Altered aryl-hydrocarbon-receptor signalling affects regulatory and effector cell immunity in autoimmune hepatitis

Vuerich, Marta; Harshe, Rasika; Frank, Luíza Abrahão; Mukherjee, Sayantani; Gromová, Barbora; Csizmadia, Eva; Nasser, Imad; Ma, Yuanfang; Bonder, Alan; Patwardhan, Vilas; Robson, Simon C.; Longhi, Maria Serena

doi:10.1016/j.jhep.2020.06.044

Cited by 33 publications

(29 citation statements)

References 45 publications

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“…Various studies aimed to answer if Treg cell frequency or function were altered in AIH livers. Some showed numerical/ functional impairment of regulatory cells in AIH (45,(47)(48)(49)(50)(51)(52)(53)(54), and others found no deficiency in their patient cohorts (55,56).…”

Section: Targeting Enclysis In Autoimmune Liver Diseasementioning

confidence: 98%

Targeting Enclysis in Liver Autoimmunity, Transplantation, Viral Infection and Cancer

et al. 2021

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Persistent liver inflammation can lead to cirrhosis, which associates with significant morbidity and mortality worldwide. There are no curative treatments beyond transplantation, followed by long-term immunosuppression. The global burden of end stage liver disease has been increasing and there is a shortage of donor organs, therefore new therapies are desperately needed. Harnessing the power of the immune system has shown promise in certain autoimmunity and cancer settings. In the context of the liver, regulatory T cell (Treg) therapies are in development. The hypothesis is that these specialized lymphocytes that dampen inflammation may reduce liver injury in patients with chronic, progressive diseases, and promote transplant tolerance. Various strategies including intrinsic and extracorporeal expansion of Treg cells, aim to increase their abundance to suppress immune responses. We recently discovered that hepatocytes engulf and delete Treg cells by enclysis. Herein, we propose that inhibition of enclysis may potentiate existing regulatory T cell therapeutic approaches in patients with autoimmune liver diseases and in patients receiving a transplant. Moreover, in settings where the abundance of Treg cells could hinder beneficial immunity, such us in chronic viral infection or liver cancer, enhancement of enclysis could result in transient, localized reduction of Treg cell numbers and tip the balance towards antiviral and anti-tumor immunity. We describe enclysis as is a natural process of liver immune regulation that lends itself to therapeutic targeting, particularly in combination with current Treg cell approaches.

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Section: Targeting Enclysis In Autoimmune Liver Diseasementioning

confidence: 98%

Targeting Enclysis in Liver Autoimmunity, Transplantation, Viral Infection and Cancer

et al. 2021

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“…Akin to Tregs, effector Th17 cells, one of the effector subsets involved in AIH liver damage, display low levels of CD39, this being associated with impaired adenosine generation and ability to acquire regulatory properties (Liberal et al, 2016 ). We have recently shown that defective CD39 levels in AIH Tregs and Th17 cells derive from altered AhR signaling (Vuerich et al, 2020 ). These alterations result from an aberrant increase in aryl hydrocarbon receptor repressor in Tregs and HIF-1α in Th17 cells.…”

Section: Autoimmune Hepatitismentioning

confidence: 99%

“…Furthermore, in AIH Tregs, there is a marked increase in estrogen receptor alpha (Erα), one of AhR alternative binding partners. Preferential binding of AhR to Erα rather than aryl hydrocarbon receptor nuclear translocator, the classical AhR binding partner, leads to impaired CD39 upregulation (Vuerich et al, 2020 ); this possibly accounting for low CD39 levels in Tregs.…”

Section: Autoimmune Hepatitismentioning

confidence: 99%

Ectonucleotidase Modulation of Lymphocyte Function in Gut and Liver

Savio

Robson

Longhi

2021

Front. Cell Dev. Biol.

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Imbalance between regulatory and effector T lymphocytes contributes to loss of immunotolerance and plays a permissive role in the initiation, perpetuation, and progression of chronic inflammatory diseases and autoimmune disorders. Regulatory/effector cell balance is governed by the CD39 ectonucleotidase, the prototype member of the NTPDase family that hydrolyzes ATP and ADP into AMP, subsequently converted into adenosine by CD73. Generation of adenosine impacts T-cell function as it contributes to the mechanism of suppression of Tregs and confers regulatory properties to pathogenic Th17-cells. CD39 cell distribution, mechanism of regulation and impact on inflammatory and regulatory signaling pathways are also discussed here. Innovative therapeutic strategies to boost CD39 levels and activity by either administering soluble ADPases or interfering with CD39 inhibitory signals are reviewed. Restoration of CD39 levels and function has enormous translational and clinical implications and should be regarded as an additional form of treatment to be deployed in the chronic inflammatory setting. The key role of CD39 in immunoregulation in the context of Crohn's disease, one of the most frequent manifestations of inflammatory bowel disease, and autoimmune hepatitis, an autoimmune disorder of the liver, is reviewed and discussed here.

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“…The shift of immune balance to Th1 predominance is noted after a decline in blood concentration of estrogen following delivery, and this could be an additional reason for a flare in AIH ( 63 ) ( Figure 2 ). Although the effect of high level estrogen during pregnancy was thought to induce tolerance, more recent investigations have shown that heightened levels of estrogen receptor alpha (ERα) is leading to the impairment of Tregs in AIH ( 64 ). A fall in P4 also leads to lack of inhibition of Th1 development which could result in a post-partum flare in AIH patients ( 16 ).…”

Section: Flare Up Of Autoimmune Hepatitis During Pregnancy Post-partmentioning

confidence: 99%

Autoimmune Hepatitis: Tolerogenic Immunological State During Pregnancy and Immune Escape in Post-partum

et al. 2020

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Altered aryl-hydrocarbon-receptor signalling affects regulatory and effector cell immunity in autoimmune hepatitis

Cited by 33 publications

References 45 publications

Targeting Enclysis in Liver Autoimmunity, Transplantation, Viral Infection and Cancer

Targeting Enclysis in Liver Autoimmunity, Transplantation, Viral Infection and Cancer

Ectonucleotidase Modulation of Lymphocyte Function in Gut and Liver

Autoimmune Hepatitis: Tolerogenic Immunological State During Pregnancy and Immune Escape in Post-partum

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