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. Sera from 138 AIH-1 patients and 295 controls (105 primary biliary cholangitis,40 primary sclerosing cholangitis,50 chronic viral hepatitis,20 alcohol-related liver disease,40 steatotic liver disease,and 40 healthy controls) were assayed for MF-SMA and for SMA-VGT using VSM-based and rodent tissue-based assays, respectively. MF-SMA and SMA-VGT were found in 96(70%) and 87(63%) AIH-1 patients, and 2 controls (p<0.0001).Compared with SMA-VGT, MF-SMA showed similar specificity (99%), higher sensitivity (70% vs 63%,p=ns) and likelihood ratio for a positive test (70 vs 65). Nine (7%) AIH-1 patients were MF-SMA positive despite being SMA-VGT negative. Overall agreement between SMA-VGT and MF-SMA was 87% (kappa coefficient 0.870,[0.789-0.952]). MF-SMA were associated with higher serum γ-globulin [26(12-55) vs 20 g/l(13-34),p<0.005] and immunoglobulin G (IgG) levels [3155(1296-7344) vs 2050 mg/dl(1377-3357), p<0.002]. The easily recognizable IFL MF-SMA pattern on VSM cells strongly correlated with SMA-VGT and has an equally high specificity for AIH-1. Confirmation of these results in other laboratories would support the clinical application of the VSM cell-based assay for reliable detection of AIH-specific SMA.

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. METHODS: English abstracts were identified in PubMed using multiple key search phases. Several hundred abstracts and 210 full-length articles were reviewed. RESULTS: Environmental induction of epigenetic changes is the prime candidate for explaining the missing causality of autoimmune hepatitis. Environmental factors (diet, toxic exposures) can alter chromatin structure and the production of micro-ribonucleic acids that affect gene expression. Epistatic interaction between unsuspected genes is the prime candidate for explaining the missing heritability. The non-additive, interactive effects of multiple genes could enhance their impact on the propensity and phenotype of autoimmune hepatitis. Transgenerational inheritance of acquired epigenetic marks constitutes another mechanism of transmitting parental adaptations that could affect susceptibility. Management strategies could range from lifestyle adjustments and nutritional supplements to precision editing of the epigenetic landscape. CONCLUSIONS: Autoimmune hepatitis has a missing causality that might be explained by epigenetic changes induced by environmental factors and a missing heritability that might reflect epistatic gene interactions or transgenerational transmission of acquired epigenetic marks. These unassessed or under-evaluated areas warrant investigation.

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. Tapasin and the transporter associated with antigen processing-binding protein influence the editing and loading of high-affinity peptides for presentation by class I molecules of the major histocompatibility complex. Their over-expression could enhance the autoimmune response, and their deficiency could weaken it. The lysosome-associated membrane protein-2a isoform in conjunction with heat shock cognate 70 supports the importation of cytosolic proteins into lysosomes. Chaperone-mediated autophagy can then process the peptides for activation of CD4+ T cells. Over-expression of autophagy in T cells may also eliminate negative regulators of their activity. The human leukocyte antigen B-associated transcript three facilitates the expression of class II peptide receptors, inhibits T cell apoptosis, prevents T cell exhaustion, and sustains the immune response. Immunization with heat shock proteins has induced immune tolerance in experimental models and humans with autoimmune disease by inducing regulatory T cells. Therapeutic manipulation of other molecular chaperones may promote T cell exhaustion and induce tolerogenic dendritic cells. In conclusion, molecular chaperones constitute an under-evaluated family of ancillary proteins that could affect the occurrence, severity, and outcome of autoimmune hepatitis. Clarification of their contributions to the immune mechanisms and clinical activity of autoimmune hepatitis could have therapeutic implications.

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. Several pathogens have linear or conformational epitopes that mimic the self-antigens of autoimmune hepatitis. The occurrence of an acute immune-mediated hepatitis after vaccination for severe acute respiratory syndrome (SARS)-associated coronavirus 2 (SARS-CoV-2) has suggested that vaccine-induced peptides may mimic disease-relevant tissue antigens. The intestinal microbiome is an under-evaluated source of gut-derived antigens that could also engage in molecular mimicry. Chaperone molecules may enhance the pathogenicity of molecular mimics, and they warrant investigation. Molecular mimics of immune dominant epitopes within cytochrome P450 IID6, the autoantigen most closely associated with autoimmune hepatitis, should be sought in diverse environmental antigens and assessed for pathogenicity. Avoidance strategies, dietary adjustments, vaccine improvement, and targeted manipulation of the intestinal microbiota may emerge as therapeutic possibilities. In conclusion, molecular mimicry may be a missing causality of autoimmune hepatitis. Molecular mimics of key immune dominant epitopes of disease-specific antigens must be sought in diverse environmental antigens. The ubiquity of molecular mimicry compels rigorous assessments of peptide mimics for immunogenicity and pathogenicity in experimental models. Molecular mimicry may complement epigenetic modifications as causative mechanisms of autoimmune hepatitis.

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. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Transforming growth factor-beta expands the natural and inducible populations of regulatory T cells, limits the proliferation of natural killer cells, suppresses the activation of naïve CD8+ T cells, decreases the production of interferon-gamma, and stimulates fibrotic repair. Interleukin 10 selectively inhibits the CD28 co-stimulatory signal for antigen recognition and impairs antigen-specific activation of uncommitted CD4+ and CD8+ T cells. It also inhibits maturation of dendritic cells, suppresses Th17 cells, supports regulatory T cells, and limits production of diverse pro-inflammatory cytokines. Contradictory immune stimulatory effects have been associated with each cytokine and may relate to the dose and accompanying cytokine milieu. Experimental findings have not translated into successful early clinical trials. The recombinant preparation of each agent in low dosage has been safe in human studies. In conclusion, transforming growth factor-beta and interleukin 10 have powerful immune inhibitory actions of potential therapeutic value in autoimmune hepatitis. The keys to their therapeutic application will be to match their predominant non-redundant function with the pivotal pathogenic mechanism or cytokine deficiency and to avoid contradictory immune stimulatory actions.

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. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Rituximab (monoclonal antibodies against CD20 on B cells), infliximab (monoclonal antibodies against tumor necrosis factor-alpha), low-dose recombinant interleukin 2 (regulatory T cell promoter), and belimumab (monoclonal antibodies against B cell activating factor) have induced laboratory improvement in small cohorts with refractory autoimmune hepatitis. Ianalumab (monoclonal antibodies against the receptor for B cell activating factor) is in clinical trial. These agents target critical pathogenic pathways, but they may also have serious side effects. Blockade of the B cell activating factor or its receptors may disrupt pivotal B and T cell responses, and recombinant interleukin 2 complexed with certain interleukin 2 antibodies may selectively expand the regulatory T cell population. A proliferation-inducing ligand that enhances T cell proliferation and survival is an unevaluated, potentially pivotal, therapeutic target. Fully human antibodies, expanded target options, improved targeting precision, more effective delivery systems, and biosimilar agents promise to improve efficacy, safety, and accessibility. In conclusion, biologic agents target key pathogenic pathways in autoimmune hepatitis, and early experiences in refractory disease encourage clarification of the preferred target, rigorous clinical trial, and comparative evaluations.

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. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Interleukin 2 is critical for the thymic selection, peripheral expansion, induction, and survival of regulatory T cells, and it is also a growth factor for activated T cells and natural killer cells. Interleukin 2 activates the signal transducer and activator of transcription 5 after binding with its trimeric receptor on regulatory T cells. Immune suppressor activity is increased; anti-inflammatory interleukin 10 is released; pro-inflammatory interferon-gamma is inhibited; and activation-induced apoptosis of CD8+ T cells is upregulated. Preliminary experiences with cyclic injections of low-dose recombinant interleukin 2 in diverse autoimmune diseases have demonstrated increased numbers of circulating regulatory T cells, preserved regulatory function, improved clinical manifestations, and excellent tolerance. Similar improvements have been recognized in one of two patients with refractory autoimmune hepatitis. In conclusion, interferon 2 has biological actions that favor the immune suppressor functions of regulatory T cells, and low-dose regimens in preliminary studies encourage its rigorous investigation in autoimmune hepatitis.

Recurrent and De Novo Autoimmune Hepatitis.

Clinical indications for liver transplantation (LT) in patients with autoimmune hepatitis (AIH) are identical to those of patients with other chronic liver diseases that end in acute or semiacute liver failure, decompensated cirrhosis, or hepatocellular carcinoma. Recurrent disease after LT has been reported in 10%-50% of patients with AIH, and the frequency of detection is influenced in part by the use of protocol or clinically indicated liver biopsy. De novo AIH connotes the development of AIH in patients transplanted for liver diseases other than AIH, and it has been reported in 5%-10% of pediatric and 1%-2% of adult recipients. Recurrent disease can negatively impact on graft and patient survival, and retransplantation has been required in 8%-23%. De novo AIH is within the spectrum of graft dysfunction that includes plasma cell-rich rejection, and it can also progress to cirrhosis and graft failure. Treatment for recurrent or de novo disease is based on the conventional regimens for AIH, and corticosteroid therapy alone or combined with azathioprine is standard. Better control of disease activity prior to LT has been associated with less recurrence, and maintenance corticosteroid treatment after LT can reduce its frequency. In conclusion, recurrent AIH is far more frequent than de novo AIH. Both may have negative impacts on graft and patient survival, and early detection and treatment are key objectives. Future investigations must codify the diagnostic criteria for each graft dysfunction, seek diagnostic biomarkers, and evaluate treatments that improve outcomes without increasing the risk of pre- and post-LT infections.

Evolving Role of Vitamin D in Immune-Mediated Disease and Its Implications in Autoimmune Hepatitis.

Vitamin D has immunomodulatory, anti-inflammatory, antioxidant, and anti-fibrotic actions that may impact on the occurrence and outcome of immune-mediated disease. The goals of this review are to describe the nature of these expanded roles, examine the implications of vitamin D deficiency in autoimmune hepatitis, and identify opportunities for future investigation. Abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Vitamin D receptors are expressed on the principal cell populations involved in the innate and adaptive immune responses. Macrophages and dendritic cells can produce 1,25-dihydroxyvitamin D within the microenvironment. This active form of vitamin D can inhibit immune cell proliferation, promote an anti-inflammatory cytokine profile, expand regulatory T cells, enhance glucocorticoid actions, increase glutathione production, and inhibit hepatic stellate cells. Vitamin D deficiency has been commonly present in patients with immune-mediated liver and non-liver diseases, and it has been associated with histological severity, advanced hepatic fibrosis, and non-response to conventional glucocorticoid therapy in autoimmune hepatitis. Vitamin D analogues with high potency, low calcemic effects, and independence from hepatic hydroxylation are possible interventions. In conclusion, vitamin D has properties that could ameliorate immune-mediated disease, and vitamin D deficiency has been a common finding in immune-mediated liver and non-liver diseases, including autoimmune hepatitis. Loss of vitamin D-dependent homeostatic mechanisms may promote disease progression. Vitamin D analogues that are independent of hepatic hydroxylation constitute an investigational opportunity to supplement current management of autoimmune hepatitis.

Epigenetic changes and their implications in autoimmune hepatitis.

BACKGROUND: The genetic risk of autoimmune hepatitis is insufficient to explain the observed risk, and epigenetic changes may explain disparities in disease occurrence in different populations within and between countries. The goal of this review was to examine how epigenetic changes induced by the environment or inherited as a phenotypic trait may affect autoimmune hepatitis and be amenable to therapeutic intervention. MATERIALS AND METHODS: Pertinent abstracts were identified in PubMed by multiple search terms. The number of abstracts reviewed was 1689, and the number of full-length articles reviewed exceeded 150. RESULTS: Activation of pro-inflammatory genes in autoimmune disease is associated with hypomethylation of deoxyribonucleic acid and modification of histones within chromatin. Organ-specific microribonucleic acids can silence genes by marking messenger ribonucleic acids for degradation, and they can promote inflammatory activity or immunosuppression. High circulating levels of the microribonucleic acids 21 and 122 have been demonstrated in autoimmune hepatitis, and they may increase production of pro-inflammatory cytokines. Microribonucleic acids are also essential for maintaining regulatory T cells. Drugs, pollutants, infections, diet and ageing can induce inheritable epigenetic changes favouring autoimmunity. Reversal is feasible by manipulating enzymes, transcription factors, gene-silencing molecules and toxic exposures or by administering methyl donors and correcting vitamin D deficiency. Gene targets, site specificity, efficacy and consequences are uncertain. CONCLUSIONS: Potentially reversible epigenetic changes may affect the occurrence and outcome of autoimmune hepatitis, and investigations are warranted to determine the nature of these changes, key genomic targets, and feasible interventions and their consequences.

Under-Evaluated or Unassessed Pathogenic Pathways in Autoimmune Hepatitis and Implications for Future Management.

Autoimmune hepatitis is a consequence of perturbations in homeostatic mechanisms that maintain self-tolerance but are incompletely understood. The goals of this review are to describe key pathogenic pathways that have been under-evaluated or unassessed in autoimmune hepatitis, describe insights that may shape future therapies, and encourage investigational efforts. The T cell immunoglobulin mucin proteins constitute a family that modulates immune tolerance by limiting the survival of immune effector cells, clearing apoptotic bodies, and expanding the population of granulocytic myeloid-derived suppressor cells. Galectins influence immune cell migration, activation, proliferation, and survival, and T cell exhaustion can be induced and exploited as a possible management strategy. The programmed cell death-1 protein and its ligands comprise an antigen-independent inhibitory axis that can limit the performance of activated T cells by altering their metabolism, and epigenetic changes can silence pro-inflammatory genes or de-repress anti-inflammatory genes that affect disease severity. Changes in the intestinal microbiota and permeability of the intestinal mucosal barrier can be causative or consequential events that affect the occurrence and phenotype of immune-mediated disease, and they may help explain the female propensity for autoimmune hepatitis. Perturbations within these homeostatic mechanisms have been implicated in experimental models and limited clinical experiences, and they have been favorably manipulated by monoclonal antibodies, recombinant molecules, pharmacological agents or dietary supplements. In conclusion, pathogenic mechanisms that have been implicated in other systemic immune-mediated and liver diseases but under-evaluated or unassessed in autoimmune hepatitis warrant consideration and rigorous evaluation.

Global Disparities and Their Implications in the Occurrence and Outcome of Autoimmune Hepatitis.

Autoimmune hepatitis has a variable occurrence, clinical phenotype, and outcome, and the factors contributing to this variability are uncertain. The goals of this review are to examine the global disparities in the occurrence and outcome of autoimmune hepatitis, suggest bases for these disparities, and encourage investigations that extend beyond single-center experiences. Disparities in the incidence and prevalence of autoimmune hepatitis in different age groups, genders, ethnicities, and geographical regions suggest that factors other than genetic predisposition are involved. Age- and gender-related antigen exposures from the external (infections, toxins, and medications) and internal (intestinal microbiome) environment may affect the incidence of the disease, and the timeliness and nature of treatment may influence its prevalence. The increasing incidence of autoimmune hepatitis in Spain, Denmark, and the Netherlands suggests that a new etiological trigger has been introduced or that the susceptible population has changed. Variations in mortality between Western and Asian-Pacific countries may result from differences in disease detection or management, and variations in gender predilection, peak age of onset, frequency of concurrent immune diseases, and serological profile may reflect gender-biased and age-related antigen exposures and genetic predispositions. Global collaborations, population-based epidemiological studies that identify case clustering, and controlled interview-based surveys are mechanisms by which to understand these disparities and improve management. In conclusion, autoimmune hepatitis has a rising incidence in some countries and variable occurrence, phenotype, and outcome between countries and subgroups within countries. These disparities suggest that unrecognized population-based environmental, infectious, or socioeconomic factors are affecting its character.

Nature and Implications of Oxidative and Nitrosative Stresses in Autoimmune Hepatitis.

Oxidative and nitrosative stresses can damage cellular membranes, disrupt mitochondrial function, alter gene expression, promote the apoptosis and necrosis of hepatocytes, and increase fibrosis in diverse acute and chronic liver diseases, including autoimmune hepatitis. The objectives of this review are to describe the mechanisms of oxidative and nitrosative stresses in inflammatory liver disease, indicate the pathogenic implications of these stresses in autoimmune hepatitis, and suggest investigational opportunities to develop interventions that counter them. The principal antioxidant defenses, including glutathione production, the activities of antioxidant enzymes, and the release of the nuclear factor erythroid 2-related factor 2, may be inadequate or suppressed by transforming growth factor beta. The generation of reactive oxygen species can intensify nitrosative stress, and this stress may not be adequately modulated by the thioredoxin-thioredoxin reductase system and induce post-translational modifications of proteins that further disrupt hepatocyte function. The unfolded protein response and autophagy may be unable to restore redox stability, meet metabolic demands, and maintain hepatocyte survival. Emerging interventions with highly selective site- and organelle-specific actions may improve outcomes, and they include inhibitors of nicotinamide adenine dinucleotide phosphate oxidase, nitric oxide synthase, and transforming growth factor beta. Pharmacological manipulation of nuclear transcription factors may favor expression of antioxidant genes, and stimulation of chaperone proteins within the endoplasmic reticulum and modulation of autophagy may prevent hepatic fibrosis and enhance cell survival. These interventions constitute investigational opportunities to improve the management of autoimmune hepatitis.

Targeting Hepatic Fibrosis in Autoimmune Hepatitis.

Hepatic fibrosis develops or progresses in 25 % of patients with autoimmune hepatitis despite corticosteroid therapy. Current management regimens lack reliable noninvasive methods to assess changes in hepatic fibrosis and interventions that disrupt fibrotic pathways. The goals of this review are to indicate promising noninvasive methods to monitor hepatic fibrosis in autoimmune hepatitis and identify anti-fibrotic interventions that warrant evaluation. Laboratory methods can differentiate cirrhosis from non-cirrhosis, but their accuracy in distinguishing changes in histological stage is uncertain. Radiological methods include transient elastography, acoustic radiation force impulse imaging, and magnetic resonance elastography. Methods based on ultrasonography are comparable in detecting advanced fibrosis and cirrhosis, but their performances may be compromised by hepatic inflammation and obesity. Magnetic resonance elastography has excellent performance parameters for all histological stages in diverse liver diseases, is uninfluenced by inflammatory activity or body habitus, has been superior to other radiological methods in nonalcoholic fatty liver disease, and may emerge as the preferred instrument to evaluate fibrosis in autoimmune hepatitis. Promising anti-fibrotic interventions are site- and organelle-specific agents, especially inhibitors of nicotinamide adenine dinucleotide phosphate oxidases, transforming growth factor beta, inducible nitric oxide synthase, lysyl oxidases, and C-C chemokine receptors types 2 and 5. Autoimmune hepatitis has a pro-fibrotic propensity, and noninvasive radiological methods, especially magnetic resonance elastography, and site- and organelle-specific interventions, especially selective antioxidants and inhibitors of collagen cross-linkage, may emerge to strengthen current management strategies.

Transitioning from Idiopathic to Explainable Autoimmune Hepatitis.

Autoimmune hepatitis lacks an identifiable cause, and its diagnosis requires the exclusion of etiologically defined diseases that resemble it. Insights into its pathogenesis are moving autoimmune hepatitis from an idiopathic to explainable disease, and the goal of this review is to describe the insights that are hastening this transition. Two types of autoimmune hepatitis are justified by serological markers, but they also have distinctive genetic associations (DRB1 and DQB1 genes) and autoantigens. DRB1 alleles are the principal susceptibility factors in white adults, and a six amino acid sequence encoded in the antigen-binding groove of class II molecules of the major histocompatibility complex can influence the selection of autoantigens. Polymorphisms, including variants of SH2B3 and CARD10 genes, may affect immune reactivity and disease severity. The cytochrome mono-oxygenase, CYP2D6, is the autoantigen associated with type 2 autoimmune hepatitis, and it shares homologies with multiple viruses that might promote self-intolerance by molecular mimicry. Chemokines, especially CXCL9 and CXCL10, orchestrate the migration of effector cells to sites of injury and are associated with disease severity. Cells of the innate and adaptive immune responses promote tissue damage, and possible deficiencies in the number and function of regulatory T cells may facilitate the injurious process. Receptor-mediated apoptosis is the principal mechanism of hepatocyte loss, and cell-mediated and antibody-dependent mechanisms of cytotoxicity also contribute. Insights that explain autoimmune hepatitis will allow triggering exogenous antigens to be characterized, risk management to be improved, prognostic indices to be refined, and site-specific therapeutic interventions to emerge.

Cell mediators of autoimmune hepatitis and their therapeutic implications.

Autoimmune hepatitis is associated with interactive cell populations of the innate and adaptive immune systems, and these populations are amenable to therapeutic manipulation. The goals of this review are to describe the key cell populations implicated in autoimmune hepatitis and to identify investigational opportunities to develop cell-directed therapies for this disease. Studies cited in PubMed from 1972 to 2014 for autoimmune hepatitis, innate and adaptive immune systems, and therapeutic interventions were examined. Dendritic cells can promote immune tolerance to self-antigens, present neo-antigens that enhance the immune response, and expand the regulatory T cell population. Natural killer cells can secrete pro-inflammatory and anti-inflammatory cytokines and modulate the activity of dendritic cells and antigen-specific T lymphocytes. T helper 2 lymphocytes can inhibit the cytotoxic activities of T helper 1 lymphocytes and limit the expansion of T helper 17 lymphocytes. T helper 17 lymphocytes can promote inflammatory activity, and they can also up-regulate genes that protect against oxidative stress and hepatocyte apoptosis. Natural killer T cells can expand the regulatory T cell population; gamma delta lymphocytes can secrete interleukin-10, stimulate hepatic regeneration, and induce the apoptosis of hepatic stellate cells; and antigen-specific regulatory T cells can dampen immune cell proliferation and function. Pharmacological agents, neutralizing antibodies, and especially the adoptive transfer of antigen-specific regulatory T cells that have been freshly generated ex vivo are evolving as management strategies. The cells within the innate and adaptive immune systems are key contributors to the occurrence of autoimmune hepatitis, and they are attractive therapeutic targets.

Cholestatic phenotypes of autoimmune hepatitis.

Autoimmune hepatitis can have cholestatic features that are outside the codified diagnostic criteria. These features have uncertain effects on the clinical presentation and progression of disease. Patients with autoimmune hepatitis can have antimitochondrial antibodies and coincidental bile duct injury or loss (2%-13% of patients), focal biliary strictures and dilations based on cholangiography (2%-11%), or histologic changes of bile duct injury or loss in the absence of other features (5%-11%). These findings probably represent atypical manifestations of autoimmune hepatitis or variants of primary biliary cirrhosis or primary sclerosing cholangitis, depending on the predominant findings. Serum levels of alkaline phosphatase and γ-glutamyl transferase, histologic features of bile duct injury, and findings from cholangiography are associated with responsiveness to corticosteroid therapy and individualized alternative treatments. Corticosteroid therapy, in combination with low-dose ursodeoxycholic acid, has been promulgated by international societies, but these recommendations are not based on strong evidence. The frequency, variable outcomes, and uncertainties in diagnosis and management of the cholestatic phenotypes must be addressed by a collaborative investigational network. This network should define the genetic and pathologic features of these disorders, standardize their nomenclature, and establish a treatment algorithm. In this review, the different cholestatic phenotypes of autoimmune hepatitis, mechanisms of pathogenesis, current management strategies and outcomes, and opportunities for improving understanding and therapy are presented.

Targeting apoptosis in autoimmune hepatitis.

Apoptosis is the predominant mechanism of liver cell death in autoimmune hepatitis, and interventions that can modulate this activity are emerging. The aim of this review was to describe the apoptotic mechanisms, possible aberrations, and opportunities for intervention in autoimmune hepatitis. Studies cited in PubMed from 1972 to 2014 for autoimmune hepatitis, apoptosis in liver disease, apoptosis mechanisms, and apoptosis treatment were examined. Apoptosis is overactive in autoimmune hepatitis, and the principal pathway of cell death is receptor mediated. Surface death receptors are activated by extrinsic factors including liver-infiltrating cytotoxic T cells and the cytokine milieu. The executioner caspases 3 and 7 cleave nuclear deoxyribonucleic acid, and the release of apoptotic bodies can stimulate inflammatory, immune, and fibrotic responses. Changes in mitochondrial membrane permeability can be initiated by caspase 8, and an intrinsic pathway of apoptosis can complement the extrinsic pathway. Defects in the apoptosis of activated effector cells can prolong their survival and sustain the immune response. Caspase inhibitors have been used in diverse experimental and human diseases to retard apoptosis. Oligonucleotides that inhibit the signaling of toll-like receptors can limit the presentation of auto-antigens, and inhibitors of apoptosis that extend the survival of effector cells can be blocked by antisense oligonucleotides. Mechanisms that enhance the clearance of apoptotic bodies and affect key signaling pathways are also feasible. Interventions that influence the survival of liver and effector cells by altering their apoptosis are candidates for study in autoimmune hepatitis.