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Vuerich M, Harshe R, Frank LA, et al. Altered aryl-hydrocarbon-receptor signalling affects regulatory and effector cell immunity in autoimmune hepatitis. J Hepatol. 2020;74(1):48-57doi: 10.1016/j.jhep.2020.06.044.
Vuerich, M., Harshe, R., Frank, L. A., Mukherjee, S., Gromova, B., Csizmadia, E., Nasser, I. A. M., Ma, Y., Bonder, A., Patwardhan, V., Robson, S. C., & Longhi, M. S. (2021). Altered aryl-hydrocarbon-receptor signalling affects regulatory and effector cell immunity in autoimmune hepatitis. Journal of hepatology, 74(1), 48-57. https://doi.org/10.1016/j.jhep.2020.06.044
Vuerich, Marta, et al. "Altered aryl-hydrocarbon-receptor signalling affects regulatory and effector cell immunity in autoimmune hepatitis." Journal of hepatology vol. 74,1 (2021): 48-57. doi: https://doi.org/10.1016/j.jhep.2020.06.044
Vuerich M, Harshe R, Frank LA, Mukherjee S, Gromova B, Csizmadia E, Nasser IAM, Ma Y, Bonder A, Patwardhan V, Robson SC, Longhi MS. Altered aryl-hydrocarbon-receptor signalling affects regulatory and effector cell immunity in autoimmune hepatitis. J Hepatol. 2021 Jan;74(1):48-57. doi: 10.1016/j.jhep.2020.06.044. Epub 2020 Jul 11. PMID: 32663496; PMCID: PMC7749856.
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J Hepatol. 2021 Jan;74(1):48-57. doi: 10.1016/j.jhep.2020.06.044. Epub 2020 Jul 11.

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

Journal of hepatology

Marta Vuerich, Rasika Harshe, Luiza Abrahão Frank, Samiran Mukherjee, Barbora Gromova, Eva Csizmadia, Imad A M Nasser, Yun Ma, Alan Bonder, Vilas Patwardhan, Simon C Robson, Maria Serena Longhi

Affiliations

  1. Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  2. Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
  3. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  4. Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Liver Sciences and Medicine, King's College London, London, UK.
  5. Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  6. Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  7. Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Electronic address: [email protected].

PMID: 32663496 PMCID: PMC7749856 DOI: 10.1016/j.jhep.2020.06.044

Abstract

BACKGROUND & AIMS: In autoimmune hepatitis (AIH), the imbalance between regulatory T cells (Tregs) and T-helper type 17 (Th17) cells has been linked to low levels of CD39, an ectoenzyme that hydrolyses ATP, ultimately generating immunosuppressive adenosine. Upregulation of CD39 results from activation of aryl hydrocarbon receptor (AHR), which mediates toxin responses to modulate T-cell immunity. In this study, we investigated whether altered AHR signalling underlies defective CD39 expression and function in AIH Tregs and Th17 cells, therefore contributing to regulatory/effector cell imbalance.

METHODS: Tregs and Th17 cells, obtained from the peripheral blood of 49 patients with AIH and 21 healthy individuals (HI), were tested for response to endogenous and exogenous AHR ligands.

RESULTS: When compared to those of HI, AIH-derived Tregs and Th17 cells displayed impaired responses to AHR activation, reflected by impaired upregulation of CD39, delayed increase in ectoenzymatic activity, and defective Treg suppressive function. These impairments resulted, at least in part, from heightened levels of AHRR and Erα in Tregs and high HIF-1α in Th17 cells, and were reverted upon molecular blockade. Importantly, in AIH-derived Tregs, the binding affinity of AHR was higher for Erα than ARNT.

CONCLUSIONS: In AIH, high levels of AHRR and HIF-1α inhibit AHR signalling in Tregs and Th17 cells. AHR non-canonical binding to Erα further amplifies the lack of effective CD39 upregulation. Blockade of these inhibitory and/or non-canonical activation pathways represents a potential therapeutic approach to restore CD39 and immunohomeostasis in AIH.

LAY SUMMARY: In patients with autoimmune hepatitis, the imbalance between regulatory T cells and T helper type-17 cells is linked to dysfunction of the aryl hydrocarbon receptor pathway, resulting from aberrant inhibition or non-canonical activation. These alterations impair Treg- and Th17 cell-induced upregulation of CD39, an ectoenzyme key to immunoregulation. Blockade of excessive inhibition or non-canonical activation of the aryl hydrocarbon receptor pathway might represent a novel therapeutic strategy to control inflammation while restoring immune balance in autoimmune hepatitis.

Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Keywords: AHR; AIH; Ectoenzyme; HIF-1α

Conflict of interest statement

Conflicts of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details.

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