FOXP3+ regulatory T cells in autoimmune hepatitis are fully functional and not reduced in frequency

Peiseler, Moritz; Sebode, Marcial; Franke, B.; Wortmann, Frederike; Schwinge, Dorothee; Quaas, Alexander; Baron, Udo; Olek, Sven; Wiegard, Christiane; Lohse, Ansgar W.; Weiler‐Normann, Christina; Schramm, Christoph; Herkel, Johannes

doi:10.1016/j.jhep.2012.02.029

Cited by 170 publications

(152 citation statements)

References 28 publications

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“…However, a recent report showed that the numbers and suppressive function of FOXP3 + T cells isolated from AIH patients were similar to those of normal controls. In addition, the intrahepatic frequency of these cells was higher and correlated with the degree of inflammation in the liver of AIH patients (47). Our results support the latter observations and suggest that in Traf6ΔTEC mice, inflammation-driven production of iTregs in the liver may compensate for the reduced nTreg thymic output and drive the chronic nature of the disease.…”

Section: Methodssupporting

confidence: 85%

Medullary thymic epithelial cell depletion leads to autoimmune hepatitis

Bonito

Aloman²,

Fiel³

et al. 2013

J. Clin. Invest.

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TRAF6, an E3 ubiquitin protein ligase, plays a critical role in T cell tolerance by regulating medullary thymic epithelial cell (mTEC) development. mTECs regulate T cell tolerance by ectopically expressing self-antigens and eliminating autoreactive T cells in the thymus. Here we show that mice with mTEC depletion due to conditional deletion of Traf6 expression in murine thymic epithelial cells (Traf6ΔTEC mice) showed a surprisingly narrow spectrum of autoimmunity affecting the liver. The liver inflammation in Traf6ΔTEC mice exhibited all the histological and immunological characteristics of human autoimmune hepatitis (AIH). The role of T cells in AIH establishment was supported by intrahepatic T cell population changes and AIH development after transfer of liver T cells into immunodeficient mice. Despite a 50% reduction in natural Treg thymic output, peripheral tolerance in Traf6ΔTEC mice was normal, whereas compensatory T regulatory mechanisms were evident in the liver of these animals. These data indicate that mTECs exert a cell-autonomous role in central T cell tolerance and organ-specific autoimmunity, but play a redundant role in peripheral tolerance. These findings also demonstrate that Traf6ΔTEC mice are a relevant model with which to study the pathophysiology of AIH, as well as autoantigen-specific T cell responses and regulatory mechanisms underlying this disease.

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Section: Methodssupporting

confidence: 85%

Medullary thymic epithelial cell depletion leads to autoimmune hepatitis

Bonito

Aloman²,

Fiel³

et al. 2013

J. Clin. Invest.

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show abstract

“…3 Moreover, we have found that the expression levels of CD25 seemed to be associated with disease activity. 3 Thus, both disease activity and treatment status of AIH patients might have an effect on the phenotype of T cells, including CD25…”

Section: Cd39mentioning

confidence: 88%

“…However, we would like to emphasize recent reports advancing a more cautionary tone concerning in vitro efficacy and safety of these medications. 3,4 Cirrhosis patients are typically excluded from clinical trials assessing anticoagulants and clinicians are often left to extrapolate when developing treatment plans in this challenging population. While our series is small and no significant bleeding occurred, there is certainly risk when using these new agents, as the ability to monitor and rescue from bleeding is currently limited.…”

Section: Treating Thrombosis In Cirrhosis Patients With New Oral Agenmentioning

confidence: 99%

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Grant

Liberal

et al. 2015

Hepatology

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“…These T cells are normally suppressed by regulatory T cells (Treg); however, once this mechanism is disrupted, immune tolerance disturbances and the onset of autoimmune disease subsequently follow. Based on the reduction in peripheral Treg cells and TGF-β production in the setting of AIH, quantitative and qualitative defects of Treg were originally suggested to be involved in the pathogenesis of AIH, until recent evidence contradicted this hypothesis (37)(38)(39). Therefore, further investigations on this issue are needed.…”

Section: ) Acquired Immunitymentioning

confidence: 99%

Autoimmune Hepatitis: Recent Advances in the Pathogenesis and New Diagnostic Guidelines in Japan

et al. 2015

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Autoimmune hepatitis (AIH) is thought to be associated with various genetic and immunological abnormalities. Concerning the pathogenesis of AIH, increasing attention has been paid to genome-wide association studies, toll-like receptors and Treg/Th17 balance. For Japanese patients with AIH, novel diagnostic guidelines have been proposed in view of the differential clinical features between Japanese and Caucasian patients. However, the diagnosis of some patients in acute hepatitis phase is not easy. Histologically, centrilobular necrosis without portal inflammation is particularly characteristic in the acute hepatitis phase. Some patients become resistant to steroid therapy and have a very poor prognosis once they progress to acute hepatic failure. Therefore, additional revision of the current diagnostic criteria, including severity grading, will be needed in the future.

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FOXP3+ regulatory T cells in autoimmune hepatitis are fully functional and not reduced in frequency

Cited by 170 publications

References 28 publications

Medullary thymic epithelial cell depletion leads to autoimmune hepatitis

Medullary thymic epithelial cell depletion leads to autoimmune hepatitis

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Autoimmune Hepatitis: Recent Advances in the Pathogenesis and New Diagnostic Guidelines in Japan

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