Different sites of xenoantigen delivery lead to a virally induced late‐onset hepatitis in mice through molecular mimicry

Piché, Chantal; Béland, Kathie; Lapierre, Pascal; Massie, Bernard; Álvarez, Fernando

doi:10.1111/j.1478-3231.2011.02600.x

Cited by 10 publications

(6 citation statements)

References 34 publications

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“…Other authors suggested that peripheral T lymphocytes could play a role in hepatic immune responses, and the hypotheses include T lymphocyte competition for antigen presentation in hepatic or peripheral lymphoid tissues, 10 late T cell activation in the liver after peripheral antigen priming, 11 peripheral IL‐12‐dependent reversion of liver‐induced immune tolerance, 12 and others 13,14 . The experimental models include AIH induced in transgenic mice and expression of hepatitis viral antigens; although we believe that part of these results further supports our model, experimental limitations impaired the unequivocal interpretation of those previous data.…”

Section: Discussionsupporting

confidence: 69%

“…Zeng et al 12 . showed that an IL‐12‐based vaccination therapy reversed immune tolerance in the liver, and other authors investigated the importance of the site of antigen expression in hepatic tolerance 13,14 …”

Section: Introductionmentioning

confidence: 99%

“…11 Zeng et al 12 showed that an IL-12-based vaccination therapy reversed immune tolerance in the liver, and other authors investigated the importance of the site of antigen expression in hepatic tolerance. 13,14 However, in these experimental approaches, the expression of antigens is not restricted to the hepatic environment or the periphery, and this mixed antigen site presentation impedes the evaluation of the primary site of danger recognition. Our results showed that adoptively transferred peripheral T lymphocytes that were activated by T. cruzi antigens were retained in the liver and led to hepatic T cell activation, which in turn partially subverted the tolerant nature of the liver.…”

mentioning

confidence: 99%

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In the presence of Trypanosoma cruzi antigens, activated peripheral T lymphocytes retained in the liver induce a proinflammatory phenotypic and functional shift in intrahepatic T lymphocyte

Meuser-Batista

Vacani-Martins

Cascabulho

et al. 2020

Journal of Leukocyte Biology

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In secondary lymphoid organs, pathogen‐derived and endogenous danger molecules are recognized by pattern recognition receptors, leading to adaptive proinflammatory immune responses. This conceptual rule does not apply directly to the liver, as hepatic immune cells tolerate gut‐derived bacterial molecules from the flora. Therefore, the recognition of danger and proinflammatory stimuli differs between the periphery and the liver. However, the tolerant nature of the liver must be overcome in the case of infections or cancer, for example. The central paradigm is the basis for danger recognition and the balance between inflammation and tolerance in the liver. Here, we observed functional integration, with activated peripheral T lymphocytes playing a role in the induction of a proinflammatory environment in the liver in the presence of Trypanosoma cruzi antigens. When only parasite extract was orally administered, it led to the up‐regulation of hepatic tolerance markers, but oral treatment plus adoptively transferred activated splenic T lymphocytes led to a proinflammatory response. Moreover, treated/recipient mice showed increased levels of TNF, IFN‐γ, IL‐6, and CCL2 in the liver and increased numbers of effector and/or effector memory T lymphocytes and F4/80+ cells. There was a reduction in FoxP3+ Treg cells, NKT cells, and γδ T lymphocytes with increased liver damage in the presence of activated peripheral T cells. Our results show that the induction of a proinflammatory liver response against T. cruzi danger molecules is at least partially dependent on cooperation with activated peripheral T cells.

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Section: Discussionsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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In the presence of Trypanosoma cruzi antigens, activated peripheral T lymphocytes retained in the liver induce a proinflammatory phenotypic and functional shift in intrahepatic T lymphocyte

Meuser-Batista

Vacani-Martins

Cascabulho

et al. 2020

Journal of Leukocyte Biology

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“…We have proven that a short, self-limiting liver-specific infection can cause chronic evolving emAIH in animals on NOD background that are prone to the development of autoimmunity [2]. The lack of viral infection during the chronic phase of disease supported a hit-and-run hypothesis for the development of AIH in which an initial stimulus was sufficient to trigger autoimmunity [34].…”

Section: Discussionmentioning

confidence: 76%

Hepatic T Cell Tolerance Induction in An Inflammatory Environment

Dywicki¹,

Noyan²,

Misslitz³

et al. 2017

Dig Dis

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For the development of autoimmune hepatitis (AIH), genetic predisposition and environmental triggers are of major importance. Although experimental AIH can be induced in genetically susceptible mice, the low precursor frequency of autoreactive T cells hampers a deeper analysis of liver-specific T cells. Here, we established a system where the model antigen hemagglutinin (HA) is expressed exclusively in hepatocytes of Rosa26-HA mice following administration of a replication deficient adenovirus expressing Cre recombinase (Ad-Cre). Under these conditions, hepatocytes mimic the generation of altered-self neoantigens. To follow autoreactive T cells during AIH, we adoptively transferred HA-specific Cl4-TCR and 6.5-TCR T cells into Ad-Cre infected Rosa26-HA mice. Alternatively, Rosa26-HA mice have been crossed with TCR transgenic mice that were infected with Ad-Cre to break hepatic tolerance and induce the expression of the HA antigen as a hepatic self-antigen. Surprisingly, neither adoptive transfer nor a very high precursor frequency of autoreactive T cells was able to break tolerance in the context of adenoviral infection. The low proliferation of the antigen experienced autoreactive T cells despite the presence of the autoantigen and inflammation points to anergy as a potential tolerance mechanism. This model underscores the crucial importance of genetic susceptibility to break tolerance against hepatic autoantigens.

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“…It was also proposed that antigen-primed T lymphocytes migrate from the lymph nodes and are retained in the liver for activation when in the presence of a more pro-inflammatory environment, in the case of second antigen exposure [ 144 ]. Other authors showed that an IL-12-based vaccine reversed immune tolerance in the liver [ 145 ], and other papers showed the importance of the anatomical site of antigen expression in hepatic tolerance [ 146 , 147 ]. However, in all experimental approaches used, the possibility of antigen presentation in both lymph nodes and the liver could not be ruled out.…”

Section: Introductionmentioning

confidence: 99%

The Liver and the Hepatic Immune Response in Trypanosoma cruzi Infection, a Historical and Updated View

et al. 2021

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Chagas disease was described more than a century ago and, despite great efforts to understand the underlying mechanisms that lead to cardiac and digestive manifestations in chronic patients, much remains to be clarified. The disease is found beyond Latin America, including Japan, the USA, France, Spain, and Australia, and is caused by the protozoan Trypanosoma cruzi. Dr. Carlos Chagas described Chagas disease in 1909 in Brazil, and hepatomegaly was among the clinical signs observed. Currently, hepatomegaly is cited in most papers published which either study acutely infected patients or experimental models, and we know that the parasite can infect multiple cell types in the liver, especially Kupffer cells and dendritic cells. Moreover, liver damage is more pronounced in cases of oral infection, which is mainly found in the Amazon region. However, the importance of liver involvement, including the hepatic immune response, in disease progression does not receive much attention. In this review, we present the very first paper published approaching the liver’s participation in the infection, as well as subsequent papers published in the last century, up to and including our recently published results. We propose that, after infection, activated peripheral T lymphocytes reach the liver and induce a shift to a pro-inflammatory ambient environment. Thus, there is an immunological integration and cooperation between peripheral and hepatic immunity, contributing to disease control.

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Different sites of xenoantigen delivery lead to a virally induced late‐onset hepatitis in mice through molecular mimicry

Cited by 10 publications

References 34 publications

In the presence of Trypanosoma cruzi antigens, activated peripheral T lymphocytes retained in the liver induce a proinflammatory phenotypic and functional shift in intrahepatic T lymphocyte

In the presence of Trypanosoma cruzi antigens, activated peripheral T lymphocytes retained in the liver induce a proinflammatory phenotypic and functional shift in intrahepatic T lymphocyte

Hepatic T Cell Tolerance Induction in An Inflammatory Environment

The Liver and the Hepatic Immune Response in Trypanosoma cruzi Infection, a Historical and Updated View

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