中性粒细胞活化和 HIV-TB 免疫重建炎症综合征中颗粒产物的释放增强。
Neutrophil Activation and Enhanced Release of Granule Products in HIV-TB Immune Reconstitution Inflammatory Syndrome.
机构信息
Department of Medicine, Wellcome Center for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, South Africa.
Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
出版信息
J Acquir Immune Defic Syndr. 2018 Feb 1;77(2):221-229. doi: 10.1097/QAI.0000000000001582.
BACKGROUND
Tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS) remains incompletely understood. Neutrophils are implicated in tuberculosis pathology but detailed investigations in TB-IRIS are lacking. We sought to further explore the biology of TB-IRIS and, in particular, the role of neutrophils.
SETTING
Two observational, prospective cohort studies in HIV/TB coinfected patients starting antiretroviral therapy (ART), 1 to analyze gene expression and subsequently 1 to explore neutrophil biology.
METHODS
nCounter gene expression analysis was performed in patients with TB-IRIS (n = 17) versus antiretroviral-treated HIV/TB coinfected controls without IRIS (n = 17) in Kampala, Uganda. Flow cytometry was performed in patients with TB-IRIS (n = 18) and controls (n = 11) in Cape Town, South Africa to determine expression of neutrophil surface activation markers, intracellular cytokines, and human neutrophil peptides (HNPs). Plasma neutrophil elastase and HNP1-3 were quantified using enzyme-linked immunosorbent assay. Lymph node immunohistochemistry was performed on 3 further patients with TB-IRIS.
RESULTS
There was a significant increase in gene expression of S100A9 (P = 0.002), NLRP12 (P = 0.018), COX-1 (P = 0.025), and IL-10 (P = 0.045) 2 weeks after ART initiation in Ugandan patients with TB-IRIS versus controls, implicating neutrophil recruitment. Patients with IRIS in both cohorts demonstrated increases in blood neutrophil count, plasma HNP and elastase concentrations from ART initiation to week 2. CD62L (L-selectin) expression on neutrophils increased over 4 weeks in South African controls whereas patients with IRIS demonstrated the opposite. Intense staining for the neutrophil marker CD15 and IL-10 was seen in necrotic areas of the lymph nodes of the patients with TB-IRIS.
CONCLUSIONS
Neutrophils in TB-IRIS are activated, recruited to sites of disease, and release granule contents, contributing to pathology.
背景
结核病免疫重建炎症综合征（TB-IRIS）仍不完全清楚。中性粒细胞与结核病的病理学有关，但在 TB-IRIS 中缺乏详细的研究。我们试图进一步探索 TB-IRIS 的生物学特性，特别是中性粒细胞的作用。
地点
在开始抗逆转录病毒治疗（ART）的 HIV/TB 合并感染患者中进行了两项观察性、前瞻性队列研究，一项用于分析基因表达，随后一项用于探索中性粒细胞生物学。
方法
在乌干达坎帕拉对 TB-IRIS 患者（n=17）与无 IRIS 的抗逆转录病毒治疗 HIV/TB 合并感染对照者（n=17）进行了 nCounter 基因表达分析。在南非开普敦对 TB-IRIS 患者（n=18）和对照者（n=11）进行了流式细胞术，以确定中性粒细胞表面激活标志物、细胞内细胞因子和人中性粒细胞肽（HNPs）的表达。使用酶联免疫吸附试验定量测定血浆中性粒细胞弹性蛋白酶和 HNP1-3。对 3 例进一步的 TB-IRIS 患者进行了淋巴结免疫组织化学检查。
结果
在乌干达的 TB-IRIS 患者中，在开始 ART 后 2 周，S100A9（P=0.002）、NLRP12（P=0.018）、COX-1（P=0.025）和 IL-10（P=0.045）的基因表达显著增加，提示中性粒细胞募集。在两个队列中，IRIS 患者从开始 ART 到第 2 周时，血液中性粒细胞计数、血浆 HNP 和弹性蛋白酶浓度均增加。南非对照组的中性粒细胞 CD62L（L-选择素）表达在 4 周内增加，而 IRIS 患者则相反。TB-IRIS 患者淋巴结的坏死区域可见强烈的中性粒细胞标志物 CD15 和 IL-10 染色。
结论
TB-IRIS 中的中性粒细胞被激活，募集到疾病部位，并释放颗粒内容物，导致病理学改变。
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