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

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.