CN108368556B - Il-3、il-33和il-12p40用于表征由合胞呼吸道病毒引起的呼吸系统感染的用途 - Google Patents

Il-3、il-33和il-12p40用于表征由合胞呼吸道病毒引起的呼吸系统感染的用途 Download PDF

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CN108368556B
CN108368556B CN201680052892.7A CN201680052892A CN108368556B CN 108368556 B CN108368556 B CN 108368556B CN 201680052892 A CN201680052892 A CN 201680052892A CN 108368556 B CN108368556 B CN 108368556B
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A·M·卡莱伊斯帕拉
S·M·布埃诺拉米雷斯
J·P·贝特兰德纳瓦雷特
M·K·莱雷莫尔科伊
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Abstract

本发明涉及使用分子标志物作为呼吸系统感染病例演变的预后工具来检测呼吸系统疾病。具体而言，在对由合胞呼吸道病毒和人偏肺病毒引起的呼吸系统感染的鉴别诊断过程中，将建立严重性标志物IL‑3、IL‑33和IL12p40的表达模式。可以使用ELISA测定、流式细胞术或实时PCR定义生物样品中分子标志物的表达模式。感染病原体的确认结合分子标志物IL‑3、IL‑33和IL12p40的模式定义将指示疾病严重性的预后。

Description

IL-3、IL-33和IL-12P40用于表征由合胞呼吸道病毒引起的呼 吸系统感染的用途
发明领域
本发明涉及分子标志物作为呼吸系统感染病例演变的检测工具的用途。具体地，在对由合胞呼吸道病毒(SRV)和人偏肺病毒(MPV)引起的呼吸系统感染的鉴别诊断过程中。
具体地，在本发明中描述了标志物IL-3、IL-12p40和IL-33用于预测由SRV引起的细支气管炎导致的反复呼吸系统事件的发生的用途。
现有技术
合胞呼吸道病毒(SRV)是呼吸道感染最常见的原因，也是婴儿下呼吸道急性感染引起住院的首要原因。SRV细支气管炎已经与哮喘和反复喘息相关联，但这种相关联的机制尚未得到阐明。
SRV是属于副粘病毒科(Paramyxoviridae)的包膜病毒，是呼吸道急性感染的更普遍的病原体之一，在公共卫生系统中造成高负荷。
SRV引起所有年龄患者的下呼吸道疾病，在6个月以下的婴儿中并且特别是在慢性疾病或基础疾病患儿中感染更严重。许多患有SRV细支气管炎的婴儿在其生命的头几个月内发展成反复喘息和哮喘，但SRV引起细支气管炎免疫发病机制的具体机制仍不明确。此外，目前的临床参数不允许预测曾经患有SRV细支气管炎的婴儿在以后的生命中遭受某些慢性疾病的可能性。
由这种病毒引起的炎症的特征是在下呼吸道中存在大量的细胞浸润，大部分是嗜中性粒细胞。肺中的这种变化已被描述为诱导特异性细胞因子和趋化因子分泌的由气道上皮细胞中、肺泡巨噬细胞和外周血嗜中性粒细胞的SRV感染的结果。这些分子对炎性细胞和另一种细胞显示趋化性质。Th1/Th2型细胞因子的失衡也被认为是SRV感染引起的细胞募集炎症中的关键事件，其可能由嗜酸性粒细胞和可能有助于哮喘发展的与过敏诱导相关的另一类细胞如嗜碱性粒细胞和肥大细胞介导。此外，已知由气道上皮细胞产生的一些细胞因子直接参与过敏诱导和哮喘，包括IL-25、IL-33和胸腺基质淋巴细胞生成素(TSL)。
在现有技术中发现了一些文献，其指出使用标志物作为呼吸系统疾病的鉴别诊断工具，其中发现：
专利申请WO2012169887A2涉及预测SRV严重性的方法，然而该文献研究标志物OLFM4、CD177、MMP8、MMP9、PTX3、IL-8、RANTES和CD4 及其组合，没有提及使用标志物IL-3、IL-12p40和IL-33。从该文献不能推导得到的是,细胞因子IL-33、IL12p40或IL-3将会与表现出反复喘息的患者或在被SRV感染后未来发展为哮喘的可能性有关系。
文献EP1867734A1描述分子标志物用于疾病的诊断和预后的用途。但是，其涉及的疾病为脑血管型，并且它没有提及用于诊断呼吸系统疾病的标志物。
只有少数研究已经分析了婴儿SRV细支气管炎期间呼吸道的上部和下部区域。本发明的目的是公开分子标志物细胞因子IL-3、IL-12p40 和IL-33用于预测由于SRV感染产生的细支气管炎的未来反复喘息发生 (IL-3和IL12p40)或在这些婴儿生命的较后阶段可能发展成哮喘 (IL-33)的用途。
附图说明
图1。图1显示与对照相比，感染SRV的患者的支气管肺泡灌洗液 (BALF)中细胞因子和趋化因子的产生模式。由Luminex分析在患有SRV 细支气管炎的婴儿和作为对照的健康婴儿的BALF中定义细胞因子和趋化因子浓度。细胞因子和趋化因子浓度以pg/ml表示，并根据它们的四分位数中位数和范围进行分组以用于它们的比较。通过Mann-Whitney 的非参数检验U定义与对照健康婴儿(N＝5)相比SRV细支气管炎(N＝14) 的显著性(*P值<0.05被认为统计学显著)。分析了BALF样品(sampler) 中IL-3、IL-4、IL-10和IL-13(a),IL-1β、IL-6、IL-7和TNF-β (b),趋化因子CCL2/MCP-1、CCL3/MIP 1α、嗜酸性粒细胞趋化因子和IL-8(c)以及IL-12p40、IL-12p70、IFN-γ和IL-17(d)的产生。
图2。图2显示与对照个体相比，感染SRV患者的鼻咽抽吸物(NPA) 样品中细胞因子和趋化因子的产生模式。使用定量RT-PCR中的TaqMan 探针通过相对定量(RQ)将患有SRV细支气管炎的婴儿(N＝14)的NPA中介质(mediator)表达与对照婴儿(N＝5)进行比较。TaqMan特异性探针用于扩增细胞因子IL-1α、IL-1β、TNFα、IL-6和IL-8(a)；趋化因子CXCL10、CCL2/MCP-1、CCL3/MIP-1α和CCL4/MIP-1β(b)。介质的相对浓度表示为相对于对照的相对诱导的增加倍数。它们的中位数和四分位数值分别显示为水平条和矩形(*P值<0.05被认为统计学显著)。
图3。图3显示根据随访期间哮喘发展的SRV细支气管炎婴儿的BALF 样品的细胞因子和趋化因子产生。根据随访期间哮喘发展分析以下细胞因子和趋化因子浓度：嗜酸性粒细胞趋化因子、IL-3、IL-5、TNF-β(a) 和IL-12p40、IL-12p70和IL-7(b)，其是通过Luminex在患有SRV引起的细支气管炎的婴儿的BALF样品中检测的(N＝14)。介质浓度表示为 pg/ml并且它们的中位数和四分位数的值分别显示为水平条和矩形(*P 值<0.05被认为统计学显著)。
图4。图4显示了根据特应性过敏家族史分析的患有SRV细支气管炎的婴儿鼻咽抽吸物中IL-33的ARN信使诱导的相对定量。在具有或不具有特应性过敏家族史的患有SRV细支气管炎的婴儿(N＝14)的鼻咽抽吸物中定义IL-33的基因表达。结果显示为相对于对照的相对诱导的增加倍数。每个组的中位数和四分位数值分别显示为水平条和矩形(*P 值<0.05被认为统计学显著)。
图5。图5显示了感染SRV的患者的BALF样品中IL-12p40和IL-3 与反复喘息发作次数之间的相关性。建立了IL-12p40(a)或IL-3(b)与患有SRV的婴儿(14)的BALF样品中反复喘息发作的Pearson相关性。结果针对随访期间的细胞因子和发作次数表示为pg/ml(*P值<0.05被认为统计学显著)。
发明描述
本发明描述了分子标志物IL-3、IL-12p40和IL-33作为预测在这些婴儿、具体是在12月龄以下的患者中生命的较后阶段在SRV感染引起的细支气管炎后反复喘息发生(IL-3、IL-12p40)和可能发展成哮喘 (IL-33)的分子标志物的用途。
用于预测由SRV和MPV感染发展成的疾病的严重性的方法包括：
-使用标志物IL-3、IL-12p40和IL-33，使用分子生物学方法如PCR 扩增呼吸系统分泌样品；
-用某种分子定量方法如ELISA定量与标志物IL-3、IL-33或 IL-12p40互补的靶序列的过表达；
-基于定量所获得的过表达关联由SRV引起的疾病的发展：如果在支气管肺泡灌洗中发现浓度大于500pg/ml的IL-12p40或IL-3，则发展喘息的可能性高；如果在支气管肺泡灌洗中发现浓度大于500pg/ml的 IL-33，则发展哮喘的可能性高。
实施例
12月龄以下的先前健康的婴儿，由于病毒性细支气管炎而住院治疗的婴儿登记在本研究中。要进入登记，患者必须为SRV免疫荧光阳性并且为12个月以下，没有严重疾病的风险因素，并且在他们第一周住院期间临床评分定义的从轻度演变至中度疾病。患有慢性医疗病况或在登记时接受皮质类固醇的婴儿被排除在本研究之外。在同一时间段内，登记的正常婴儿因非传染性疾病而遭受侵入性手术(腹股沟疝＝4，甲状舌管瘘(fistulatiroglosa)＝1)。其样品用作对照。
评估感染SRV引起细支气管炎的患儿的上呼吸道和下呼吸道中的细胞因子和趋化因子谱。另外，考虑了在三年的随访期间的临床结果。将 SRV细支气管炎和健康对照的住院婴儿的鼻咽抽吸物和BALF联合并通过Luminex和定量实时RT-PCR分析以检测细胞因子和趋化因子。结果，与对照相比，在患有SRV细支气管炎的婴儿的BALF中观察到Th2型细胞因子(IL-3、IL-4、IL-10和IL-13)、促炎细胞因子和趋化因子(IL-1 β、IL-6、TNF-β、MCP-1/CCL2、MIP-1α/CCL3和IL-8)的水平升高。鉴定了显示有特应性过敏家族史的那些患者比没有该家族背景的那些患者产生更高水平的IL-33(图4)。非常特别的是，在感染SRV的婴儿中，IL-3和IL-12p40水平与其生命较后期反复喘息的发展直接相关。实际上，在随访期间，发现SRV感染患者的BALF样品中的IL-12p40和 IL-3水平与反复喘息的次数有显著的直接相关性(Pearson相关性分别如下：r＝0.68；p＝0.0071；r＝0.71；p＝0.0058)(图5)。这些结果表明，IL-3和IL-12p40是患有由SRV引起的细支气管炎的婴儿中反复喘息的分子预测物。
纳入十四个患有SRV细支气管炎的患者和五个对照。患有SRV细支气管炎的婴儿平均住院4.5天(范围：1-9天)，严重性评分中位数相当于4。所有这些患者在头两天、进行手术之前能够用氧气治疗(leave the therapy with oxygen)。他们没有因手术而出现并发症，并在良好的条件下出院。所有患者都进行了三年监测，没有因其他原因导致住院的报告。对照组中的一个患者在24个月后不能随访。评估的临床变量为：医生报告的反复喘息，医生报告的哮喘诊断和长期使用皮质类固醇治疗，在临床随访期间没有显示出两组之间具有显著差异的特征。表 1总结了临床特征。
表1.登记患者的临床特征。
RSV(n＝14) 对照(n＝5)
月龄(范围) 2.2(0-9) 2.8(1-6)
性别：男/女 6-8 3-2
亲本特应性过敏 7-14 2-5
临床评分(范围) 4(1-7) -
住院天数(范围) 4.5(1-9) -
反复喘息 4-14 2-5
哮喘 3-14 0-5
用皮质类固醇治疗 6-14 1-5
患有SRV细支气管炎的婴儿的BALF样品中细胞因子和趋化因子的产生。
通过Luminex测量了与对照婴儿相比，患有SRV细支气管炎的婴儿 BALF样品中的细胞因子和趋化因子蛋白浓度水平。与对照相比，观察到患有SRV细支气管炎的婴儿BALF样品中的IL-3、IL-4、IL-10、IL-13 (与Th2相关的细胞因子)；IL-1β、IL-6、TNF-β(促炎细胞因子)； MCP-1/CCL2、MIP-1α/CCL3、IL-8(趋化因子)；IL-12p40(与Th1相关的细胞因子)；和IL-7(生长因子)的水平升高。与对照婴儿相比，发现患有SRV细支气管炎的婴儿BALF样品中的嗜酸性粒细胞趋化因子 (趋化因子)和IL-12p70的水平显著降低。无论是感染患者还是健康对照的BALF中没有检测到IFN-γ(与Th1相关的细胞因子)和IL-17 (与Th17相关的细胞因子)的产生(图1)。
与没有发展成哮喘的患者相比，在随访期间发展成哮喘的患有SRV 细支气管炎的婴儿BALF样品中观察到IL-12p40、IL-12p70(与Th1 相关的细胞因子)、IL-3、IL-5(与Th2相关的细胞因子)、TNF-β(促炎细胞因子)、嗜酸性粒细胞趋化因子(趋化因子)和IL-7(生长因子) 的水平显著升高(图3)。此外，与没有特应性过敏家族史的患者相比，有特应性过敏家族史的感染有SRV的患者的鼻咽抽吸物中观察到相对于 GAPDH标准化的信使ARN IL-33的显著增加(图4)。

Claims (3)

1.分子标志物IL-3、IL-12p40和IL-33组合在制备试剂盒中的用途，其中所述试剂盒用于评估由呼吸道合胞病毒(RSV)引起的呼吸感染后反复喘息和哮喘的预测。
2.根据权利要求1所述的分子标志物IL-3、IL-12p40和IL-33组合的用途，其中呼吸感染之一是细支气管炎。
3.根据权利要求1所述的分子标志物IL-3、IL-12p40和IL-33组合的用途，其中评估由RSV引起的呼吸感染后的反复喘息和哮喘包括：
使用标志物IL-3、IL-12p40和IL-33，使用选自PCR和ELISA的分子或免疫学技术进行扩增和检测；
定量与标志物IL-3、IL-33或IL-12p40互补的靶序列的过表达；
基于定量所获得的过表达关联由RSV引起的疾病的发展：如果在支气管肺泡灌洗中发现浓度大于500pg/ml的IL-12p40或IL-3，则发展喘息的可能性高；如果在支气管肺泡灌洗中发现浓度大于500pg/ml的IL-33，则发展哮喘的可能性高。
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