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

Table 1 Factors affecting susceptibility to autoimmune hepatitis

Factors	Features	Pathogenic Implications in AIH
Genetic predispositions	DRB1*03:01 and DRB1*04:01 in white European and North American patients[16,18,47]	DRB1*03:01 associated with young age, severity, cirrhosis, and poor outcome[18,47]
		DRB1*04:01 associated with elderly, concurrent immune diseases, treatment response[16,18,373]
	DRB1*04:04 and DRB1*04:05 in Asian and Mexican patients[49,51,52,55,367]
	DRB1*13:01 in South American children in and DRB1*04:05 in adults[50,53,58,368]
		DRB1*13:01 distinguishes South American children from adults[58,368]
	DQB1*0201, DRB1*07 and DRB1*03 in patients (mainly children) with anti-LKM1[369]
		DQB1*02:01 and DRB1*07 associated with type 2 (anti-LKM1-positive) AIH[369,374,375] Genetics explain 51%-55% of risk-burden[23,25,47,65]
	Polymorphisms of TNFα, Fas, CTLA4, and SH2B3 variably involved[48,56,60-62,65,370-372]
		Polymorphisms may be discovered by GWAS[23]
Epigenetic changes	Alter structure of nucleosomes[25,26]	miR-21 and miR-122 increased in AIH[103]
	Affect transcriptional activity of genes[67,69]	Hypomethylation of gene promoters in SLE and PBC may promote autoimmunity[82-85]
	Responsive to environmental cues[26,67]
	Changes may be inherited[26,67]	Histone acetylation can increase Tregs or expression of pro-inflammatory genes[88,89]
	DNA methylation represses gene activity[70] DNA hypomethylation activates gene[77-81]
		Histone changes can weaken self-tolerance[71,93]
	Histone acetylation, phosphorylation, methylation, and ubiquitination can activate or repress gene activity[72,86,87,92]
		May explain population risk differences[25,26]
		Contributes to risk burden of AIH[23,25]
	MiRNAs silence genes[73,94-96]	Epigenetics in AIH under-evaluated[25]
Escaped autoreactive lymphocytes	Self-reactive thymocytes normally eliminated (negative selection)[27-29]	Escaped self-reactive CD4+ T cells may promote autoimmunity[112-114]
	Thymocytes recognizing foreign antigens normally retained (positive selection)[27-29]
		PD-1 expression on thymocytes and lymphocytes may be impaired[109,112,116]
	Escaped self-reactive CD4+ T cells become self-tolerant, autoreactive, or Tregs depending on PD-1 and FoxP3 expression[112-114]
		PD-1 expression in AIH unassessed[22]
		Regulatory role of sPD-1 unknown in AIH[22]

Superscripted numbers are references. AIH: Autoimmune hepatitis; anti-LKM1: Antibodies to liver kidney microsome type 1; CTLA4: Cytotoxic T lymphocyte antigen 4 gene; DNA: Deoxyribonucleic acid; Fas: Tumor necrosis factor receptor superfamily member 6 gene; FoxP3: Forkhead box P3; GWAS: Genome-wide association studies; HLA: Human leukocyte antigen; PBC: Primary biliary cholangitis; PD-1: Programmed cell death antigen-1; SH2B3: Src homology 2-B adaptor protein 3 gene; miRNAs: Micro-ribonucleic acids; TNF-α: Tumor necrosis factor-alpha gene; sPD-1: Soluble programmed cell death antigen-1; Tregs: Regulatory T cells.