Research Article: Pediatric autoimmune hepatitis shows a disproportionate decline of regulatory T cells in the liver and of IL-2 in the blood of patients undergoing therapy

Date Published: July 11, 2017

Publisher: Public Library of Science

Author(s): Jana Diestelhorst, Norman Junge, Jerome Schlue, Christine S. Falk, Michael P. Manns, Ulrich Baumann, Elmar Jaeckel, Richard Taubert, Pierre Bobé.

http://doi.org/10.1371/journal.pone.0181107

Abstract

The autoimmune hepatitis (AIH) is a chronic hepatitis driven by the adaptive immunity that affects all age groups. A functional and numerical regulatory T cell (Treg) defect has been reported in pediatric AIH (pAIH), while an intrahepatic increase in adult AIH (aAIH) patients has been detected in current research findings.

Therefore, we quantified the intrahepatic numbers of Treg, T and B cells, as well as serum cytokine levels before and during therapy in pAIH.

We found a disproportional intrahepatic enrichment of Tregs in untreated pAIH compared to pediatric non-alcoholic fatty liver disease. The increase of Treg/total T cells was even more pronounced than in aAIH due to fewer infiltrating T and B cells. Portal densities of Treg, as well as total T and B cells, declined significantly during therapy. However, portal Treg densities decreased disproportionately, leading to even decreasing ratios of Treg to T and B cells during therapy. Out of 28 serum cytokines IL-2 showed the strongest (10fold) decrease under therapy. This decline of IL-2 was associated with decreasing intrahepatic Treg numbers under therapy. None of the baseline T and B cell infiltration parameters were associated with the subsequent treatment response in pAIH.

Intrahepatic Tregs are rather enriched in untreated pAIH. The disproportional decrease of Tregs during therapy may be caused by a decrease of IL-2 levels. New therapies should, therefore, aim in strengthening intrahepatic immune regulation.

Partial Text

Autoimmune hepatitis (AIH) is a chronic immune mediated hepatitis that manifests in all age groups and is currently displaying an increase of incidences [1]. In contrast to adult AIH (aAIH), the pediatric form (pAIH) often manifests more acutely and has a more aggressive disease course [2]. In pAIH patients the proportions of AIH type 2 (AIH-2), that is characterized by the presence of antibodies against Cytochrome P450 2D6 and/or Formimidoyltransferase Cyclodeaminase, and biliary autoimmune manifestation, the so called autoimmune sclerosing cholangitis are higher [3]. Furthermore, the frequencies of the major genetic risk alleles of the MHC class II locus are age dependent. While both HLA-DRB1*03 and *04 predispose to adult manifestations, pAIH is associated with HLA-DRB1*03 and HLA-DRB1*13, relative to the geographical region [2, 4, 5].

The present study closes a gap in the current controversy about a Treg defect as a driver of AIH. Previously, we and others could not confirm such a Treg deficiency in the blood and livers of aAIH patients with the application of the latest markers for human Treg (mostly FOXP3, CD127 and demethylation of TSDR of the FOXP3 gene locus) but rather consistently found an intrahepatic enrichment of Treg in untreated aAIH [11, 13, 14]. However, at least lower Treg numbers in the peripheral blood of pediatric autoimmune liver diseases could be confirmed with the latest Treg markers [15].

 

Source:

http://doi.org/10.1371/journal.pone.0181107

 

0 0 vote
Article Rating
Subscribe
Notify of
guest
0 Comments
Inline Feedbacks
View all comments