Aetiopathogenesis of autoimmune hepatitis

Longhi, Maria Serena; Ma, Yuanfang; Mieli‐Vergani, Giorgina; Vergani, Diego

doi:10.1016/j.jaut.2009.08.010

Cited by 182 publications

(142 citation statements)

References 64 publications

(111 reference statements)

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“…In addition to regulating the negative selection of autoreactive T cells, mTECs have also been shown to regulate production of nTregs in the thymus (7)(8)(9). Because a reduction in the numbers and/or functional impairment of Tregs is thought to correlate with AIH development (43,44) and because Tregs are potent suppressors of inflammation and autoimmunity, we next examined whether Treg production and function is impaired in Traf6ΔTEC mice. Staining of thymocyte cell suspensions with the Treg-specific marker FOXP3 revealed a 50% decrease in the total number of FOXP3 + thymocytes ( Figure 8A), consistent with a role for mTECs in nTreg production.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

Medullary thymic epithelial cell depletion leads to autoimmune hepatitis

Bonito

Aloman²,

Fiel³

et al. 2013

J. Clin. Invest.

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show abstract

“…Duarte-Rey et al reported in a meta-analysis study that HLA DQB1*02, DQB1*06:03, DRB1*04:05, and DRB1*13:01 were risk factors for AIH in Latin America, while DRB1*13:02 and DQB1*03:01 were protective factors [22]. Differing genetic associations may be thus present in type 1 AIH and the antigenic peptides presented by HLA class II molecules may be different for each race [4,23].…”

Section: Hla Susceptibility Genesmentioning

confidence: 99%

“…Specifically, human leukocyte antigen (HLA) class II genes located on the short arm of chromosome 6 are suggested to play a crucial role in the susceptibility to AIH [1,4]. However, HLA class II genes or gene products cannot completely explain disease predisposition; additional susceptibility genes (either HLA or non-HLA) and/or environmental factors may also contribute to the development of type 1 AIH [1,4]. This study summarizes the susceptibility genes associated with AIH development that have been published worldwide and incorporates our own findings from association analyses using microsatellite markers distributed throughout the HLA region and the whole genome.…”

Section: Introductionmentioning

confidence: 99%

Genetic background of autoimmune hepatitis in Japan

2010

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“…Although the mechanism of antibody production is unknown, intrahepatic T helper cells in patients with autoimmune hepatitis can stimulate the production of the autoantibody. Few Tregs are observed in these livers, with those present having impaired function (Longhi et al, 2010), suggesting that decreased functional activity of Tregs may predispose to enhanced autoimmune reactions.…”

Section: Autoimmune Hepatitis (Aih)mentioning

confidence: 99%