Examining pathogenic concepts of autoimmune hepatitis for cues to future investigations and interventions

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]

Superscripted numbers are references. AIH: Autoimmune hepatitis; anti-LKM1: Antibodies to liver kidney microsome type 1; CTLA4: Cytotoxic T lymphocyte antigen 4 gene; DNA: Deoxyribonucleic acid; Fas: Tumor necrosis factor receptor superfamily member 6 gene; FoxP3: Forkhead box P3; GWAS: Genome-wide association studies; HLA: Human leukocyte antigen; PBC: Primary biliary cholangitis; PD-1: Programmed cell death antigen-1; SH2B3: Src homology 2-B adaptor protein 3 gene; miRNAs: Micro-ribonucleic acids; TNF-α: Tumor necrosis factor-alpha gene; sPD-1: Soluble programmed cell death antigen-1; Tregs: Regulatory T cells.

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

Superscripted numbers are references. AIH: Autoimmune hepatitis; APC: Antigen-presenting cell; DNA: Deoxyribonucleic acid; MHC: Major histocompatibility complex; MS: Multiple sclerosis; RA: Rheumatoid arthritis; TCR: T cell antigen receptor; VDR: Vitamin D receptor; Vβ region: Variable region of the β chain.

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]

Superscripted numbers are references. AIH: Autoimmune hepatitis; APCs: Antigen presenting cells; CMV: Cytomegalovirus; CYP 2D6: Cytochrome P450 2D6; HCV: Hepatitis C virus; MHC: Major histocompatibility complex; PBC: Primary biliary cholangitis.

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]

AIH: Autoimmune hepatitis; TCR: T cell antigen receptor; TLRs: Toll-like receptors; Tregs: Regulatory T cells.