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Original article
Activity of the kynurenine pathway and its interplay with immunity in patients with pulmonary arterial hypertension
  1. Malgorzata Jasiewicz1,
  2. Marcin Moniuszko2,3,
  3. Dariusz Pawlak4,
  4. Malgorzata Knapp1,
  5. Malgorzata Rusak5,
  6. Remigiusz Kazimierczyk1,
  7. Wlodzimierz Jerzy Musial1,
  8. Milena Dabrowska5,
  9. Karol Adam Kaminski1,6
  1. 1Department of Cardiology, Medical University of Bialystok, Bialystok, Poland
  2. 2Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, Bialystok, Poland
  3. 3Department of Allergology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
  4. 4Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, Poland
  5. 5Department of Haematological Diagnostics, Medical University of Bialystok, Bialystok, Poland
  6. 6Department of Population Medicine and Prevention of Civilization Diseases, Medical University of Bialystok, Bialystok, Poland
  1. Correspondence to Professor Karol Adam Kaminski, Department of Cardiology, Medical University of Bialystok, Ul. M. Sklodowskiej-Curie 24A, Bialystok 15-276, Poland, fizklin{at}wp.pl

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.

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