嗜碱性粒细胞活化试验在过敏诊断中的应用

Inmaculada Doña; Adriana Ariza; Tahia D. Fernández; María J. Torres

doi:10.3791/62600

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方法文章

嗜碱性粒细胞活化试验在过敏诊断中的应用

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DOI：

10.3791/62600

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2021年5月31日

Inmaculada Doña^*¹^,² , Adriana Ariza^*² , Tahia D. Fernández²^,³ , María J. Torres¹^,²^,⁴^,⁵

¹Allergy Unit, Hospital Regional Universitario de Málaga, ²Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, ³Universidad de Málaga, Departamento de Biología celular, Genética y Fisiología, Universidad de Málaga, ⁴Departamento de Medicina, Universidad de Málaga, ⁵Nanostructures for Diagnosing and Treatment of Allergic Diseases Laboratory, Andalusian Center for Nanomedicine and Biotechnology-BIONAND

^* These authors contributed equally

本文内容

摘要

嗜碱性粒细胞活化试验是一种补充性体外基于流式细胞术检测特定刺激下嗜碱性粒细胞活化标志物，用于评估IgE介导的过敏反应的诊断试验。

摘要

嗜碱性粒细胞活化试验（BAT）是一种补充性的体外诊断方法，可用于评估由IgE介导的食物、昆虫毒液、药物以及某些类型的慢性荨麻疹过敏反应，可作为临床病史、皮肤试验（ST）和特异性IgE（sIgE）检测的辅助手段。然而，该技术在诊断流程中的作用存在较大差异，尚不明确。

嗜碱性粒细胞活化试验（BAT）基于通过流式细胞术检测嗜碱性粒细胞对过敏原/药物交联IgE激活的反应，以测定其活化标志物（如CD63、CD203c）。该检测可作为避免进行受控激发试验以确诊过敏反应的有用且互补的工具，尤其适用于经历严重危及生命反应的患者。通常情况下，当出现以下情形时应考虑进行BAT检测：i）该过敏原/药物在皮肤试验（ST）中产生假阳性结果；ii）缺乏可用于皮肤试验或特异性IgE（sIgE）检测的过敏原/药物来源；iii）患者的临床病史与皮肤试验或sIgE检测结果不一致；iv）患者的症状提示皮肤试验可能引发全身性反应；v）在考虑进行受控激发试验（CCT）以确认致敏过敏原/药物之前。该检测的主要局限性包括：敏感性欠佳，尤其是在药物过敏中；需在样本采集后24小时内完成检测；以及各实验室在操作流程、试剂浓度和细胞标志物选择方面缺乏标准化。

引言

IgE介导的过敏诊断基于临床病史、皮肤试验（STs）、血清特异性IgE（sIgE）定量检测，以及在必要且有指征时进行的受控激发试验（CCTs）¹^,²^,³^,⁴^,⁵^,⁶然而，临床病史可能并不可靠，因为可能存在信息不准确的情况，且激发试验和结膜激发试验并非无风险的操作，在出现严重危及生命反应的受试者中可能属于禁忌。¹^,²^,³^,⁴^,⁵^,⁶这些问题，加上经验证的商用荧光酶免疫测定法仅能检测少数过敏原和药物的sIgE，凸显了其他方法的重要作用体外功能检测，例如嗜碱性粒细胞活化试验（BAT）。

嗜碱性粒细胞是参与IgE介导的过敏反应的关键效应细胞，在过敏原或药物暴露后，细胞表面高亲和力受体（FcεRI）上相邻的sIgE发生交联，从而激活嗜碱性粒细胞。嗜碱性粒细胞活化后触发脱颗粒反应，并释放胞质分泌颗粒中预先形成及新合成的炎症介质⁷^,⁸^,⁹. BAT 是一种体外一种旨在模拟嗜碱性粒细胞在刺激物（过敏原或药物）存在下活化的方法，并通过流式细胞术检测嗜碱性粒细胞活化标志物表达水平的变化⁷^,¹⁰. 鉴定嗜碱性粒细胞有不同的策略（IgE⁺，CCR3⁺，CRTH2⁺，CD203c⁺以及使用荧光染料标记的抗体组合检测细胞活化（主要是CD63和CD203c的上调）⁷^,¹⁰CD63，临床上验证最充分的活化标志物¹¹^,¹²^,¹³^,¹⁴是一种膜蛋白，锚定于含有组胺的分泌颗粒上，在细胞活化及颗粒与膜融合后，表达于嗜碱性粒细胞表面¹⁵^,¹⁶^,¹⁷^,¹⁸^,¹⁹^,²⁰^,²¹CD203c 是一种在嗜碱性粒细胞表面组成型表达的标志物，在 FcεRI 刺激后表达上调，该标志物在嗜碱性粒细胞活化试验（BAT）中也显示出可靠的结果¹⁵^,²²^,²³^,²⁴^,²⁵此外，它似乎与 CD63 共表达²⁶.

近几十年来，嗜碱性粒细胞活化试验（BAT）已被证明在诊断由药物、食物或吸入性物质等不同诱因引起的IgE介导的过敏反应中具有应用价值，同时也可用于某些类型的慢性荨麻疹，如下文所述。然而，该技术在诊断流程中的定位存在较大差异，尚不明确。

药物超敏反应
对于某些特定药物和患者，嗜碱性粒细胞活化试验（BAT）已被证明可作为有价值的补充检测方法，尤其适用于那些发生严重反应的患者，因为对于大多数药物而言，皮试（ST）的诊断价值尚未明确，且仅针对有限种类的药物进行了验证和标准化²⁷^,²⁸^,²⁹^,³⁰。此外，目前仅有少数药物可进行特异性IgE（sIgE）的定量检测，且其敏感性低于皮试²⁷^,²⁸^,²⁹^,³⁰^,³¹^,³²。因此，药物超敏反应的诊断通常依赖于药物激发试验，但对于曾发生严重危及生命反应的患者，该试验可能存在禁忌³³。

已有研究报道，在报告对不同药物（如β-内酰胺类药物（BLs）²⁰^,³⁴^,³⁵^,³⁶^,³⁷^,³⁸^,³⁹、神经肌肉阻滞剂（NMBAs）¹⁹^,²²^,⁴⁰^,⁴¹^,⁴²^,⁴³^,⁴⁴^,⁴⁵、氟喹诺酮类药物（FQs）⁴⁶^,⁴⁷^,⁴⁸^,⁴⁹、吡唑酮类药物⁵⁰^,⁵¹^,⁵²、放射造影剂（RCM）⁵³^,⁵⁴^,⁵⁵^,⁵⁶以及铂类化合物⁵⁷^,⁵⁸^,⁵⁹）产生即刻型超敏反应的特定患者中，嗜碱性粒细胞活化试验（BAT）具有良好的应用前景。据报道，BAT的敏感性和特异性分别为51.7%-66.9%和89.2%-97.8%；其阳性预测值和阴性预测值分别约为93.4%和66.3%²⁷^,³¹。此外，BAT已被提议作为铂类化合物脱敏治疗过程中发生突破性反应的预测生物标志物，因为在药物脱敏期间具有较高不良反应风险的患者中，CD203c的表达水平较CD63更高⁵⁷。

需要注意的是，只有当药物超敏反应涉及嗜碱性粒细胞脱颗粒时，嗜碱性粒细胞活化试验（BAT）才有用；因此，对于由环氧化酶酶活性抑制所引起的反应，该试验并无用处¹⁴²。

食物过敏
由于针对全变应原提取物或单一变应原的血清特异性IgE（sIgE）检测结果常不明确，往往需要通过口服食物激发试验来确诊，而该方法与药物超敏反应类似，是一种成本较高且存在风险的程序，因此嗜碱性粒细胞活化试验（BAT）已逐渐成为一种潜在的食物过敏诊断工具⁶⁰。已有多个研究报道了BAT在牛乳⁶¹^,⁶²、鸡蛋⁶¹^,⁶³、小麦⁶⁴^,⁶⁵^,⁶⁶^,⁶⁷^,⁶⁸、花生⁶³^,⁶⁹^,⁷⁰^,⁷¹^,⁷²、榛子⁷³^,⁷⁴^,⁷⁵^,⁷⁶^,⁷⁷、贝类⁷⁸、桃子⁷⁹^,⁸⁰^,⁸¹、苹果²¹、芹菜和胡萝卜⁸²^,⁸³等食物过敏中的相关应用结果。

与皮肤试验（STs）和血清sIgE检测相比，嗜碱性粒细胞活化试验（BAT）在食物过敏诊断中的主要附加价值在于其具有更高的特异性和相似的敏感性。因此，BAT是一种有效的工具，可用于区分临床上真正过敏的患者与那些致敏但耐受的个体，其特异性（75–100%）和敏感性（77–98%）均较高⁶³^,⁶⁹^,⁸⁴。敏感性和特异性数值取决于过敏原以及其他因素，如表型（例如口腔过敏综合征 versus 过敏性休克）、年龄以及与地理区域相关的致敏模式⁶³^,⁸⁵。

使用单一变应原组分进行BAT检测可能提高某些食物变应原的诊断准确性⁶¹^,⁸⁰。已有研究采用种子贮藏蛋白（如花生中的Ara h 1、Ara h 2、Ara h 3和Ara h 6）⁸⁶；脂质转移蛋白（如桃中的Pru p 3和花生中的Ara h 9）⁸⁰^,⁸⁶；以及Bet v 1同源物（如花生中的Ara h 8）⁸⁷。其他潜在应用包括在花粉-食物过敏综合征²¹^,⁸⁷^,⁸⁸、红肉过敏⁸⁹或食物依赖性运动诱发性过敏反应⁶⁶病例中识别致敏变应原。

有趣的是，嗜碱性粒细胞活化试验（BAT）可以提供有关过敏反应严重程度和反应阈值的信息，因为在花生和牛奶过敏患者的研究中发现，过敏反应更严重的患者其活化嗜碱性粒细胞的比例更高⁸⁴^,⁹⁰^,⁹¹；而对极微量过敏原即产生反应的患者则表现出更高的嗜碱性粒细胞敏感性⁸⁴^,⁹⁰^,⁹²。这些数据表明，BAT可能有助于识别高风险过敏患者，从而进行更密切的随访和强化的健康教育⁹³。此外，已有研究报道，BAT可预测食物激发试验的反应结果⁷⁰^,⁹¹^,⁹²^,⁹⁴以及反应阈值⁹⁰^,⁹⁵，以帮助判断何时可安全地（重新）引入某种食物⁸⁴。然而，部分研究对上述发现存在争议⁶³^,⁹⁶，仍需进一步研究加以验证。

另一方面，BAT 已被用于长期监测食物过敏的缓解情况（无论是自然缓解还是在免疫调节治疗下的缓解），而此前这一监测仅能通过口服食物激发试验进行，但该方法存在相关风险和较高成本⁸⁴^,⁹⁷^,⁹⁸^,⁹⁹^,¹⁰⁰^,¹⁰¹^,¹⁰²^,¹⁰³^,¹⁰⁴^,¹⁰⁵^,¹⁰⁶^,¹⁰⁷^,¹⁰⁸。此外，BAT 还被用于监测奥马珠单抗在食物过敏治疗中的效果，因为在奥马珠单抗治疗期间嗜碱性粒细胞的活化水平会降低，但治疗停止后其活化水平又会上升¹⁰⁹。

吸入性过敏
由于吸入性过敏的诊断通常可通过特异性IgE（sIgE）定量和皮肤试验（ST）常规建立，因此嗜碱性粒细胞活化试验（BAT）在此类过敏中很少具有优势。然而，在局部过敏性鼻炎（sIgE水平无法检出、皮肤试验阴性但鼻激发试验阳性）的情况下，BAT已在50%的病例中实现了诊断¹¹⁰。另有研究报道，嗜碱性粒细胞的敏感性与鼻/支气管激发试验的反应之间存在相关性，同时哮喘严重程度与奥马珠单抗治疗疗效之间也存在相关性¹¹¹^,¹¹²。

BAT 还被用于监测屋尘螨和花粉变应原免疫治疗的效果，因为在免疫治疗过程中，嗜碱性粒细胞的敏感性会降低，这可能是由于阻断性 IgG 抗体的干扰所致¹¹³^,¹¹⁴^,¹¹⁵^,¹¹⁶^,¹¹⁷。

膜翅目毒液过敏
膜翅目毒液过敏的诊断通常基于皮肤试验（ST）和血清特异性IgE（sIgE）检测。嗜碱性粒细胞活化试验（BAT）已显示出较高的敏感性（85–100%）和特异性（83–100%），据报道，在检测结果不明确的情况下，或对于临床病史提示毒液过敏但sIgE无法检出且皮肤试验阴性的患者，BAT具有应用价值¹¹⁸^,¹¹⁹。然而，BAT似乎无法预测此类反应的严重程度¹²⁰^,¹²¹。

高达60%的患者对黄蜂和蜜蜂毒液均表现出sIgE阳性，因此确定主要过敏原对于实施适当的免疫治疗至关重要。在这些情况下，嗜碱性粒细胞活化试验（BAT）已被报道可用于识别主要过敏原¹¹⁹^,¹²²^,¹²³^,¹²⁴。尽管对蜜蜂和黄蜂毒液主要过敏原的sIgE阳性可能降低BAT在对两种毒液均呈双阳性患者中的应用价值，但在sIgE检测结果为阴性的受试者中，BAT仍可提供有价值的信息¹²³。

一些研究表明，在毒液免疫治疗的剂量递增阶段，嗜碱性粒细胞活化试验（BAT）可能作为预测不良反应的生物标志物具有潜在用途，因为已有报道显示该治疗方案可降低嗜碱性粒细胞的敏感性。然而，嗜碱性粒细胞的反应性并未随之下降，因此目前BAT的这一应用价值存在争议¹³^,¹²⁰^,¹²⁵^,¹²⁶^,¹²⁷^,¹²⁸^,¹²⁹^,¹³⁰。

荨麻疹和血管性水肿
部分慢性荨麻疹患者的发病机制属于自身免疫性，其原因是体内存在针对自身变应原的IgE自身抗体，以及针对肥大细胞表面FcεRI或IgE-FcεRI复合物的IgG自身抗体¹³¹^,¹³²在临床实践中，此类慢性荨麻疹的诊断依赖于自体血清皮肤试验（autologous serum ST）阳性结果，但该方法存在意外感染的风险。BAT 已被提出作为替代方案体外用于诊断和监测疑似慢性荨麻疹患者的检测方法。已有报道显示，在用慢性荨麻疹患者血清刺激后，嗜碱性粒细胞表面的CD63和CD203c表达均升高，表明该方法可检测到活性自身抗体。¹³³^,¹³⁴^,¹³⁵^,¹³⁶^,¹³⁷最近有报道称，与BAT阴性患者相比，BAT阳性患者的疾病活动度通常最高，通过荨麻疹活动评分进行评估，并且需要更高剂量的抗组胺药以及三线治疗（环孢素A或奥马珠单抗）。¹³⁸.

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方案

该方案的实施遵循赫尔辛基宣言原则，并已获得当地伦理委员会（Comité de Ética para la Investigación Provincial de Málaga，西班牙）的批准。所有受试者均接受了关于研究内容的口头说明，并签署了相应的知情同意书。

注意：本方案详细描述了作者日常使用的嗜碱性粒细胞活化试验（BAT）操作流程。然而，该方法并非标准化流程，与其他作者发表的方案存在差异。主要的方案修改包括刺激缓冲液中使用IL-3、刺激物孵育时间、终止嗜碱性粒细胞脱颗粒的方法以及流式细胞术分析策略。此外，不同商业来源的BAT试剂盒均包含制造商推荐的特定操作步骤。

1. 样品制备

采集外周血至9 mL肝素抗凝管中，并将样本置于室温（RT）下旋转保存，直至实验方案需要时使用。
标记5 mL流式管用于阴性对照（2管）、阳性对照（2管）以及不同浓度的过敏原/药物（每种过敏原/药物浓度各1管）。将试管放置于试管架中，确保试管完全贴合、不会滑动。
在双蒸水中配制刺激缓冲液，含2%（v/v）HEPES、78 mg/L NaCl、3.7 mg/L KCl、7.8 mg/L CaCl₂、3.3 mg/L MgCl₂、1 g/L HSA。调节pH至7.4，并加入IL-3至终浓度为2 ng/mL。通常配制100 mL，分装为每份2.5 mL，于-20 °C冻存。
在含0.05%（v/v）PBS-Tween-20（PBS-T）中配制阳性对照：阳性对照1为N-甲酰甲硫氨酰-亮氨酰-苯丙氨酸（fMLP）（4 µM），用于确认嗜碱性粒细胞质量；阳性对照2为抗IgE抗体（0.05 mg/mL），作为IgE介导的阳性对照。
在PBS-T中将过敏原/药物配制为所需终浓度的2倍。
注意：应通过广泛浓度梯度、剂量-反应曲线以及按照相同实验步骤进行的细胞毒性研究，预先确定所用过敏原/药物的最佳浓度¹³⁹。

2. 染色液的配制

根据制造商推荐的抗体浓度或先前的抗体滴定结果，将荧光染料标记的单克隆抗体加入刺激缓冲液中。在本方案中，每20 µL刺激缓冲液加入1 µL每种抗体（CCR3-APC和CD203c-PE用于嗜碱性粒细胞鉴定；CD63-FITC用于嗜碱性粒细胞活化）¹⁴⁰。
注意：染色混合物的配制过程需避光。
向每根试管中加入23 µL染色混合物。

3. 血液刺激

向1号和2号管中各加入100 µL PBS-T（阴性对照），向3号管中加入100 µL fMLP，向4号管中加入100 µL 抗IgE，向后续各管中加入100 µL 不同浓度的过敏原/药物。在37 °C水浴中以中等振荡孵育10分钟，以预热试剂。
轻柔地向每管中加入100 µL 血液，避免溶血。轻轻涡旋混匀各管，并在37 °C水浴中以中等振荡孵育25分钟。
通过将各管置于4 °C环境中至少5分钟，终止脱颗粒反应。
注意：如有需要，可在4 °C暂停本实验流程，暂停时间为30–45分钟¹⁴¹^,¹⁴²^,¹⁴³。

4. 红细胞裂解

向每支试管中加入 2 mL 1x 裂解缓冲液以裂解红细胞。涡旋振荡每支试管，并在室温下孵育 5 分钟。
注意：此步骤中，由于缓冲液含有固定剂（甲醛），细胞会被固定。
在 4 °C 下以 300 × g 离心 5 分钟。将上清液倾倒至水槽中，试管架倒置。细胞将保留在试管底部。
向每支试管中加入 3 mL PBS-T 以洗涤细胞。涡旋振荡每支试管。
在 4 °C 下以 300 × g 离心 5 分钟。将上清液倾倒至水槽中，试管架倒置。
注意：样品需在 4 °C 避光保存，直至进行流式细胞仪检测。

5. 流式细胞术数据采集

使用流式细胞仪（例如 BD FACSCalibur 流式细胞仪）获取样本。将流式细胞仪连接至计算机软件，并等待仪器准备就绪。加载模板和仪器设置（表 1）。
开始样本采集。
采用以下流式细胞仪分析策略筛选活化嗜碱性粒细胞¹³⁹。
1. 在侧向散射光（SSC）- 前向散射光（FSC）图中圈选淋巴细胞群。
2. 从淋巴细胞群体中圈选 CCR3⁺CD203c⁺ 细胞作为嗜碱性粒细胞。每管至少采集 500 个嗜碱性粒细胞。
3. 绘制 CCR3 - CD63 图，以 CD63 作为活化标志物分析细胞活化情况。利用阴性对照管将 CD63 阴性阈值设定为约 2.5%。
4. 采集所有样本。

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结果

使用过敏原或药物进行嗜碱性粒细胞活化试验（BAT），可用于研究IgE依赖性超敏反应。为了获得最佳结果，应至少在两个最佳浓度下测定嗜碱性粒细胞的反应性³⁴，并通过细胞表面CD63的上调来可视化激活情况。此外，在使用过敏原的情况下，为确认嗜碱性粒细胞的反应性，还应通过检测多个递减浓度的过敏原刺激下的反应性来分析嗜碱性粒细胞的敏感性¹¹⁴。该检测可确定诱导50%嗜碱性粒细胞发生反应的过敏原浓度（EC50），该值可表示为“CD-sens”¹⁴¹。最近有研究提出，通过计算剂量-反应曲线下的面积（AUC）来同时评估嗜碱性粒细胞的反应性和敏感性⁵⁸。

用于分析BAT结果的流式细胞术策略如图1和图2所示，包括从SSC-FSC图中圈选淋巴细胞（步骤1），从淋巴细胞群体中圈选CCR3

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讨论

BAT 是一种用于评估 IgE 介导的过敏反应的互补性体外诊断试验，已被证明在诊断由不同诱因（如药物、食物或吸入物）引起的过敏反应以及某些类型的慢性荨麻疹中具有实用价值。通常在以下情况下应考虑进行 BAT 检测：i）过敏原/药物在皮肤试验（ST）中产生假阳性结果；ii）过敏原/药物无法用于皮肤试验或特异性 IgE（sIgE）定量检测；iii）临床病史与皮肤试验或 sIgE 检测结果不一致；iv）临床症状提示皮肤试验可能诱发全身性反应；v）在进行受累过敏原/药物的确证性激发试验（CCT）之前¹⁰。

关于实验方案，为获得适用于检测的合适血液样本，需考虑若干重要方面。全身性类固醇¹⁴⁶ 以及免疫抑制剂，包括口服皮质类固醇，¹⁴⁷ 检测前应避免，因为会降低嗜碱性粒细胞反应¹⁴⁶ （抗组胺药和局部用类固醇不影响BAT检测结果）¹⁴⁶不应在...

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披露

作者无任何利益冲突需要披露。

致谢

我们感谢 Claudia Corazza 在英语语言方面提供的宝贵支持。本工作由西班牙经济与竞争力部（MINECO）下属的 Carlos III 健康研究所（ISCIII）资助（由欧洲区域发展基金 ERDF 共同资助："Una manera de hacer Europa"；项目编号：PI20/01715；PI18/00095；PI17/01410；PI17/01318；PI17/01237 及 RETIC ARADYAL RD16/0006/0001）；以及安达卢西亚自治区卫生部（项目编号：PI-0127-2020、PIO-0176-2018、PE-0172-2018、PE-0039-2018、PC-0098-2017、PI-0075-2017、PI-0241-2016）。ID 是临床研究员（B-0001-2017），AA 持有高级博士后合同（RH-0099-2020），两人均由安达卢西亚自治区卫生部资助（由欧洲社会基金 ESF 共同资助："Andalucía se mueve con Europa"）。

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材料

本文使用的材料清单
姓名	公司	目录编号
5 mL 圆底聚苯乙烯试管，无盖，非无菌	Corning	352008
APC 抗人 CD193 (CCR3) 抗体	BioLegend	310708
BD FACSCalibur 流式细胞仪	BD Biosciences
氯化钙	Sigma-Aldrich	C1016
FITC 抗人 CD63 抗体	BioLegend	353006
HEPES (1 M)	Thermo-Fisher	15630106
溶血液，10 倍浓缩	BD Biosciences	349202
氯化镁	Sigma-Aldrich	M8266
N-甲酰基-甲硫氨酰-亮氨酰-苯丙氨酸	Sigma-Aldrich	F3506
PE 抗人 CD203c (E-NPP3) 抗体	BioLegend	324606
氯化钾	Sigma-Aldrich	P9541
纯化小鼠抗人 IgE 抗体	BD Biosciences	555857
重组人 IL-3	R&D Systems	203-IL
鞘液	BD Biosciences	342003
氯化钠	Sigma-Aldrich	S3014
9 mL LH 锂肝素试管	Greiner Bio-One	455084
吐温 20	Sigma-Aldrich	P1379

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嗜碱性粒细胞活化试验在过敏诊断中的应用

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