Cellular senescence and its pathogenic and therapeutic implications in autoimmune hepatitis.

Introduction: Senescent cells are characterized by replicative arrest and phenotypes that produce diverse pro-inflammatory and pro-oxidant mediators. The senescence of diverse hepatic cell types could constitute an unrecognized pathogenic mechanism and prognostic determinant in autoimmune hepatitis. The impact of cellular senescence in autoimmune hepatitis is unknown, and it may suggest adjunctive management strategies.

Easy recognition and high autoimmune hepatitis specificity of smooth muscle antibodies giving an actin microfilament immunofluorescent pattern on embryonal vascular smooth muscle cells.

Smooth muscle antibodies (SMA) with anti-microfilament actin (MF-SMA) specificity are regarded as highly specific markers of type 1 autoimmune hepatitis (AIH-1) but their recognition relying on immunofluorescence of vessel, glomeruli, and tubules (SMA-VGT pattern) in rodent kidney tissue, is restricted by operator-dependent interpretation. A gold standard method for their identification is not available. We assessed and compared the diagnostic accuracy for AIH-1 of an embryonal aorta vascular smooth muscle (VSM) cell line-based assay with those of the rodent tissue-based assay for the detection of MF-SMA pattern in AIH-1 patients and controls.

Introducing Molecular Chaperones into the Causality and Prospective Management of Autoimmune Hepatitis.

Molecular chaperones influence the immunogenicity of peptides and the activation of effector T cells, and their pathogenic roles in autoimmune hepatitis are unclear. Heat shock proteins are pivotal in the processing and presentation of peptides that activate CD8 T cells. They can also induce regulatory B and T cells and promote immune tolerance.

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

Molecular mimicry between foreign and self-antigens has been implicated as a cause of autoimmune hepatitis in experimental models and cross-reacting antibodies in patients. This review describes the experimental and clinical evidence for molecular mimicry as a cause of autoimmune hepatitis, indicates the limitations and uncertainties of this premise, and encourages investigations that assess diverse environmental antigens as sources of disease-relevant molecular mimics. Pertinent articles were identified in PubMed using multiple search phrases.

Missing Causality and Heritability of Autoimmune Hepatitis.

Background: Autoimmune hepatitis has an unknown cause and genetic associations that are not disease-specific or always present. Clarification of its missing causality and heritability could improve prevention and management strategies.

Aims: Describe the key epigenetic and genetic mechanisms that could account for missing causality and heritability in autoimmune hepatitis; indicate the prospects of these mechanisms as pivotal factors; and encourage investigations of their pathogenic role and therapeutic potential.

Epigenetic Aspects and Prospects in Autoimmune Hepatitis.

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.

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

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.

Advancing Biologic Therapy for Refractory Autoimmune Hepatitis.

Biologic agents may satisfy an unmet clinical need for treatment of refractory autoimmune hepatitis. The goals of this review are to present the types and results of biologic therapy for refractory autoimmune hepatitis, indicate opportunities to improve and expand biologic treatment, and encourage comparative clinical trials. English abstracts were identified in PubMed by multiple search terms.

Review article: targeting the B cell activation system in autoimmune hepatitis.

Background: The B cell activation system, consisting of B cell activating factor and a proliferation-inducing ligand, may have pathogenic effects in autoimmune hepatitis.

Aims: To describe the biological actions of the B cell activation system, indicate its possible role in autoimmune diseases, and evaluate its prospects as a therapeutic target in autoimmune hepatitis METHODS: English abstracts were identified in PubMed by multiple search terms. Full length articles were selected for review, and secondary and tertiary bibliographies were developed.

Incorporating mucosal-associated invariant T cells into the pathogenesis of chronic liver disease.

Mucosal-associated invariant T (MAIT) cells have been described in liver and non-liver diseases, and they have been ascribed antimicrobial, immune regulatory, protective, and pathogenic roles. The goals of this review are to describe their biological properties, indicate their involvement in chronic liver disease, and encourage investigations that clarify their actions and therapeutic implications. English abstracts were identified in PubMed by multiple search terms, and bibliographies were developed.

Immune Inhibitory Properties and Therapeutic Prospects of Transforming Growth Factor-Beta and Interleukin 10 in Autoimmune Hepatitis.

Transforming growth factor-beta and interleukin 10 have diverse immune inhibitory properties that have restored homeostatic defense mechanisms in experimental models of autoimmune disease. The goals of this review are to describe the actions of each cytokine, review their investigational use in animal models and patients, and indicate their prospects as interventions in autoimmune hepatitis. English abstracts were identified in PubMed by multiple search terms.

Exploring the Pathogenic Role and Therapeutic Implications of Interleukin 2 in Autoimmune Hepatitis.

Interleukin 2 is essential for the expansion of regulatory T cells, and low-dose recombinant interleukin 2 has improved the clinical manifestations of diverse autoimmune diseases in preliminary studies. The goals of this review are to describe the actions of interleukin 2 and its receptor, present preliminary experiences with low-dose interleukin 2 in the treatment of diverse autoimmune diseases, and evaluate its potential as a therapeutic intervention in autoimmune hepatitis. English abstracts were identified in PubMed by multiple search terms.

Review article: opportunities to improve and expand thiopurine therapy for autoimmune hepatitis.

Background: Thiopurines in combination with glucocorticoids are used as first-line, second-line and maintenance therapies in autoimmune hepatitis and opportunities exist to improve and expand their use.

Aims: To describe the metabolic pathways and key factors implicated in the efficacy and toxicity of the thiopurine drugs and to indicate the opportunities to improve outcomes by monitoring and manipulating metabolic pathways, individualising dosage and strengthening the response.

Methods: English abstracts were identified in PubMed by multiple search terms.

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

Multiple pathogenic mechanisms have been implicated in autoimmune hepatitis, but they have not fully explained susceptibility, triggering events, and maintenance or escalation of the disease. Furthermore, they have not identified a critical defect that can be targeted. The goals of this review are to examine the diverse pathogenic mechanisms that have been considered in autoimmune hepatitis, indicate investigational opportunities to validate their contribution, and suggest interventions that might evolve to modify their impact.

Immune inhibitory proteins and their pathogenic and therapeutic implications in autoimmunity and autoimmune hepatitis.

Key inhibitory proteins can blunt immune responses to self-antigens, and deficiencies in this repertoire may promote autoimmunity. The goals of this review are to describe the key immune inhibitory proteins, indicate their possible impact on the development of autoimmune disease, especially autoimmune hepatitis, and encourage studies to clarify their pathogenic role and candidacy as therapeutic targets. English abstracts were identified in PubMed by multiple search terms.

Review article: iron disturbances in chronic liver diseases other than haemochromatosis - pathogenic, prognostic, and therapeutic implications.

Background: Disturbances in iron regulation have been described in diverse chronic liver diseases other than hereditary haemochromatosis, and iron toxicity may worsen liver injury and outcome.

Aims: To describe manifestations and consequences of iron dysregulation in chronic liver diseases apart from hereditary haemochromatosis and to encourage investigations that clarify pathogenic mechanisms, define risk thresholds for iron toxicity, and direct management METHODS: English abstracts were identified in PubMed by multiple search terms. Full length articles were selected for review, and secondary and tertiary bibliographies were developed.

Severe vitamin D deficiency is a prognostic biomarker in autoimmune hepatitis.

Background: Vitamin D deficiency has been implicated in the outcome of chronic liver disease.

Aim: To determine the frequency of severe vitamin D deficiency in autoimmune hepatitis (AIH), assess its association with treatment non-response, and evaluate the relationship between vitamin D status and liver-related mortality and need for transplantation.

Methods: Two hundred and nine patients were evaluated by liver tissue examination at presentation.