Examining micro-ribonucleic acids as diagnostic and therapeutic prospects in autoimmune hepatitis

ABSTRACT

Introduction: Micro-ribonucleic acids modulate the immune response by affecting the post-transcriptional expression of genes that influence the proliferation and function of activated immune cells, including regulatory T cells. Individual expressions or patterns in peripheral blood and liver tissue may have diagnostic value, reflect treatment response, or become therapeutic targets. The goals of this review are to present the properties and actions of micro-ribonucleic acids, indicate the key individual expressions in autoimmune hepatitis, and describe prospective clinical applications in diagnosis and management.

Areas covered: Abstracts were identified in PubMed using the search words “microRNAs,” “microRNAs in liver disease,” and “microRNAs in autoimmune hepatitis.” The number of abstracts reviewed exceeded 2000, and the number of full-length articles reviewed was 108.

Expert opinion: Individual micro-ribonucleic acids, miR-21, miR-122, and miR-155, have been associated with biochemical severity, histological grade of inflammation, and pivotal pathogenic mechanisms in autoimmune hepatitis. Antisense oligonucleotides that down-regulate deleterious individual gene expressions, engineered molecules that impair targeting of gene products, and drugs that non-selectively up-regulate the biogenesis of potentially deficient gene regulators are feasible treatment options. Micro-ribonucleic acids constitute an under-evaluated area in autoimmune hepatitis that promises to improve diagnosis, pathogenic concepts, and therapy.

KEYWORDS:

• autoimmune hepatitis
• diagnosis
• gene silencing
• micro-ribonucleic acids
• pathogenesis
• therapeutic targets

Article highlights

• MiRNAs silence gene expression by inducing degradation of mRNA or by decreasing its translation by ribosomes (translational repression), and miRNAs can modulate the immune response in autoimmune hepatitis.

• MiRNAs can silence genes that promote or prevent pro-inflammatory immune responses, and the severity and outcome of autoimmune hepatitis may reflect the composite effect of multiple miRNAs with contradictory actions.

• Circulating miR-21 and miR-122 levels are increased in untreated autoimmune hepatitis, and miR-155 is preferentially expressed in liver tissue.

• MiR-21 is produced by lymphocytes, and blood levels correlate positively with laboratory and histological features of liver inflammation and negatively with the histological stage of fibrosis.

• MiR-122 is produced by hepatocytes, and blood levels correlate directly with laboratory indices of liver injury and inversely with stage of fibrosis, but not with histological grade of inflammation.

• MiR-155 is expressed in diverse cells, including hepatocytes, fibroblasts, and Tregs, and its over-expression in the liver may silence critical genes that suppress the immune response.

• Patterns of miR-21 and miR-122 may emerge as biomarkers of disease activity and treatment response in autoimmune hepatitis, and miR-155 may be recognized as a therapeutic target.

• Microarray analyses are needed to define the types and predominance of up-regulated and down-regulated miRNAs in autoimmune hepatitis to clarify their pathogenic contributions and formulate therapeutic interventions.

• Antisense oligonucleotides are the principal means of down-regulating over-expressed miRNAs, and non-selective drug therapies and selective transgene transfer are theoretical interventions for up-regulating or restoring deficient miRNA responses.

• Therapeutic manipulations of miRNA expression have not been approved for clinical use in autoimmune hepatitis, and their development must always be guided by a concern for unwanted and unexpected adverse events, especially since gene products are usually multifunctional and many are tumor suppressors.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.