Dysfunctional Immune Regulation in Autoimmune Hepatitis: From Pathogenesis to Novel Therapies

Vuerich, Marta; Wang, Na; Kalbasi, Ahmadreza; Graham, Jill; Longhi, Maria Serena

doi:10.3389/fimmu.2021.746436

Cited by 20 publications

(17 citation statements)

References 124 publications

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“…The imbalance between pro-inflammatory mechanisms and regulatory ones is presumed to play a pivotal role in the pathogenesis of autoimmune diseases in general and autoimmune hepatitis in particular 8788. The activities of the regulatory cells, Th1 cells, Th17/Th22 cells, activated macrophages, complement, and natural killer cells are all interconnected and finely tuned, and when such a system becomes dysfunctional, the autoimmune disorder may ensue 89.…”

Section: Pathogenesismentioning

confidence: 99%

Diagnosis and management of autoimmune hepatitis

Muratori

Lohse

Lenzi

2023

BMJ

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Autoimmune hepatitis is an inflammatory disease of the liver of unknown cause that may progress to liver cirrhosis and end stage liver failure if diagnosis is overlooked and treatment delayed. The clinical presentation is often that of acute hepatitis, sometimes very severe; less frequently, it can be insidious or completely asymptomatic. The disease can affect people of any age and is more common in women; its incidence and prevalence seem to be on the rise worldwide. An abnormal immune response targeting liver autoantigens and inducing persistent and self-perpetuating liver inflammation is the pathogenic mechanism of the disease. A specific set of autoantibodies, increased IgG concentrations, and histological demonstration of interface hepatitis and periportal necrosis are the diagnostic hallmarks of autoimmune hepatitis. Prompt response to treatment with corticosteroids and other immunomodulatory drugs is almost universal and supports the diagnosis. The aims of treatment are to induce and maintain long term remission of liver inflammation. Treatment can often even reverse liver fibrosis, thus preventing progression to advanced cirrhosis and its complications. Most patients need lifelong maintenance therapy, and repeated follow-up in experienced hands improves the quality of care and quality of life for affected patients.

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Section: Pathogenesismentioning

confidence: 99%

Diagnosis and management of autoimmune hepatitis

Muratori

Lohse

Lenzi

2023

BMJ

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“…The trigger underlying the switch towards an overwhelming immune response against autoantigens is still unknown. From an immunological view, the autoantigen presentation by conventional and unconventional liver APCs, the unsuccessful control of autoreactive T cells and the production of autoantibodies play a crucial role ( 43 , 44 ). Dysregulated Treg cells which are also susceptible to Fas ligand-mediated apoptosis can be observed within the liver of AIH patients ( 45 – 48 ).…”

Section: Initiation Of the Autoimmune Responsementioning

confidence: 99%

“…Treg cells are key players in autoimmune diseases including AIH. Functional impairment and altered frequency of Treg cells in AIH patients cause breakdown of self-tolerance mechanisms ( 46 ) with consequent beginning and progression of autoimmune liver injury ( 44 , 65 ). In patients with AIH, the frequency of circulating Treg cells and their ability to suppress T cell proliferation are lower than in healthy subjects, especially at diagnosis and during relapses than during drug-induced remission ( 66 – 68 ).…”

Section: Initiation Of the Autoimmune Responsementioning

confidence: 99%

“…Th1 cell differentiation results in the secretion of IL-2, INF-γ and TNF-α and in the activation of cytotoxic CD8 + T lymphocytes (CTLs) which, after interaction with antigens presented by the MHC class I-antigenic peptide complexes on hepatocytes, attack hepatocytes causing liver damage ( 10 , 74 , 75 ). INF-γ is a crucial mediator of tissue damage since it not only stimulates CD8 + T cells, increases the expression of MHC class I, and promotes aberrant expression of MHC class II molecules on hepatocytes, making them able to present antigens on their surface, thus enhancing T cell activation and perpetuating liver damage ( 44 ). Moreover, INF-γ activates monocytes/macrophages, which in turn release IL-1 and TNF-α ( 76 ) and enhances NK cell activity ( 77 ).…”

Section: Initiation Of the Autoimmune Responsementioning

confidence: 99%

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Impact of Antigen Presentation Mechanisms on Immune Response in Autoimmune Hepatitis

et al. 2022

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The liver is a very tolerogenic organ. It is continually exposed to a multitude of antigens and is able to promote an effective immune response against pathogens and simultaneously immune tolerance against self-antigens. In spite of strong peripheral and central tolerogenic mechanisms, loss of tolerance can occur in autoimmune liver diseases, such as autoimmune hepatitis (AIH) through a combination of genetic predisposition, environmental factors, and an imbalance in immunological regulatory mechanisms. The liver hosts several types of conventional resident antigen presenting cells (APCs) such as dendritic cells, B cells and macrophages (Kupffer cells), and unconventional APCs including liver sinusoidal endothelial cells, hepatic stellate cells and hepatocytes. By standard (direct presentation and cross-presentation) and alternative mechanisms (cross-dressing and MHC class II-dressing), liver APCs presents self-antigen to naive T cells in the presence of costimulation leading to an altered immune response that results in liver injury and inflammation. Additionally, the transport of antigens and antigen:MHC complexes by trogocytosis and extracellular vesicles between different cells in the liver contributes to enhance antigen presentation and amplify autoimmune response. Here, we focus on the impact of antigen presentation on the immune response in the liver and on the functional role of the immune cells in the induction of liver inflammation. A better understanding of these key pathogenic aspects could facilitate the establishment of novel therapeutic strategies in AIH.

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“…Unfortunately, there are currently no data available to this study ( ). Clearly such studies are aiming at the re-establishment of a healthy immune balance by enhancing the regulatory side, which has been shown to be impaired in patients with AIH ( 42 , 43 ). In contrast, the immune balance can also be restored by dampening the aggressive side via a direct targeting of activated, autoaggressive T cells.…”

Section: Are Therapies At a Standstill?mentioning

confidence: 99%

Animal Models for Autoimmune Hepatitis: Are Current Models Good Enough?

Christen

Hintermann

2022

Front. Immunol.

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Autoimmune liver diseases like autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and IgG4-related cholangitis are chronic inflammatory diseases of the liver with an autoimmune background. The therapy of autoimmune hepatitis targets the autoreactive immune system and is largely dependent on the use of glucocorticoids and cytostatic drugs. In contrast, the treatment of cholestatic autoimmune liver diseases is restricted to the use of secondary or semi-synthetic bile acids, like ursodeoxycholic acid or obeticholic acid. Although the management of the disease using such drugs works well for the majority of patients, many individuals do not respond to standard therapy. In addition, chronic treatment with glucocorticoids results in well-known side effects. Further, the use of bile acids is a symptomatic therapy that has no direct immunomodulatory effect. Thus, there is still a lot of room for improvement. The use of animal models has facilitated to elucidate the pathogenesis of autoimmune liver diseases and many potential target structures for immunomodulatory therapies have been identified. In this review, we will focus on autoimmune hepatitis for which the first animal models have been established five decades ago, but still a precise treatment for autoimmune hepatitis, as obtainable for other autoimmune diseases such as rheumatoid arthritis or multiple sclerosis has yet to be introduced. Thus, the question arises if our animal models are too far from the patient reality and thus findings from the models cannot be reliably translated to the patient. Several factors might be involved in this discrepancy. There is first and foremost the genetic background and the inbred status of the animals that is different from human patients. Here the use of humanized animals, such as transgenic mice, might reduce some of the differences. However, there are other factors, such as housing conditions, nutrition, and the microbiome that might also play an important role. This review will predominantly focus on the current status of animal models for autoimmune hepatitis and the possible ways to overcome discrepancies between model and patient.

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Dysfunctional Immune Regulation in Autoimmune Hepatitis: From Pathogenesis to Novel Therapies

Cited by 20 publications

References 124 publications

Diagnosis and management of autoimmune hepatitis

Diagnosis and management of autoimmune hepatitis

Impact of Antigen Presentation Mechanisms on Immune Response in Autoimmune Hepatitis

Animal Models for Autoimmune Hepatitis: Are Current Models Good Enough?

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