# Alterations of aryl hydrocarbon receptor signaling in autoimmune hepatitis

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $385,000

## Abstract

Abstract
Autoimmune hepatitis (AIH) is a severe liver disease of unknown etiology that typically follows a relapsing-
remitting course and may often become refractory to conventional immunosuppression. This important illness
may progress over months or years to end-stage liver disease with jaundice, requiring transplantation in about
20% of cases. Dysfunctional Tregs co-exist, in AIH, along with heightened Th17 immune responses, which are
refractory to immunoregulation. CD39 is an ectonucleotidase that hydrolyzes extracellular ATP to ultimately
generate immunosuppressive adenosine. This ectoenzyme is expressed by Tregs and a subset of effector Th17
cells, where it marks the acquisition of regulatory properties. Induction of CD39 results, at least in part, from
activation of aryl hydrocarbon receptor (AhR), which mediates toxin responses to modulate Treg and Th17 cell
immunity. AhR binds exogenous and endogenous ligands, including xenobiotics and heme derivatives e.g.
unconjugated bilirubin. AhR functions are mediated through interactions with the aryl hydrocarbon receptor
nuclear translocator or other ‘non-canonical’ binding factors like the estrogen receptor-a (Era) or the Kruppel-
like factor 6. AhR is also regulated by hypoxia inducible factor 1 alpha (HIF-1a), the AhR repressor (AhRR) and
TGF-b and is induced by NF-kB through the Rel-A subunit. We have noted that AIH-derived Tregs and Th17
cells express decreased levels of CD39. This alteration is associated with defective Treg function and
persistence of pro-inflammatory Th17 cells. We also observe that both Tregs and Th17 cells fail to upregulate
CD39 in response to AhR activation. Tregs and Th17 cells in AIH also express heightened Era, KLF6, AhRR
and HIF-1a levels. These data suggest that AhR binding to non-canonical partners and/or aberrant AhR
regulation might interfere with T cell responses, ultimately resulting in CD39 downregulation in AIH. We therefore
hypothesize that Treg and Th17 cell purinergic dysfunction in AIH can be linked to aberrant AhR signaling
and/or regulation. These alterations perpetuate Treg/Th17 cell imbalances that favor tissue damage and disease
progression in AIH. In Aim 1, we will determine whether aberrant AhR interactions with non-canonical partners
impact the purinergic response, metabolic profiles and function of Tregs and Th17 cells; either derived from the
peripheral blood or liver biopsies of AIH patients. In Aim 2, we will define the cellular mechanisms regulating
AhR signaling and how these impact CD39 in AIH-derived Tregs and Th17 cells. In both Aims 1 and 2, the effects
of altered AhR signaling and regulation will be also tested in an in vivo model of acute hepatitis induced by
Concanavalin-A in immunodeficient NOD/scid/gamma mice. Lastly, in Aim 3, we will test innovative strategies
a) to enhance AhR signaling, either by pharmacological blockade of HIF-1a or AhRR; and/or b) directly boost
CD39 activity through administration of exogenous ADPase. Our...

## Key facts

- **NIH application ID:** 10117722
- **Project number:** 1R01DK124408-01A1
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Maria Serena Longhi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,000
- **Award type:** 1
- **Project period:** 2020-09-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10117722

## Citation

> US National Institutes of Health, RePORTER application 10117722, Alterations of aryl hydrocarbon receptor signaling in autoimmune hepatitis (1R01DK124408-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10117722. Licensed CC0.

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