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

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.