Immunopathogenic Mechanisms of Autoimmune Hepatitis: How Much Do We Know from Animal Models?

Christen, Urs; Hintermann, Edith

doi:10.3390/ijms17122007

Cited by 34 publications

(24 citation statements)

References 125 publications

(197 reference statements)

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“…The latter is mainly a pediatric condition and has a higher risk of acute liver failure [7]. AIH is a worldwide health problem and a significant cause of mortality; it has been estimated that AIH has an annual incidence of approximately 2 in 100, 000 individuals and a prevalence of 15 cases per 100, 000 persons worldwide [8]. Without treatment, nearly 50% of patients with severe AIH die in approximately 5 years [9, 10].…”

Section: Introductionmentioning

confidence: 99%

“…Animal models are needed to elucidate the early pathogenic events in this process, namely, the priming of autoreactive T cells [16]. Many animal models for AIH have been developed since the early 1970s [8]. The early models of AIH were based on the administration of crude liver homogenates of heterologous origin and complete Freund’s adjuvant, with no knowledge of the target antigens responsible for the disease [8, 17, 18].…”

Section: Introductionmentioning

confidence: 99%

“…Many animal models for AIH have been developed since the early 1970s [8]. The early models of AIH were based on the administration of crude liver homogenates of heterologous origin and complete Freund’s adjuvant, with no knowledge of the target antigens responsible for the disease [8, 17, 18]. The second phase began in 1983 when Kuriki et al established transient hepatitis in mice by immunizing them with syngeneic liver homogenates or liver-specific lipoproteins with polysaccharides from Klebsiella pneumonia [19].…”

Section: Introductionmentioning

confidence: 99%

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Comparison of Concanavalin a-Induced Murine Autoimmune Hepatitis Models

Wang

Yang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Autoimmune hepatitis (AIH) is a chronic necroinflammatory disease of the liver whose pathogenic mechanisms have not yet been elucidated. Moreover, the current treatment used for the vast majority of AIH patients is largely dependent on immunosuppressant administration and liver transplantation. However, research on the pathogenesis of AIH and effective new treatments for AIH have been hampered by a lack of animal models that accurately reproduce the human condition. Methods: AIH models created by concanavalin A (ConA) injections at different times and doses. The levels of ALT, AST, LDH and inflammatory cytokines were examined at various times after 20 mg/kg ConA was administered by ELISA using commercially available kits. Moreover, liver pathological changes were observed by flow cytometry (FCM) and H&E staining. Results: Our experiments demonstrated that the levels of ALT, AST, LDH and several inflammatory cytokines, including TNF-α, IFN-γ, and IL-6, were higher in the 20 mg/kg 12 h ConA group than in the other groups. Importantly, the numbers of activated CD4⁺ and CD8⁺ T lymphocytes in the blood, spleen and liver were calculated. These results showed that ConA (20 mg/kg for 12 h)-induced hepatitis was similar to that in clinical AIH patients. Furthermore, we found that the number of MDSCs in the blood was significantly increased in the ConA (20 mg/kg for 12 h) group compared with controls. Our findings indicated that ConA (20 mg/kg for 12 h)-induced hepatitis could be used as an experimental murine model that mirrors most of the pathogenic properties of human type I AIH. Conclusion: This model [ConA (20 mg/kg for 12 h)] provides a valuable tool for studying AIH immunopathogenesis and rapidly assessing novel therapeutic approaches.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comparison of Concanavalin a-Induced Murine Autoimmune Hepatitis Models

Wang

Yang

et al. 2018

Cell Physiol Biochem

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“…This fact supports the hypothesis of treating patients with autologous Tregs expanded ex vivo and may lead to tolerance to hepatic antigens during the development of chronic disease, with remission of the clinical signs and symptoms of AIH. The use of IL-2 for Treg expansion in vivo is an option for treatment in patients with reduced Treg numbers [82][83][84].…”

Section: Autoimmune Hepatitis and Systemic Lupus Erythematosusmentioning

confidence: 99%

Regulatory T Lymphocytes (Treg): Modulation and Clinical Application

Reichert¹,

Cunha²,

Levy³

et al. 2017

Lymphocyte Updates - Cancer, Autoimmunity and Infection

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Treg cells CD4+CD25+FOXP3+ have a specific function in the tolerance of autoantigens and regulation of the immune response. Modulation of differentiation pathways and the use of Treg cells in cell therapy have been reported in autoimmune diseases, systemic lupus erythromatosis, autoimmune hepatitis, type 1 diabetes mellitus, multiple sclerosis, rheumatoid arthritis, graft-versus-host disease, bone marrow transplantation and solid organs. The expansion of Treg cells in vivo occurs through low-dose IL-2 treatment. However, because of the heterogeneity and variability of Treg cells, the isolation of peripheral blood cells, through the technique of leucopheresis by GMP (good manuring practice), for in vitro expansion is difficult, necessitating a large combination of specific and reliable cellular markers. Currently, two specific markers, Helios and neuropilin-1, are being studied to facilitate the differentiation of thymus Treg cells and peripheral Treg cells. However, Treg cells induced in vitro are unstable. Modulation of the FOXP3 gene in the CNS1 and CNS2 region is an alternative to maintaining the stability of expanded Treg cells in vitro.

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“…Autoimmune hepatitis (AIH) is another form of chronic hepatitis with an unknown etiology. Activated immune cells, involving cytokines and macrophages, characterize the disease [16], however, overall knowledge about autophagy in AIH is limited. Autophagy is known to be involved in the activation of adaptive immunity, promoting the direct elimination of pathogens and simultaneous antigen processing and presentation to T cells [17].…”

Section: Introductionmentioning

confidence: 99%

Autophagy, Mitophagy and MicroRNA Expression in Chronic Hepatitis C and Autoimmune Hepatitis

Szekerczés

Gógl

Illyés

et al. 2020

Pathol. Oncol. Res.

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Although the role of autophagy has been implicated in several forms of chronic hepatitis, it is still not fully understood. Active autophagy eliminates damaged molecules and organelles (such as mitochondria) by lysosomal degradation. In the present study, we aimed to examine and compare autophagy activity in chronic hepatitis C (CHC) and autoimmune hepatitis (AIH) by detecting the expression of autophagy (LC3 and p62) and mitochondrium-related (TOMM20) proteins, as well as the levels of selected microRNAs (miR-101, -155, -204 and − 224) known to be involved in the regulation of autophagy. In addition, the expression levels were related to pathohistological parameters. Liver biopsy samples, including 45 CHC and 18 AIH cases, were immunohistochemically stained for LC3, p62 and TOMM20 and the expression of miRNAs was determined using real-time PCR. We found elevated LC3 and p62 in AIH samples as compared with CHC ones, indicating an activated autophagy that is impaired in AIH as no degradation of p62 seemed to occur. Moreover, p62 showed strong correlation with necroinflammatory grades in the AIH group. The observed elevated levels of TOMM20 and p62 suggest a less efficient elimination of damaged mitochondria in AIH as opposed to CHC, in which autophagy seems to have a more active function. The level of miR-101 was increased in case of CHC as compared with AIH, however, miR-155, -204 and 224 resulted in no expressional. Furthermore, miR-224 level correlated with steatosis and miR-155 expression with fibrosis stage in CHC. In conclusion, dissimilar autophagic activity was observed in CHC and AIH, suggesting a close association between impaired autophagy and severity of necroinflammation. This impairment may not be regulated by the analyzed miRNAs. Nevertheless, miR-224 and − 155 seem to be associated with CHC progression.

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Immunopathogenic Mechanisms of Autoimmune Hepatitis: How Much Do We Know from Animal Models?

Cited by 34 publications

References 125 publications

Comparison of Concanavalin a-Induced Murine Autoimmune Hepatitis Models

Comparison of Concanavalin a-Induced Murine Autoimmune Hepatitis Models

Regulatory T Lymphocytes (Treg): Modulation and Clinical Application

Autophagy, Mitophagy and MicroRNA Expression in Chronic Hepatitis C and Autoimmune Hepatitis

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