Epigenetic Aspects and Prospects in Autoimmune Hepatitis

Abstract

The observed risk of autoimmune hepatitis exceeds its genetic risk, and epigenetic factors that alter gene expression without changing nucleotide sequence may help explain the disparity. Key objectives of this review are to describe the epigenetic modifications that affect gene expression, discuss how they can affect autoimmune hepatitis, and indicate prospects for improved management. Multiple hypo-methylated genes have been described in the CD4+ and CD19+ T lymphocytes of patients with autoimmune hepatitis, and the circulating micro-ribonucleic acids, miR-21 and miR-122, have correlated with laboratory and histological features of liver inflammation. Both epigenetic agents have also correlated inversely with the stage of liver fibrosis. The reduced hepatic concentration of miR-122 in cirrhosis suggests that its deficiency may de-repress the pro-fibrotic prolyl-4-hydroxylase subunit alpha-1 gene. Conversely, miR-155 is over-expressed in the liver tissue of patients with autoimmune hepatitis, and it may signify active immune-mediated liver injury. Different epigenetic findings have been described in diverse autoimmune and non-autoimmune liver diseases, and these changes may have disease-specificity. They may also be responses to environmental cues or heritable adaptations that distinguish the diseases. Advances in epigenetic editing and methods for blocking micro-ribonucleic acids have improved opportunities to prove causality and develop site-specific, therapeutic interventions. In conclusion, the role of epigenetics in affecting the risk, clinical phenotype, and outcome of autoimmune hepatitis is under-evaluated. Full definition of the epigenome of autoimmune hepatitis promises to enhance understanding of pathogenic mechanisms and satisfy the unmet clinical need to improve therapy for refractory disease.

Incorporating the Molecular Mimicry of Environmental Antigens into the Causality of Autoimmune Hepatitis

“…Management strategies based on predominant pathogenic mechanism (molecular mimicry vs epigenetics) [ 48 , 55 ]…”

“…Environmental factors may influence the causality of autoimmune hepatitis outside of molecular mimicry [ 52 , 53 , 55 , 286 ]. Epigenetic changes induced by the environment can alter the transcriptional activity of immune regulatory genes without changing the nucleotide sequence of DNA [ 54 , 287 , 288 ].…”

“…Diverse pathogens have been evaluated as the principal sources of environmentally-derived molecular mimics of self-antigens in autoimmune hepatitis [ 23 – 26 ], and vaccination [ 27 – 41 ] and the intestinal microbiome [ 25 , 26 , 42 – 47 ] have emerged as sources of antigens that could also promote autoimmunity by molecular mimicry. Molecular mimicry could be a mechanism that complements epigenetic transformations in shaping the autoreactive response to environmental stimuli [ 48 – 55 ].…”

Inflammasome and pyroptosis in autoimmune liver diseases

“…AIH is a group of conditions in which the body’s immune system attacks its own liver cells, leading to chronic liver damage ( 79 ). Previous studies have suggested that AIH involves T cells (in a T cell receptor independent manner) and activation of natural killer T (NKT) cells mediated by cytokines ( 80 ).…”

MicroRNAs: Small molecules with big impacts in liver injury

“…The intricacy of the underlying immunological processes is reflected in the diverse phenotypes of AIH (Isac et al, 2022). The observed risk of AIH surpasses the hereditary risk, and the discrepancy may be explained by epigenetic factors that change gene expression (Czaja, 2022). There have been few studies on the epigenetic changes in patients with AIH, and those that have been done have partially centered on the profile of circulating miRNAs (Migita et al, 2015).…”