Factoring the intestinal microbiome into the pathogenesis of autoimmune hepatitis

Table 1 Key Requirements for gut-derived systemic immune response

Key requirement	Features	Mechanisms
Activation of TLRs	Intestinal receptors responsive to MAMPs and DAMPS[34,47,48,120]	Increases pro-inflammatory cytokines[126]
	Signaling dependent on MyD88[124,125]	Upregulates class II MHC[127]
	Activates NF-κB[123,125,126]	Increases co-stimulatory molecules[41,127]
	Favors T lymphocyte activation[41]	Promotes pathogen-specific responses[142]
	Modulates actions of Tregs[141,142]	LPS activates TLR4[123,134]
	Present in hepatocytes, HSCs, Kupffer cells, sinusoidal epithelial cells, BEC[48]	Sequences in bacteria activate TLR9[135]
		TLR4 in HSCs promote fibrosis[46,144]
		Implicated in other liver diseases[58,148]
Stimulation of inflammasomes	Protein complexes that release pro-inflammatory IL-1β and IL-18[111-113]	Upregulated in hepatocytes by LPS[113]
	NLRs sense microbial products[156]	Activates pro-caspase 1[156]
	Upregulated in Kupffer cells, hepatocytes, and sinusoidal epithelial cells[113]	Promotes hepatic fibrosis[50]
	Activation by highly diverse ligands[112]	Shapes innate and adaptive immunity[112,160]
		Implicated in NAFLD[51]
		Activation separate from TLRs[112,155]
Emergence of dysbiosis	Microflora differ from commensals[116]	Can activate TLRs and NLRs[116,173]
	Dysbiosis varies in specific diseases[116]	Genetic factors may affect composition[177]
	Less bacterial diversity common[170]	Gender-related compositional differences[179]
	Antibiotics most frequent basis[165,175]	May affect gender-related autoimmunity[180]
	Uncertain cause or effect of disease[116]	Present in AIH and experimental NASH[47,69]
Molecular mimicry	Microbial and self-homologies[33,185]	pANCA react with bacterial antigen[53]
	Cross-reacting antibodies[53,57,184]	AMA cross-reacts with Escherichia coli[56,57]
	Promiscuous activity of effectors[186]	Increasingly distant homologues targeted[187]
	Epitope spread[187]
Breech of intestinal mucosal barrier	Gut-derived products enter system[195]	Gut-derived lymphocytes in lymph nodes[118]
	Translocation prime basis[46,195]	Microbial components in peripheral blood[195]
	Active transport also possible[230]	Activates TLRs and NLRs[123,130]
		Implicated in NASH and diabetes[197,198]

AMA: Antimitochondrial antibodies; BEC: Biliary epithelial cells; DAMPS: Damage-associated molecular patterns; HSCs: Hepatic stellate cells; IL: Interleukin; LPS: Lipopolysaccharide; MAMPs: Microbe-associated molecular patterns; MHC: Major histocompatibility complex; MyD88: Myeloid differentiation factor 88; NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis; NF-κB: Nuclear factor kappa B; NLRs: Non-obese diabetes-like receptors; pANCA: Atypical perinuclear anti-neutrophil cytoplasm antibodies; TLRs: Toll-like receptors; Tregs: Regulatory T cells. Superscripted numbers in brackets are references.