Animal Models for Autoimmune Liver Disease – What Is Relevant for Immune-Mediated Liver Disease

Hardtke‐Wolenski, Matthias; Taubert, Richard; Jaeckel, Elmar

doi:10.1159/000341114

Cited by 9 publications

(7 citation statements)

References 126 publications

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“…Particularly, in young and middle-aged AIH persons with 20–50 years, serum A2M level was greatly increased significantly in female group (Figure 7B). Our results were also supported previous conclusions that AIH can be found more often in younger patients with prevalence for females [23]. …”

Section: Resultssupporting

confidence: 92%

Complementary serum proteomic analysis of autoimmune hepatitis in mice and patients

Zhao

et al. 2013

J Transl Med

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BackgroundAutoimmune hepatitis (AIH) is a chronic liver disease caused by inflammation of the liver. The etiology of AIH remains elusive, and there are no reliable serum biomarkers.MethodsIn order to identify candidate biomarkers, 2-DE analysis of serum proteins was performed using a mouse model of AIH induced by treatment with concanavalin A (ConA). To enrich samples for low abundance molecules a commercial albumin removal reagent was used. In an independent analysis, candidate biomarkers were identified in AIH patient’s serum by a targeted iTRAQ (isobaric tags for relative and absolute quantification) identification. Candidates were validated in independent cohorts of ConA treated mice and AIH patients by ELISA (enzyme-linked immuno sorbent assay).ResultsNine proteins were differentially expressed in AIH mice treated with con-A. Two of these, the third component of complement (C3) and alpha-2-macroglobulin (A2M) were also up-regulated in AIH patient’s sera by a targeted iTRAQ identification. In separate validation studies, serum C3 and A2M levels were increased in mice with ConA treatment after 20-40 h and in 34 AIH patients in a subgroup analysis, females with AIH aged 20–50 years old displayed the largest increases in serum A2M level. Biological network analysis implements the complement cascade and protease inhibitors in the pathogenesis of AIH.ConclusionThe serum proteins C3 and A2M are increased both in a mouse model and in patients with AIH by both 2-DE and iTRAQ methods. This integrated serum proteomics investigation should be applicable for translational researchers to study other medical conditions.

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Section: Resultssupporting

confidence: 92%

Complementary serum proteomic analysis of autoimmune hepatitis in mice and patients

Zhao

et al. 2013

J Transl Med

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“…Thus far, the etiology and pathogenesis of AIH are unclear, but it is assumed that AIH is driven by an adaptive immune response to hepatocellular autoantigens (12). Indeed, several antigen-driven AIH mouse models have demonstrated that T cell responses to liver antigens can cause liver inflammation (13)(14)(15)(16)(17)(18)(19). Nonetheless, the mechanisms that produce the loss of tolerance to liver antigens in AIH are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Failure of thymic deletion and instability of autoreactive Tregs drive autoimmunity in immune-privileged liver

Preti¹,

Schlott²,

Lübbering³

et al. 2021

JCI Insight

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The liver is an immune-privileged organ that can deactivate autoreactive T cells. Yet in autoimmune hepatitis (AIH), autoreactive T cells can defy hepatic control and attack the liver. To elucidate how tolerance to self-antigens is lost during AIH pathogenesis, we generated a spontaneous mouse model of AIH, based on recognition of an MHC class II–restricted model peptide in hepatocytes by autoreactive CD4 + T cells. We found that the hepatic peptide was not expressed in the thymus, leading to deficient thymic deletion and resulting in peripheral abundance of autoreactive CD4 + T cells. In the liver, autoreactive CD4 + effector T cells accumulated within portal ectopic lymphoid structures and maturated toward pathogenic IFN-γ and TNF coproducing cells. Expansion and pathogenic maturation of autoreactive effector T cells was enabled by a selective increase of plasticity and instability of autoantigen-specific Tregs but not of nonspecific Tregs. Indeed, antigen-specific Tregs were reduced in frequency and manifested increased IL-17 production, reduced epigenetic demethylation, and reduced expression of Foxp3 . As a consequence, autoantigen-specific Tregs had a reduced suppressive capacity, as compared with that of nonspecific Tregs. In conclusion, loss of tolerance and the pathogenesis of AIH were enabled by combined failure of thymic deletion and peripheral regulation.

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“…Data from basic and translational research have drawn attention to the role of T‐cell populations, such as regulatory T cells (Tregs), but also to T‐helper (Th)17 cells . Recent studies employing animal models started to dissect the contribution of different T‐cell populations to the initiation and modulation of disease in vivo , but the molecular factors determining the distinct fate of pathogenic T‐cell differentiation have remained largely elusive.…”

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confidence: 99%

Cyclic adenosine monophosphate–responsive element modulator alpha overexpression impairs function of hepatic myeloid‐derived suppressor cells and aggravates immune‐mediated hepatitis in mice

Hammerich¹,

Warzecha²,

Stefkova³

et al. 2015

Hepatology

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Molecular factors driving immune-mediated inflammation in the liver are incompletely understood. The transcription factor, cyclic adenosine monophosphate-responsive element modulator alpha (CREMa) can endorse differentiation of T lymphocytes toward T-helper (Th)17 cells, thereby promoting autoimmunity in systemic lupus erythematosus or lung inflammation. To investigate the role of CREMa in liver disease, we subjected transgenic (Tg) mice overexpressing CREMa under control of the CD2 promoter (crem tg mice), which restrains expression mainly to lymphocytes (T, natural killer [NK], and NKT cells), to acute and chronic liver injury models. Already in steady state, Tg CREMa overexpression broadly reduced hepatic immune cell numbers by decreasing their viability, but did not affect immune cell migration or the fibrogenic response to chronic liver injury. Strikingly, crem tg mice developed more severe immune-mediated hepatitis with a higher mortality rate, compared to wild-type (wt) mice, upon concanavalin A (ConA) administration. Unlike in T cells from spleen, CREMa overexpression did not induce a predominant Th17 response in intrahepatic T cells, given that hepatic crem tg CD4 1 T cells expressed less interleukin (IL)-17 than wt T cells. Reconstitution of Rag1 2/2 mice with Crem 2/2 T cells did not ameliorate ConA hepatitis. Overexpression of CREMa did not influence NK and NKT-cell effector functions either. Interestingly, a subset of monocytic myeloid-derived suppressor cells (MDSCs) also expressed CD2 and CREMa. Crem tg MDSCs isolated from liver expressed reduced inducible nitric oxide synthase and arginase 1 and displayed a reduced T-cell suppressive activity. The adoptive transfer of wt MDSCs was capable of reducing the fulminant immune-mediated liver damage in crem tg mice to wt level. Conclusion: These results suggest compartmental differences of T cell activation pathways between liver and other organs in autoimmunity and define a functional role of CREMa in hepatic monocytic MDSCs for the pathogenesis of immune-mediated liver disease. (HEPATOLOGY 2015;61:990-1002) A utoimmune hepatitis (AIH) has a wide spectrum of clinical presentations, ranging from asymptomatic disease, acute or chronic hepatitis, to fulminant hepatic failure, and is characterized by intrahepatic lymphocyte activation, interface hepatitis, circulating autoantibodies, hypergammaglobulinemia, and a favorable response to immunosuppression. 1In concordance with other autoimmune diseases, AIH is associated with non-organ-specific antibodies (Abs), such as antinuclear Abs, in the context of hepatic

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Animal Models for Autoimmune Liver Disease – What Is Relevant for Immune-Mediated Liver Disease

Cited by 9 publications

References 126 publications

Complementary serum proteomic analysis of autoimmune hepatitis in mice and patients

Complementary serum proteomic analysis of autoimmune hepatitis in mice and patients

Failure of thymic deletion and instability of autoreactive Tregs drive autoimmunity in immune-privileged liver

Cyclic adenosine monophosphate–responsive element modulator alpha overexpression impairs function of hepatic myeloid‐derived suppressor cells and aggravates immune‐mediated hepatitis in mice

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