Liver injury in acute hepatitis A is associated with decreased frequency of regulatory T cells caused by Fas-mediated apoptosis

Yoon Seok Choi, Jeewon Lee, Hyun Woong Lee, Dong Yeop Chang, Pil Soo Sung, Min Kyung Jung, Jun Yong Park, Ja Kyung Kim, Jung Il Lee, Hana Park, Jae Youn Cheong, Kyung Suk Suh, Hyung Joon Kim, June Sung Lee, Kyung Ah Kim, Eui Cheol Shin

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Abstract

Objective Foxp3+CD4+CD25+ regulatory T cells (Tregs) control immune responses, but their role in acute viral hepatitis remains elusive. Herein, we investigated alteration in the peripheral blood Treg population during acute hepatitis A (AHA) and its implication in the immune-mediated liver injury. Design The study included 71 patients with AHA, and peripheral blood mononuclear cells (PBMCs) were isolated. The suppressive activity of Treg population was determined by assessing anti-CD3/CD28-stimulated proliferation of Treg-depleted and reconstituted PBMCs. Treg cell frequency, phenotype and apoptosis in PBMCs were analysed by flow cytometry. Results The frequency of circulating Tregs was reduced during AHA. Moreover, the suppressive activity of the total Treg pool in the peripheral blood was attenuated during AHA. Treg frequency and suppressive activity of the Treg population inversely correlated with the serum alanine aminotransferase level. Fas was overexpressed on Tregs during AHA, suggesting their susceptibility to Fas-induced apoptosis. Indeed, increased apoptotic death was observed in Tregs of patients with AHA compared with healthy controls. In addition, agonistic anti-Fas treatment further increased apoptotic death of Tregs from patients with AHA. The decreased Treg frequency and Fas overexpression on Tregs were not observed in other acute liver diseases such as acute hepatitis B, acute hepatitis C and toxic/drug-induced hepatitis. Conclusions The size of the Treg pool was contracted during AHA, resulting from apoptosis of Tregs induced by a Fas-mediated mechanism. Decrease in Treg numbers led to reduced suppressive activity of the Treg pool and consequently resulted in severe liver injury during AHA.

Original languageEnglish
Pages (from-to)1303-1313
Number of pages11
JournalGut
Volume64
Issue number8
DOIs
Publication statusPublished - 2015 Aug 1

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All Science Journal Classification (ASJC) codes

  • Gastroenterology

Cite this

Choi, Y. S., Lee, J., Lee, H. W., Chang, D. Y., Sung, P. S., Jung, M. K., Park, J. Y., Kim, J. K., Lee, J. I., Park, H., Cheong, J. Y., Suh, K. S., Kim, H. J., Lee, J. S., Kim, K. A., & Shin, E. C. (2015). Liver injury in acute hepatitis A is associated with decreased frequency of regulatory T cells caused by Fas-mediated apoptosis. Gut, 64(8), 1303-1313. https://doi.org/10.1136/gutjnl-2013-306213