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Published on: September 25, 2019
Skewed CD39/CD73/adenosine pathway contributes to B-cell hyperactivation and disease progression in patients with
Shuang-Nan Zhou1,2,3, Ning Zhang4, Hong-Hong Liu5
1Medical School of Chinese PLA, Beijing, P. R. China.
Insights
In chronic hepatitis B (CHB) patients, reduced CD39/CD73 expression on B-cells is linked to high viral load and inflammation. Targeting this pathway with metformin may help reverse immune dysfunction.
Area of Science:
- Immunology
- Hepatology
- Pharmacology
Background:
- Mechanisms of B-cell hyperactivation in chronic hepatitis B virus (HBV) infection are not fully understood.
- The CD39/CD73/adenosine pathway's role in chronic hepatitis B (CHB) requires further investigation.
Purpose of the Study:
- To assess the clinical characteristics of the CD39/CD73/adenosine pathway in HBV-infected patients.
- To investigate the impact of this pathway on B-cell function and potential therapeutic interventions.
Main Methods:
- Examined CD39 and CD73 expression and adenosine production by B-cells in 202 HBV-infected patients.
- Assessed B-cell activation phenotypes via flow cytometry with or without adenosine pathway modulation.
- Investigated metformin's effect on B-cells and AMP-activated protein kinase.
Main Results:
- Decreased CD39/CD73 expression on circulating B-cells correlated with high viral load, HBeAg positivity, and liver inflammation.
- Expression was restored in responders but not increased in memory B-cell subsets.
- Intra-hepatic B-cells showed decreased CD39/CD73 expression in inflammatory livers.
- CHB B-cells had reduced adenosine production and increased activation markers upon blockade.
- Metformin reduced B-cell activation markers by regulating AMP-activated protein kinase.
Conclusions:
- Skewed CD39/CD73 expression on B-cells is associated with viral burden, inflammation, and treatment response in CHB.
- The dysregulated CD39/CD73/adenosine pathway contributes to B-cell hyperactivation in CHB.
- Metformin's regulation of this pathway offers a potential therapeutic strategy for HBV-induced immune pathogenesis.
Background:
The mechanisms underlying B-cell hyperactivation in patients with chronic hepatitis B virus (HBV) infection remain largely undefined. The present study assessed the clinical characteristics of the CD39/CD73/adenosine pathway in patients with chronic hepatitis B (CHB).
Methods:
We examined CD39 and CD73 expression and adenosine production by B-cells from 202 HBV-infected patients. B-cell-activation phenotypes were assessed by flow cytometry after CpG+CD40 ligand stimulation with or without blockade and activation of the adenosine pathway.
Results:
CD39 and CD73 expression on circulating B-cells was decreased in CHB patients with high HBV DNA, HBeAg positivity, high HBsAg levels, and active liver inflammation, and was hierarchically restored in complete responders according to HBeAg seroconversion or HBsAg reduction. However, CD39 and CD73 expression on activated memory and tissue-like memory B-cell subsets in complete responders was not increased despite effective antiviral treatments. Furthermore, CD39 and CD73 expression on intra-hepatic B-cells was decreased in inflammatory livers. In vitro, B-cells from CHB patients showed a markedly reduced capacity to generate CD39/CD73-dependent extracellular adenosine and expressed increased levels of activation markers after adenosine-production blockade. Contrastingly, metformin significantly reduced activation-marker expression via regulating AMP-activated protein kinase.
Conclusions:
The skewed CD39 and CD73 expression on B-cells was associated with a high viral burden, liver inflammation, and antiviral efficacy in CHB patients, and the skewed CD39/CD73/adenosine pathway contributed to B-cell hyperactivation. Regulation of the CD39/CD73/adenosine pathway using metformin may represent a therapeutic option to reverse HBV-induced immune pathogenesis.
