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
Published online Dec 7, 2019. doi: 10.3748/wjg.v25.i45.6579
Table 1 Factors affecting susceptibility to autoimmune hepatitis
Factors | Features | Pathogenic Implications in AIH |
Genetic predispositions | DRB1*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 changes | Alter 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 lymphocytes | Self-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
Factors | Features | Pathogenic Implications in AIH |
Microbial triggers | Infections 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] | ||
Superantigens | Induced 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 exposure | Metabolites 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 pressures | Diet, 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
Factors | Features | Pathogenic implications in AIH |
Molecular mimicry | Structural 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 spread | Antibodies 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-antigens | Antigens 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 activation | Induced 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
Factors | Features | Pathogenic implications in AIH |
TCR polyspecificity | TCRs 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 dysbiosis | Intestinal 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] |
- Citation: Czaja AJ. Examining pathogenic concepts of autoimmune hepatitis for cues to future investigations and interventions. World J Gastroenterol 2019; 25(45): 6579-6606
- URL: https://www.wjgnet.com/1007-9327/full/v25/i45/6579.htm
- DOI: https://dx.doi.org/10.3748/wjg.v25.i45.6579