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Immunologic Research

, Volume 67, Issue 1, pp 39–47 | Cite as

Tryptophan-kynurenine profile in pediatric autoimmune hepatitis

  • Simon D. LyttonEmail author
  • Marcin Osiecki
  • MałgorzataWoźniak
  • Bożena Cukrowska
  • Aldona Wierzbicka
  • Maria Goliszek
  • Piotr Socha
  • Wojciech Janczyk
  • Dilek Dayanakli
  • Dieter Abendroth
  • Sabine Kramp
  • Kai Fechner
  • Thomas Scheper
  • Michael Mahler
  • Chelsea Bentow
  • Dimietrios Bogdanos
  • Dietmar Fuchs
  • Marek Woynarowski
Original Article

Abstract

The impairment of regulatory T cells (Tregs) is a characteristic feature of autoimmune hepatitis (AIH), and the degradation of tryptophan (Trp) to kynurenine (Kyn), by gamma interferon-induced indoleamine-2,3-dioxygenase-1 (IDO-1), is a central metabolomics check point in the differentiation of Tregs. For this reason, we investigate whether or not Kyn and IDO activity is potentially useful biomarkers in pediatric AIH.

Between January 2016 and January 2017, children of AIH type-1 (AIH-1, n = 37), AIH type-2 with liver kidney microsome-1 autoantibodies (AIH-2-LKM-1, n = 8), and autoantibody-negative Wilsons Disease (WD, n = 8) and alpha-1 anti-trypsin deficiency (AATD, n = 10), were enrolled in a cross-sectional survey of Kyn and Trp levels and Kyn/Trp ratios (IDO activity) by HPLC, and neopterin levels by ELISA.

The mean Kyn and mean Kyn/Trp ratios of AIH-1 with smooth muscle antigen (SMA) 1.85 μM and 27 μmole/mmole, and AIH-2-LKM-1; 1.7 μM and 28.6 μmole/mmole were lower than that of the WD; 2.2 μM p = 0.03 and 33 μmole/mmole p = 0.02 and of AATD; 2.3 μM, p = 0.02 and 55 μM, p = 0.001. Kyn/Trp ratios of AIH relapse; 23.6 μmole/mmole were lower than Kyn/Trp ratios of AIH remission; 27.6 μmole/mmole (p < 0.05). The stage of liver disease and grade of liver biopsies in AIH-1 patients negatively correlated with the Kyn/Trp ratios.

The serum Kyn levels and Kyn/Trp ratio of AIH patients, within or below the normal range, indicate a trend of IDO activity lower than non-autoimmune WD or AATD. Prospective monitoring of serum tryptophan metabolomics in larger cohorts of pediatric AIH patients is required to confirm the apparent paradigm of weak IDO activity contributing to the Treg deficit and pathogenesis of pediatric AIH.

Keywords

Pediatric autoimmune hepatitis Autoantibodies Tryptophan Kynurenine Treg cells Serum IDO activity 

Abbreviations

AIH-1

type 1 autoimmune hepatitis

AIH-2

type II autoimmune hepatitis

ALT

alanine aminotransferase

IDO

indoleamine-2,3-dioxygenase-1

Tregs

T-regulatory cells

IFNγ

interferon gamma

IFA

immune fluorescence assay

ANA

anti-nuclear antigen

AST

aspartate aminotransferase

AZA

azathioprine

GGTP

gamma-glutamyltranspeptidase

LC1

anti-liver cytosol antigen 1

LKM-1

anti-liver kidney microsome 1

SMA

anti-smooth muscle antigen

AATD

anti-alpha trypsin deficiency

WD

Wilsons Disease

Kyn

kynurenine

Trp

tryptophan

Notes

Acknowledgements

We thank all the patients who kindly consented to participate in this study and the cooperation of nursing staff for the collection and storage of serum.

Financial support

The research expenses were incurred in part by SeraDiaLogistics and EB Group Sp. All material support is identified in the acknowledgements section.

Compliance with ethical standards

The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by Ethics Committee of the Children’s Memorial Health Institute no 192/KBE/2015 and 231/KBE/2015.

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Simon D. Lytton
    • 1
    Email author
  • Marcin Osiecki
    • 2
    • 3
  • MałgorzataWoźniak
    • 2
    • 3
  • Bożena Cukrowska
    • 2
    • 3
  • Aldona Wierzbicka
    • 2
    • 3
  • Maria Goliszek
    • 2
    • 3
  • Piotr Socha
    • 2
    • 3
  • Wojciech Janczyk
    • 2
    • 3
  • Dilek Dayanakli
    • 3
  • Dieter Abendroth
    • 4
  • Sabine Kramp
    • 5
  • Kai Fechner
    • 5
  • Thomas Scheper
    • 5
  • Michael Mahler
    • 6
  • Chelsea Bentow
    • 5
  • Dimietrios Bogdanos
    • 6
  • Dietmar Fuchs
    • 7
  • Marek Woynarowski
    • 2
    • 3
  1. 1.SeraDiaLogisticsMunichGermany
  2. 2.Children’s Memorial Health InstituteWarsawPoland
  3. 3.Zentrum für Chirurgie Universitätsklinikum Universität UlmULMGermany
  4. 4.Division of Biological Chemistry, Biocenter Innsbruck Medical UniversityCenter for Chemistry and BiomedicineInnsbruckAustria
  5. 5.Euroimmun AGLübeckGermany
  6. 6.Department of Rheumatology and Clinical Immunology, University General Hospital of Larissa, Faculty of Medicine, School of Health SciencesUniversity of ThessalyLarissaGreece
  7. 7.Inova DiagnosticsSan DiegoUSA

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