title: Activity of the kynurenine pathway and its interplay with immunity in patients with pulmonary arterial hypertension.
abstract: OBJECTIVE
  We evaluated blood concentrations of kynurenine pathway metabolites, natural and induced regulatory T cells (nTreg, iTreg), and Th17 cells in order to examine the activity of the kynurenine pathway and its relation to immune status in patients with pulmonary arterial hypertension (PAH).
  
  
  METHODS
  Plasma concentrations of tryptophan, kynurenine, kynurenic acid, anthranilic acid, and 3-hydroxykynurenine were quantified in 26 patients with PAH (vs 30 healthy controls) at baseline and after 6 months, and assessed them in relation to clinical parameters, frequencies of lymphocyte subsets, and outcome.
  
  
  RESULTS
  The PAH group presented higher concentrations of tryptophan (52.9 (IQR 46.3-57.5) vs 40.3 (35.2-46.3) µmol/L, p=0.00003), kynurenine 2.8 (2.4-3.4) vs 1.9 (1.5-2.3) µmol/L, p=0.000007), kynurenine/tryptophan ratio (0.051 (0.044-0.064) vs 0.043 (0.039-0.055), p=0.03), iTreg frequencies (10.5 (8.8-13.9)% vs 6.8 (5.2-9.5)%, p=0.002) and iTreg/Th17 (1.73 (1.2-2.8) vs 0.93 (0.61-1.27), p=0.003) together with lower ratios of kynurenic acid/kynurenine, 3-hydroxykynurenine/kynurenine, and anthranilic acid/kynurenine. Kynurenine concentrations and kynurenine/tryptophan ratio correlated positively with iTreg/Th17, and inversely with Th17 subsets, whereas kynurenic acid/kynurenine and anthranilic acid/kynurenine ratios correlated positively with Th17. Adverse outcomes occurred in 9 of 26 patients and they showed higher baseline concentrations of kynurenine (3.6 (2.8-4.3) vs 2.7 (2.1-3.2) µmol/L, p=0.033). Median kynurenine values ≥3.4 µmol/L (67% sensitivity, 94% specificity) identified patients with a worse clinical course.
  
  
  CONCLUSIONS
  PAH is characterised by upregulated tryptophan metabolism and enhanced biosynthesis of kynurenine. Elevated kynurenine concentration is associated with an adverse clinical course. Dysregulated immunity, delineated by Treg-Th17 imbalance, is directly related to diverse activation of the kynurenine pathway, indicating the potential interplay between kynurenines and the immune system in PAH.
authors.affiliation: Department of Cardiology, Medical University of Bialystok, Bialystok, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Jasiewicz
authors.affiliation: Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, Bialystok, Poland Department of Allergology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Moniuszko
authors.affiliation: Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, Poland.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Pawlak
authors.affiliation: Department of Cardiology, Medical University of Bialystok, Bialystok, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Knapp
authors.affiliation: Department of Haematological Diagnostics, Medical University of Bialystok, Bialystok, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Rusak
authors.affiliation: Department of Cardiology, Medical University of Bialystok, Bialystok, Poland.
authors.forename: Remigiusz
authors.initials: R
authors.lastname: Kazimierczyk
authors.affiliation: Department of Cardiology, Medical University of Bialystok, Bialystok, Poland.
authors.forename: Wlodzimierz Jerzy
authors.initials: WJ
authors.lastname: Musial
authors.affiliation: Department of Haematological Diagnostics, Medical University of Bialystok, Bialystok, Poland.
authors.forename: Milena
authors.initials: M
authors.lastname: Dabrowska
authors.affiliation: Department of Cardiology, Medical University of Bialystok, Bialystok, Poland Department of Population Medicine and Prevention of Civilization Diseases, Medical University of Bialystok, Bialystok, Poland.
authors.forename: Karol Adam
authors.identifier: http://orcid.org/0000-0002-9465-2581
authors.initials: KA
authors.lastname: Kaminski
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D016022:Case-Control Studies; D018450:Disease Progression; D015150:Echocardiography, Doppler; D005080:Exercise Test; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood* / Q000276:immunology; D007736:Kynurenic Acid / Q000097:blood; D007737:Kynurenine / Q000031:analogs & derivatives / Q000097:blood*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012372:ROC Curve; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D014364:Tryptophan / Q000097:blood; D062367:ortho-Aminobenzoates / Q000097:blood
chemical_list: D062367:ortho-Aminobenzoates; C031385:anthranilic acid; C005045:3-hydroxykynurenine; D007737:Kynurenine; D014364:Tryptophan; D007736:Kynurenic Acid