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.