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.
This is a preview of subscription content, log in to check access.
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.
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.
Doherty DG. Immunity, tolerance and autoimmunity in the liver: a comprehensive review. J Autoimmun. 2018;66:60–75.CrossRefGoogle Scholar
Grant CR, Holder BS, Liberal R, Heneghan MA, Ma Y, Mieli-Vergani G, et al. Immunosuppressive drugs affect interferon (IFN)-γ and programmed cell death 1 (PD-1) kinetics in patients with newly diagnosed autoimmune hepatitis. Clin Exp Immunol. 2017;189:71–82.CrossRefGoogle Scholar
Behairy BE, El-Araby HA, Abd El Kader HH, et al. Assessment of intrahepatic regulatory T cells in children with autoimmune hepatitis. Ann Hepatol. 2016;15:682–90.Google Scholar
Xue Y, Michalopoulos G. Tregs: a therapeutic target for the treatment of portal fibrosis? Dig Dis Sci. 2015;60:1878–80.CrossRefGoogle Scholar
Alvarez F, Berg PA, Bianchi FP. International autoimmune hepatitis group report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 1999;31:929e938.CrossRefGoogle Scholar
Manns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli-Vergani G, Vergani D, et al. Diagnosis and management of autoimmune hepatitis. Hepatology. 2010;51:2193–213.CrossRefGoogle Scholar
Hennes EM, Zeniya M, Czaja AI, Pares A, Dalekos GN, et al. International autoimmune hepatitis group simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology. 2008;48:169–76.CrossRefGoogle Scholar
EASL Clinical Practice Guidelines. Autoimmune hepatitis European association for the study of the liver. J Hepatol. 2015;63:971–1004.CrossRefGoogle Scholar
Mieli-Vergani G, Vergani D, Baumann U, Czubkowski P, Debray D, Dezsofi A, et al. Diagnosis and management of paediatric autoimmune liver disease: ESPGHAN hepatology committee position statement. J Pediatr Gastroenterol Nutr. 2017;66(2):345–60.CrossRefGoogle Scholar
Floreani A, Liberal R, Vergani D, Mieli-Vergani G. Autoimmune hepatitis: contrast and comparison in children and adults-a comprehensive review. J Autoimmun. 2013;46:7–16.CrossRefGoogle Scholar
Healey R, Corless L, Gordin P, Holding S. Do anti-smooth muscle antibodies predict development of autoimmune hepatitis in patients with normal liver function? A retrospective cohort review. Autoimmun Rev. 2016;15:668–72.CrossRefGoogle Scholar
Liberal R, Vergani D, Mieli-Vergani G. Update on autoimmune hepatitis. J Clin Trans Hepatol. 2015;3:42–52.CrossRefGoogle Scholar
Woynarowski M, Woźniak M, Cukrowska B, Cukrowska B, Wierzbicka A, Lytton SD. Autoantibody profile of adult patients with childhood onset type 2 autoimmune hepatitis. J Clin Lab Anal. 2016;30(5):590–6.CrossRefGoogle Scholar
Duchini A, McHutchison JG, Pockros PJ. LKM-positive autoimmune hepatitis in the western United States: a case series. Am J Gastroenterol. 2000;95:3238–41.CrossRefGoogle Scholar
Gregorio GV, Portmann B, Reid F, Donaldson PT, Doherty DG, McCartney M, et al. Autoimmune hepatitis in childhood: a 20-year experience. Paedatic J Clin Transl Hepatol. 2015;42–52(43):3.Google Scholar
Gatselis NK, Zachou K, Koukoulis GK, Dalekos GN. Autoimmune hepatitis, one disease with many faces: etiopathogenetic, clinico-laboratory and histological characteristics. World J Gastroenterol. 2015;21:60–83.CrossRefGoogle Scholar
Bogdanos DP, Invernizzi P, Mackay IR, Vergani D. Autoimmune liver serology: current diagnostic and clinical challenges. World J Gastroenterol. 2008;14:3374–87.CrossRefGoogle Scholar
Villata D, Girolami E, Alessio MG, et al. Autoantibody profiling in a cohort of pediatric and adult patients with autoimmune hepatitis. J Clin Lab Anal. 2016;30:41–6.CrossRefGoogle Scholar
Paolo M, Cumali E, Luigi M, Ersan O Schiano T, Yoshida EM, Heurgué-Berlot, et al. Clinical implications of antimitochondrial antibody seropositivity in autoimmune hepatitis: a multicentre study. Eur J Gastroenterol Hepatol. 2017;29:777–80.CrossRefGoogle Scholar
Roggenbruck D, Mytilnaiou MG, Lapin SV, Rheinhold D, Conrad K. Asialoglycoprotein receptor (ASGPR): a peculiar target of liver-specific autoimmunity. Autoimmun Highlights. 2012;3:119–25.CrossRefGoogle Scholar
Norman GL, Yang CY, Ostendorff HP, Lim MJ, Wang J, et al. Anti-Kelch-like 12 and anti-hexokinase 1: novel autoantibodies in primary biliary cirrhosis. Liver Int. 2015;35:642–51.CrossRefGoogle Scholar
Lytton SD, Berg U, Nemeth A, Ingelman-Sundberg M. Autoantibodies against cytochrome P450s in sera of children treated with immunosuppressive drugs. Clin Exp Immunol. 2012;127:293–302.CrossRefGoogle Scholar
Woynarowski M, Nemeth A, Baruch Y. Budesonide versus prednisone with azathioprine for the treatment of autoimmune hepatitis in children and adolescents. J Pediatr. 2013;163:1347–53.CrossRefGoogle Scholar
Batts KP, Ludwig J. Chronic hepatitis. An update on terminology and reporting. Am J Surg Pathol. 1995;19:1409–17.CrossRefGoogle Scholar
Goodman GD. Grading and staging systems for inflammation and fibrosis in chronic liver diseases. J Hepatol. 2007;47:598–607.CrossRefGoogle Scholar
Roberts EA, Schilsky ML. Diagnosis and treatment of Wilson Disease: an update. Hepatology. 2008;47:2090–111.CrossRefGoogle Scholar
Lauletta G, Russi S, Pavone F, Marzullo A, Tampoia A, Sansonno D, et al. Autoimmune hepatitis: factors involved in initiation and methods of diagnosis and treatment. Crit Rev Immunol. 2016;36:407.428.CrossRefGoogle Scholar
Dhaliwal HK, Hoeroldt BS, Dube AK, McFarlane E, Underwood JC, Karajeh MA, et al. Long-term prognostic significance of persisting histological activity despite biochemical remission in autoimmune hepatitis. Am J Gastroenterol. 2015;110:993–9.CrossRefGoogle Scholar
Aizawaa Y, Abea H, Sugitaa T, Sekia N, Chuganjic Y, Furumotoc Y, et al. Centrilobular zonal necrosis as a hallmark of a distinctive subtype of autoimmune hepatitis. Eur J Gastroenterol Hepatol. 2016;28:391–7.Google Scholar
Abdel-Razik A, Mousa N, Zakaria S, Elhelaly R, Elzehery R, Zalata K, et al. New predictive factors of poor response to therapy in autoimmune hepatitis: role of mean platelet volume. Eur J Gastroenterol Hepatol. 2017;29:1373–9.CrossRefGoogle Scholar
Diestelhorst J, Junge N, Jonigk D, Schlue J, Falk CS, Manns MP, et al. Baseline IL-2 and the AIH score can predict the response to standard therapy in paediatric autoimmune hepatitis. Sci Rep. 2018;8:419.CrossRefGoogle Scholar
Dounay AB, Tuttle JB, Verhoest PR. Challenges and opportunities in the discovery of new therapeutics targeting the kynurenine pathway. J Med Chem. 2015;58:8762–82.CrossRefGoogle Scholar
Zuo H, Ueland PM, Ulvik A, Eussen S, et al. Plasma biomarkers of inflammation, the kynurenine pathway, and risks of all-cause, cancer, and cardiovascular disease mortality: the Hordaland health study. Am J Epidemiol. 2016;183:249–58.CrossRefGoogle Scholar
Lippens C, Duraes FV, Dubrot J, Brighouse D, Lacroix M, Irla M, et al. IDO-orchestrated crosstalk between pDCs and Tregs inhibits autoimmunity. J Autoimmun. 2016;75:39–49.CrossRefGoogle Scholar
Llamas-Velasco M, Bonay P, José Concha-Garzón M, Corvo-Villén L, Cibrián D, Sanguino-Pascual A, et al. Immune cells from patients with psoriasis are defective in inducing indoleamine 2,3-dioxygenase expression in response to inflammatory stimuli. Br J Dermatol. 2017;176:695–704.CrossRefGoogle Scholar
Bernard NJ. Rheumatoid arthritis: who knows why regulatory T cells are defective in RA. IDO Nat Rev Rheumatol. 2014;10:381–96.CrossRefGoogle Scholar
Konstantia-Maria C, Shukla D, Keteepe-Arachi T, Sekel JA, Fuchs D, Pussey CD, et al. Regulation of myeloperoxidase-specific T cell responses during disease remission in anti-neutrophil cytoplasmic antibody–associated vasculitis: the role of Treg cells and tryptophan degradation. Arthritis Rheum. 2010;62:1539–48.CrossRefGoogle Scholar
Palabiyik SS, Keles S, Girgin G, Arpali-Tanas E, Topdagi E, Baydar T. Neopterin release and tryptophan degradation in patients with uveitis. Curr Eye Res. 2016;41:1513–7.CrossRefGoogle Scholar
Kaden J, Abendroth DE, Völp M, Marzinzig M, Wesslau C. Causes and prognostic value of pre-transplant elevated kynurenine level in kidney allograft recipients. Ann Transplant. 2014;19:51–9.CrossRefGoogle Scholar
Kaden J, Abendroth D, Völp A, Marzinzig M. Dynamics and diagnostic relevance of kynurenine serum level after kidney transplantation. Ann Transpl. 2015;20:327–37.Google Scholar
Yoshio S, Sugiyama M, Shoji H, et al. Indoleamine-2,3-dioxygenase as an effector and an indicator of protective immune responses in patients with acute hepatitis B. Hepatol. 2016;63:3–94.CrossRefGoogle Scholar
Bipath P, Levay PF, Viljoen M. The kynurenine pathway activities in a sub-Saharan HIV/AIDS population. BMC Infect Dis. 2015;15:346–61.CrossRefGoogle Scholar
Mehraj J, Routy JP. Tryptophan catabolism in chronic viral infections: handling uninvited guests. Int J Tryptophan Res. 2015;8:41–6.CrossRefGoogle Scholar
Zoller H, Jenal A, Staettermayer AF, Schroecksnadel S, Ferenci P, Fuchs D. Tryptophan breakdown in patients with HCV infection is influenced by IL28B polymorphism. Pharmaceuticals. 2015;8:337–50.CrossRefGoogle Scholar
Danikowski KM, Jayaraman S, Prabhaka BS. Regulatory T cells in multiple sclerosis and myasthenia gravis. J Neuroinflammation. 2017;14:117–33.CrossRefGoogle Scholar
Geisler S, Mayersbach P, Becker K, Schennach H, Fuchs D, Gostner JM. Serum tryptophan, kynurenine, phenylalanine, tyrosine and neopterin concentrations in 100 healthy blood donors. Pteridines. 2015;26:31–6.CrossRefGoogle Scholar
Schröcksnadel K, Wirleitner B, Winkler C, Fuchs D. Monitoring tryptophan metabolism in chronic immune activation. Clin Chim Acta. 2016;364:82–90.CrossRefGoogle Scholar
Gibson RN, Donlan JD, Ditchfield MR, Bhathal PS. Duplex Doppler ultrasound of the ligamentum teres and portal vein: a clinically useful adjunct in the evaluation of patients with known or suspected chronic liver disease or portal hypertension. J Gastroenterol Hepatol. 1991;6:61–5.CrossRefGoogle Scholar