Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium ; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
PLoS One. 2013 Nov 28;8(11):e81856. doi: 10.1371/journal.pone.0081856. eCollection 2013.
Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) remains a poorly understood complication in HIV-TB co-infected patients initiating antiretroviral therapy (ART). The role of the innate immune system in TB-IRIS is becoming increasingly apparent, however the potential involvement in TB-IRIS of a leaky gut and proteins that interfere with TLR stimulation by binding PAMPs has not been investigated before. Here we aimed to investigate the innate nature of the cytokine response in TB-IRIS and to identify novel potential biomarkers.
From a large prospective cohort of HIV-TB co-infected patients receiving TB treatment, we compared 40 patients who developed TB-IRIS during the first month of ART with 40 patients matched for age, sex and baseline CD4 count who did not. We analyzed plasma levels of lipopolysaccharide (LPS)-binding protein (LBP), LPS, sCD14, endotoxin-core antibody, intestinal fatty acid-binding protein (I-FABP) and 18 pro-and anti-inflammatory cytokines before and during ART.
We observed lower baseline levels of IL-6 (p = 0.041), GCSF (p = 0.036) and LBP (p = 0.016) in TB-IRIS patients. At IRIS event, we detected higher levels of LBP, IL-1RA, IL-4, IL-6, IL-7, IL-8, G-CSF (p ≤ 0.032) and lower I-FABP levels (p = 0.013) compared to HIV-TB co-infected controls. Only IL-6 showed an independent effect in multivariate models containing significant cytokines from pre-ART (p = 0.039) and during TB-IRIS (p = 0.034).
We report pre-ART IL-6 and LBP levels as well as IL-6, LBP and I-FABP levels during IRIS-event as potential biomarkers in TB-IRIS. Our results show no evidence of the possible contribution of a leaky gut to TB-IRIS and indicate that IL-6 holds a distinct role in the disturbed innate cytokine profile before and during TB-IRIS. Future clinical studies should investigate the importance and clinical relevance of these markers for the diagnosis and treatment of TB-IRIS.
在开始抗逆转录病毒治疗（ART）的 HIV-TB 合并感染患者中，结核相关免疫重建炎症综合征（TB-IRIS）仍然是一种了解甚少的并发症。先天免疫系统在 TB-IRIS 中的作用变得越来越明显，但是以前尚未研究过肠道通透性增加以及通过结合 PAMP 干扰 TLR 刺激的蛋白质在 TB-IRIS 中的潜在作用。在这里，我们旨在研究 TB-IRIS 中细胞因子反应的先天性质，并确定新的潜在生物标志物。
从接受 TB 治疗的大型前瞻性 HIV-TB 合并感染患者队列中，我们比较了在 ART 的第一个月中发生 TB-IRIS 的 40 例患者与年龄，性别和基线 CD4 计数匹配的 40 例未发生 TB-IRIS 的患者。我们分析了在 ART 前后血浆中内毒素结合蛋白（LBP），内毒素，sCD14，内毒素核心抗体，肠脂肪酸结合蛋白（I-FABP）和 18 种促炎和抗炎细胞因子的水平。
我们发现 TB-IRIS 患者的 IL-6（p = 0.041），GCSF（p = 0.036）和 LBP（p = 0.016）的基线水平较低。在 IRIS 事件中，与 HIV-TB 合并感染对照相比，我们检测到 LBP，IL-1RA，IL-4，IL-6，IL-7，IL-8，G-CSF（p≤0.032）的水平较高，而 I-FABP 水平较低（p = 0.013）。仅在包含 ART 前（p = 0.039）和 IRIS 期间（p = 0.034）有显著细胞因子的多元模型中，IL-6 显示出独立作用。
我们报告了 ART 前的 IL-6 和 LBP 水平以及 IRIS 事件期间的 IL-6，LBP 和 I-FABP 水平作为 TB-IRIS 的潜在生物标志物。我们的结果表明，肠道通透性增加可能对 TB-IRIS 没有贡献，并且表明 IL-6 在 TB-IRIS 之前和期间的失调先天细胞因子谱中具有独特的作用。未来的临床研究应研究这些标志物对 TB-IRIS 的诊断和治疗的重要性和临床相关性。
