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

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.