryStructural or conformational similarity between foreign and self-antigen[30-33,215]Mimicries between CYP 2D6 of AIH and HCV, herpes simplex, CMV[244-246]
Introduced by infection, environment, or xenobiotic modification of self-antigen[215,222]Structural mimicry with bacteria in PBC[247-251]
Generates cross-reacting antibodies and immune cells[31,216]Virus expressing human CYP 2D6 induces experimental AIH[226,252]
More mimicries between bacterial motifs and self-antigens than AIH occurrence suggest low impact or other factors involved[64,253,257]
Requires similarity not identity to self-epitope[31]
Must mimic biologically active homologue[31]
Epitope spreadAntibodies or immune cells target multiple epitopes on same or other molecules[37,38,264,268]Autoantibody-response in murine AIH model spreads from immune-dominant epitope to neighboring and remote regions[40]
Initiating immune-dominant epitope may be lost as range of immune reactivity increases[40,268]
Patients with AIH show similar response[40]
Enhanced by endocytic processing and variability of peptide fragments presented by class II MHC molecules[271,380,381]
Somatic hypermutation diversifies B cell receptors and their reactivity to wider spectrum of antigens[41,266,272,273]
Neo-antigensAntigens released from injured tissue or formed during inflammatory activity[42,264]Can increase epitope spreading[264,265]
May re-enforce immune response[42]
Expressed only under certain conditions[42]Unassessed in AIH
Can be variable between individuals[42,264]
Bystander activationInduced by viral infection, bacterial products, and virus-mimetics (vaccines)[274-278]Can intensify collateral tissue injury[274,282]
Activate APCs (dendritic cells)[274]
Pro-inflammatory cytokines released from T cells and macrophages activate pre-primed polyclonal memory T cells[274]
Mobilize autoreactive T cells[274]
Unassessed in AIH
Memory CD8+ T cells mainly involved[275,276]
Memory CD4+ T cells also activated[279,280]
Table 4 Pathogenic implications of T cell antigen receptor polyspecificity and intestinal dysbiosis in autoimmune hepatitis
FactorsFeaturesPathogenic implications in AIH
TCR polyspecificityTCRs have plasticity that increase cross-reactivity and polyspecificity[45,284-286]Increased cross-reactivity, promiscuous targeting, and less self-tolerance[45]
Dual TCRs escape thymic negative selection[290]
Unassessed in autoimmune hepatitis
Dual TCRs may recognize both foreign and self-antigens[44,288]
Intestinal dysbiosisIntestinal dysbiosis associated with activation of TLRs, inflammasomes, and stimulation of immune response[296,303,304,306,307,309]Present in diverse liver and non-liver autoimmune diseases[249,302,303,318,323,325]
Deficient structural proteins of mucosal barrier in AIH[325]
Gut-derived activated immune cells migrate to peripheral lymph nodes[310,311]
Circulating gut-derived bacterial lipopolysaccharide in AIH[325]
Transfer experiments using intestinal microbiota affect female bias for diabetes[300,332,333]
Decreased intestinal anaerobes in AIH[325]
Exposure to gut-derived microbial products at young age may protect against intolerance to self-antigens (“hygiene hypothesis”)[334-337]
Dysbiosis associated with flares in experimental AIH[326]
May influence female gender bias in autoimmune disease[300,332,333]