Department of Cardiology, Medical University of Bialystok, Bialystok, Poland.
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.
Heart. 2016 Feb;102(3):230-7. doi: 10.1136/heartjnl-2015-308581.
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).
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.
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.
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.
我们评估了犬尿氨酸途径代谢物、天然和诱导调节性 T 细胞（nTreg、iTreg）和 Th17 细胞的血液浓度，以检查犬尿氨酸途径的活性及其与肺动脉高压（PAH）患者免疫状态的关系。
在基线和 6 个月时，在 26 例 PAH 患者（与 30 例健康对照相比）中定量测定血浆色氨酸、犬尿氨酸、犬尿氨酸酸、邻氨基苯甲酸和 3-羟基犬尿氨酸的浓度，并评估它们与临床参数、淋巴细胞亚群频率和结局的关系。
PAH 组色氨酸浓度较高（52.9（IQR 46.3-57.5）比 40.3（35.2-46.3）µmol/L，p=0.00003），犬尿氨酸 2.8（2.4-3.4）比 1.9（1.5-2.3）µmol/L，p=0.000007），犬尿氨酸/色氨酸比值（0.051（0.044-0.064）比 0.043（0.039-0.055），p=0.03），iTreg 频率（10.5（8.8-13.9）%比 6.8（5.2-9.5）%，p=0.002）和 iTreg/Th17（1.73（1.2-2.8）比 0.93（0.61-1.27），p=0.003）以及犬尿氨酸酸/犬尿氨酸、3-羟基犬尿氨酸/犬尿氨酸和邻氨基苯甲酸/犬尿氨酸的比值降低。犬尿氨酸浓度和犬尿氨酸/色氨酸比值与 iTreg/Th17 呈正相关，与 Th17 亚群呈负相关，而犬尿氨酸酸/犬尿氨酸和邻氨基苯甲酸/犬尿氨酸比值与 Th17 呈正相关。26 例患者中有 9 例发生不良结局，他们的犬尿氨酸基线浓度较高（3.6（2.8-4.3）比 2.7（2.1-3.2）µmol/L，p=0.033）。中位数犬尿氨酸值≥3.4µmol/L（67%敏感性，94%特异性）可识别出临床病程较差的患者。
PAH 的特点是色氨酸代谢上调和犬尿氨酸生物合成增强。升高的犬尿氨酸浓度与不良临床病程相关。免疫失调，表现为 Treg-Th17 失衡，与犬尿氨酸途径的不同激活直接相关，表明犬尿氨酸与免疫系统在 PAH 中可能存在相互作用。
