MAIT cells are chronically activated in patients with autoimmune liver disease and promote profibrogenic hepatic stellate cell activation

Böttcher, Katrin; Rombouts, Krista; Saffioti, Francesca; Roccarina, Davide; Rosselli, Matteo; Hall, Andrew; Luong, TuVinh; Tsochatzis, Emmanuel; Thorburn, Douglas; Pinzani, Massimo

doi:10.1002/hep.29782

Cited by 140 publications

(187 citation statements)

References 49 publications

(121 reference statements)

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“…To summarize, MAIT cells were decreased in the blood, displayed an activated phenotype ex vivo , infiltrated the inflamed liver, and were impaired in their capacity to respond to bacterial antigen in vitro . Finally, MAIT cell activity correlated with the stage of fibrosis, in agreement with the recently reported role of MAIT cells in fibrosis development during liver autoimmune diseases …”

Section: Resultssupporting

confidence: 90%

“…Fibrosis development is one of the major consequences of active AIH and could be enhanced by MAIT cell activity . Thus, we investigated the possible link between fibrosis stage at diagnosis and GrB expression by MAIT cells in AIH patients, at all stages of the disease.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, among AIH patients, those diagnosed with severe fibrosis (F3‐F4) had a higher MAIT cell activity. This relationship could be explained by the recently described profibrogenic role of MAIT cells in liver autoimmune diseases, by promoting hepatic stellate cell activation . Liver cirrhosis is known to be associated with a higher exposure of hepatocytes to bacterial‐derived antigens because of an increased permeability of the gut wall, favoring systemic infections .…”

Section: Discussionmentioning

confidence: 99%

“…This activation defect may be the consequence of their persistent activation (GrB+) ex vivo and could reflect an exhaustion phenomenon as recently observed during liver autoimmune diseases. (25)…”

Section: Mait Cells From Aih Patients Are Functionally Altered Upon Bmentioning

confidence: 99%

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Immune Alterations in Patients With Type 1 Autoimmune Hepatitis Persist Upon Standard Immunosuppressive Treatment

Renand

Habes

Mosnier

et al. 2018

Hepatology Communications

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Autoimmune hepatitis (AIH) is a rare disease characterized by an immune attack of the liver. This study consists of a comprehensive analysis of immune alterations related to AIH at diagnosis, and during remission phase under treatment. A total of 37 major lymphocyte populations were analyzed from the peripheral blood of new‐onset AIH patients (AIHn; n = 14), AIH patients with controlled disease (n = 11), and healthy subjects (n = 14). Liver biopsy analyses were performed to complete the blood phenotypic analysis. Four blood lymphocyte populations were significantly altered in AIHn patients at diagnosis compared with healthy subjects. Levels of mucosal‐associated invariant T cells (MAIT), Type 1/Type 17 helper (Th1/ Th17) cells, clusters of differentiation (CD4) T cells, and invariant natural killer T cells were decreased, whereas MAIT granzyme B+ (GrB) cells were increased. A trend toward an increase of CD8+CD161+GrB+ cells was also observed. These alterations were not restored with standard immunosuppressive treatments. In the liver of AIHn patients, CD4, forkhead box P3 (Foxp3), and MAIT cell markers were enriched in the portal tract, and CD8, CD161, and GrB markers were enriched in the hepatic lobule. During remission, the hepatic lobule was clear of infiltrating T cells, but residual CD4 and MAIT cells were found in the portal tract, where Foxp3 was decreased, as previously described. In vitro, MAIT cells were functionally altered in AIH patients. Ex vivo MAIT cell activity (GrB) was linked to severe fibrosis. Conclusion: Our work proposes a global view of the lymphocyte alterations from diagnosis to remission phase in AIH patients. The absence of blood immune homeostasis restoration and the persistence of a CD4 infiltrate in the liver under standard immunosuppression could form the basis of the high risk of relapse observed in AIH. (Hepatology Communications 2018; 00:000‐000)

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Mait Cells From Aih Patients Are Functionally Altered Upon Bmentioning

confidence: 99%

See 2 more Smart Citations

Immune Alterations in Patients With Type 1 Autoimmune Hepatitis Persist Upon Standard Immunosuppressive Treatment

Renand

Habes

Mosnier

et al. 2018

Hepatology Communications

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“…Therefore, complex interactions between infiltrated immune cells and resident liver cells such as HSCs and hepatocytes occur during chronic hepatitis. Moreover, co-cultures of human HSCs and mucosal-associated invariant T cells enhanced the expression of IL-6, IL-1β, IL-8 and MCP-1 and the profibrotic gene TIMP1 via direct cell-cell contact and also partially through IL-17 [30]. Indeed, HSC exposure to conditioned medium from activated PBMCs increased HSC secretion of growth-related oncogene-α and IL-17 contributed to this effect [29].…”

Section: Discussionmentioning

confidence: 97%

IL-17 and TNF-α co-operation contributes to the proinflammatory response of hepatic stellate cells

Beringer

Miossec

2019

Clinical and Experimental Immunology

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Hepatic stellate cells (HSCs) have a central role in liver inflammation and fibrosis by producing inflammatory and fibrotic mediators. Their activation is regulated through direct cell-cell interactions, but also through systemic and local effects of soluble factors such as cytokines. The effects of the proinflammatory cytokines interleukin (IL)-17 and tumor necrosis factor (TNF)-α and cell interactions with hepatocytes on HSC activation were assessed. Human HSC and HepaRG cells were exposed to IL-17 and/ or TNF-α. IL-17 and TNF-α contribution from immune cells was determined in a co-culture model with phytohemagglutinin (PHA)-activated peripheral blood mononuclear cells (PBMC), HSC and/or hepatocytes. IL-17 enhanced TNF-α effects on the induction of IL-6, IL-1β, and the chemokine IL-8, chemokine (C-C motif) ligand 20 (CCL20) and monocyte chemoattractant protein-1 (MCP-1) expression/secretion in isolated HSC cultures. HSC-hepatocyte interactions did not enhance IL-6, IL-8 and CCL20 production compared to hepatocyte alone. However, HSC-hepatocyte interactions increased C-reactive protein expression. IL-17 and/or TNF-α had no direct profibrotic effects on collagen 1 α1, tissue inhibitor of matrix metalloproteinase (TIMP) and matrix metalloproteinase (MMP) 2 gene expression, whereas mRNA levels of MMP3, an enzyme involved in matrix destruction, were up-regulated in HSCs. The use of specific inhibitors of IL-17 and TNF-α indicated their contribution to the strong increase of IL-6 and IL-8 production induced by PBMC, HSC and/or hepatocyte interactions. As chronic liver inflammation leads to liver fibrosis, IL-17 and/or TNF-α neutralization can be of interest to control liver inflammation and therefore its effects on fibrosis.

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Microarray‐based transcriptional profiling of a mouse model of autoimmune hepatitis

et al. 2020

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Changes in long noncoding RNA expression in autoimmune hepatitis (AIH) have not been studied previously. We investigated differentially expressed long noncoding RNAs and differentially expressed mRNAs in a Con A‐induced AIH mouse model with microarray for the first time and reveal expression changes involved in the pathogenesis of AIH. These candidates might have potential to serve as potential diagnostic and therapeutic biomarkers for AIH.

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MAIT cells are chronically activated in patients with autoimmune liver disease and promote profibrogenic hepatic stellate cell activation

Cited by 140 publications

References 49 publications

Immune Alterations in Patients With Type 1 Autoimmune Hepatitis Persist Upon Standard Immunosuppressive Treatment

Immune Alterations in Patients With Type 1 Autoimmune Hepatitis Persist Upon Standard Immunosuppressive Treatment

IL-17 and TNF-α co-operation contributes to the proinflammatory response of hepatic stellate cells

Microarray‐based transcriptional profiling of a mouse model of autoimmune hepatitis

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