妊娠会影响对 1 型刺激物--葡萄球菌肠毒素 A 的过敏反应差异。

IF 4.6 2区 医学 Q2 ALLERGY Clinical and Translational Allergy Pub Date : 2024-10-26 DOI:10.1002/clt2.70007
Claudia Arasa, Niamh Hyland, Caroline Nilsson, Eva Sverremark-Ekström
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引用次数: 0

摘要

致编辑:金黄色葡萄球菌是 90% 气道疾病患者的间歇性或永久性皮肤定植菌,葡萄球菌肠毒素-IgE 血清水平与过敏和严重哮喘都有关联。4 在此,我们使用过敏性和非过敏性、孕妇和非孕妇的外周血单核细胞(PBMC),研究了 Th2 偏移5 的个体对葡萄球菌肠毒素 A(SEA)的免疫反应(图 1A),SEA 是 1 型反应的强诱导剂。葡萄球菌肠毒素会引起多克隆 T 细胞活化,使抗原递呈细胞(APC)上的 MHC-II 与 T 细胞上的 T 细胞受体(TCR)交联(图 1B),从而导致强烈的促炎反应,可能会增加 IgE 的产生或破坏母胎耐受性。过敏个体的 Tbet 表达减少(图 1C),这与 Th1 反应有关,而且 1 型细胞因子(IFN-γ 和 TNF;图 1D)产生较少。在妊娠期间未观察到这些差异(图 S1A)。与 Th2 反应相关的 GATA3 表达在过敏个体中较低,与妊娠状态无关(图 1E),但 2 型细胞因子分泌(IL-5 和 IL-13;图 S1B 和图 1F)没有差异。3型和调节性T细胞标志物(分别为RORγt或FoxP3的表达以及IL-17和IL-10的分泌)在任何组别中都没有差异(图S1C、D)。对妊娠期外常规 T 细胞中 IFN-γ 和 TNF 的分泌进行分析表明,过敏性和非过敏性个体的 IFN-γ 水平相当(图 1G)。在怀孕期间,非过敏性个体的 IFN-γ 生成明显减少(图 1H),而过敏性个体则没有减少(图 1I)。我们之前已经证明,非常规淋巴细胞对 SEA 的反应是延迟的,它们的活化在很大程度上导致了细胞因子风暴的产生7(图 2A)。因此,我们想弄清常规 T 细胞活化中出现的过敏相关差异是否与非常规淋巴细胞区系的变化有关。所有分析的细胞类型都显示出一致的模式,即过敏女性的 IFN-γ(图 2B)和 TNF(图 S2B)表达明显较低。此外,在分析过敏性孕妇的非常规淋巴细胞对 SEA 的纵向反应时,我们发现所有研究细胞类型的 IFN-γ (图 2C)和 TNF (图 S2C)的产生量都显著增加。有趣的是,在非过敏性妇女的纵向样本中,除了γδ T 细胞产生的 TNF 外(图 S2D、E),这两种细胞因子的产生都没有出现与妊娠相关的增加。总之,这些发现强调了常规和非常规淋巴细胞在 SEA 暴露和妊娠中的微妙相互作用。APC 是最先遇到 SEA 的细胞,但人们对它们遇到超级抗原时的活化情况知之甚少。我们在这里观察到,在 SEA 刺激下,表型标记 CD14 在所有组别中都出现了下调,在非妊娠、非过敏个体中最为显著,CD163 也是如此。除了非妊娠非过敏者外,CD16 也在所有组别中下调(图 2D)。在分析 T 细胞相互作用标记物时,我们观察到 HLADR 转录在非怀孕非过敏个体中下调,而其转录在所有其他组别中保持稳定。其他因子,如 CD80 和 CD274(PDL1),在所有组别中也同样上调。我们首次发现,过敏性妇女对 SEA 的 1 型免疫反应受到抑制,而这种抑制在怀孕期间得到恢复,这归因于非常规淋巴细胞的强烈反应。了解免疫改变的轨迹对于优化面对环境暴露(如 SEA)时的警惕和治疗策略至关重要,从而保障母婴健康:研究设计:Eva Sverremark-Ekström、Caroline Nilsson、Claudia Arasa:Eva Sverremark-Ekström、Caroline Nilsson;患者纳入和样本收集:Caroline Nilsson;实验设计:Claudia Arasa、Eva Sverremark-Ekström;实验工作:克劳迪娅-阿拉萨、尼姆-海兰;数据分析:数据分析:Claudia Arasa、Niamh Hyland;数据解释:Claudia Arasa、Eva Sverremark-Ekström:Claudia Arasa、Eva Sverremark-Ekström。撰写手稿克劳迪娅-阿拉萨;手稿审阅:所有共同作者。 ESE 从 BioGaia AB 获得了讲课酬金和另一个研究项目的资助。CN 报告了 Aimmune Therapeutics a Nestlé Company 的机构资助,以及 MEDA ALK、Thermofisher 和 GSK 的讲课费。其他作者无利益冲突需要声明。
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Pregnancy impacts allergy-related differences in the response to a type-1 stimulus, staphylococcal enterotoxin A

To the Editor,

Staphylococcus (S.) aureus is an intermittent or permanent skin colonizer in 90% of patients with airway diseases, and staphylococcal enterotoxin-IgE serum levels have been linked to both allergy and severe asthma.1, 2 During pregnancy, immune adaptation is required to ensure fetal growth,3 and type 2 responses are enhanced. These changes potentially worsen allergic conditions and increase the susceptibility to certain infections.4

Here we investigate the immune response to Staphylococcal enterotoxin A (SEA), a strong inducer of type 1 responses, in individuals with Th2-skewing,5 using peripheral blood mononuclear cells (PBMC) from allergic and non-allergic, pregnant and non-pregnant women6 (Figure 1A). Staphylococcal enterotoxins cause polyclonal T cell activation crosslinking the MHC-II on antigen-presenting cells (APCs) to the T-cell receptor (TCR) on T-cells (Figure 1B), leading to a strong proinflammatory response, potentially increasing IgE-production or disrupting the maternal-fetal tolerance.

Allergic individuals exhibited reduced Tbet expression (Figure 1C), associated with Th1 response, and lower type 1 cytokine production (IFN-γ and TNF; Figure 1D). These differences were not observed during pregnancy (Figure S1A). GATA3 expression, linked to Th2 responses, was lower in allergic individuals regardless of their pregnancy status (Figure 1E), but there was no difference in type 2 cytokine secretion (IL-5 and IL-13; Figure S1B and Figure 1F). Type 3- and regulatory T cell markers (RORγt or FoxP3 expression and IL-17 and IL-10 secretion, respectively) did not differ in any of the groups (Figure S1C,D). Analyzing IFN-γ and TNF production in conventional T cells outside of pregnancy showed comparable IFN-γ levels between allergic and non-allergic individuals (Figure 1G). During pregnancy, IFN-γ production was significantly reduced in non-allergic individuals (Figure 1H) but not in allergic (Figure 1I). TNF production was lower in allergic individuals, but it increased during pregnancy (Figure S2A).

We have previously shown that the response to SEA by unconventional lymphocytes is delayed, and that their activation strongly contributes to the elicited cytokine storm7 (Figure 2A). Therefore, we wanted to elucidate whether the allergy-related differences seen in conventional T cell activation correlated with variations in the unconventional lymphocyte compartment. All the analyzed cell types showed a consistent pattern, characterized by a significantly lower expression of IFN-γ (Figure 2B) and TNF (Figure S2B) in allergic women. Furthermore, analyzing the longitudinal response of unconventional lymphocytes to SEA in pregnant allergic women, we identified significantly higher production of both IFN-γ (Figure 2C) and TNF (Figure S2C) across all the studied cell types. Interestingly, this pregnancy-related increase in the production of both cytokines was absent in the longitudinal samples from non-allergic women, where the levels were comparable in and out of pregnancy, except for TNF produced by γδ T cells (Figure S2D,E). Overall, these findings underscore the nuanced interplay between conventional and unconventional lymphocytes in the context of SEA exposure and pregnancy. APCs are the first cells to encounter SEA, but very little is known regarding their activation upon superantigen encounter. We here observed that, upon SEA stimulation, the phenotypic marker CD14 was downregulated in all groups, most prominently on non-pregnant, non-allergic individuals, as was CD163. CD16 was also downregulated in all groups except for the non-pregnant non-allergic (Figure 2D). When analysing T cell interaction markers, we observed that HLADR transcription was downregulated in non-pregnant non-allergic individuals, whereas its transcription remained stable in all other groups. Other factors such as CD80 and CD274 (PDL1) were similarly upregulated in all groups. Transcription of type-1 associated cytokine IL12 showed high variability among individuals in all groups (Figure 2E).

We are the first to show that allergic women have a suppressed type 1 immune response to SEA, which is restored during pregnancy and is attributed to the strong response by unconventional lymphocytes. An understanding of the trajectory of immune alterations is crucial to optimize the vigilance and therapy strategies in the face of environmental exposures such as SEA, to safeguard the health of both mother and child.

Study design: Eva Sverremark-Ekström, Caroline Nilsson, Claudia Arasa; Funding acquisition: Eva Sverremark-Ekström, Caroline Nilsson; Patient inclusion and sample collection: Caroline Nilsson; Experimental design: Claudia Arasa, Eva Sverremark-Ekström; Experimental work: Claudia Arasa, Niamh Hyland; Data analysis: Claudia Arasa, Niamh Hyland; Data interpretation: Claudia Arasa, Eva Sverremark-Ekström. Writing of the manuscript: Claudia Arasa; Critical review of the manuscript: All co-authors.

ESE has received honoraria for lectures and a grant for another research project from BioGaia AB. CN report grants to institution from Aimmune Therapeutics a Nestlé Company and Lecture fees from: MEDA ALK; Thermofisher and GSK. The other authors have no conflict of interest to declare.

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来源期刊
Clinical and Translational Allergy
Clinical and Translational Allergy Immunology and Microbiology-Immunology
CiteScore
7.50
自引率
4.50%
发文量
117
审稿时长
12 weeks
期刊介绍: Clinical and Translational Allergy, one of several journals in the portfolio of the European Academy of Allergy and Clinical Immunology, provides a platform for the dissemination of allergy research and reviews, as well as EAACI position papers, task force reports and guidelines, amongst an international scientific audience. Clinical and Translational Allergy accepts clinical and translational research in the following areas and other related topics: asthma, rhinitis, rhinosinusitis, drug hypersensitivity, allergic conjunctivitis, allergic skin diseases, atopic eczema, urticaria, angioedema, venom hypersensitivity, anaphylaxis, food allergy, immunotherapy, immune modulators and biologics, animal models of allergic disease, immune mechanisms, or any other topic related to allergic disease.
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