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Altered chromatin landscape in circulating T follicular helper and regulatory cells following grass pollen subcutaneous and sublingual immunotherapy
Journal of Allergy and Clinical Immunology ( IF 11.4 ) Pub Date : 2020-11-06 , DOI: 10.1016/j.jaci.2020.10.035
Hanisah Sharif 1 , Swati Acharya 2 , Gopal Krishna R Dhondalay 2 , Gilda Varricchi 3 , Shoshanna Krasner-Macleod 4 , Wannada Laisuan 5 , Amy Switzer 4 , Madison Lenormand 5 , Elena Kashe 4 , Rebecca V Parkin 5 , Yi Yi 5 , Merve Koc 5 , Oleksandra Fedina 4 , Gemma Vilà-Nadal 4 , Gianni Marone 6 , Aarif Eifan 4 , Guy W Scadding 4 , David J Fear 7 , Kari C Nadeau 2 , Stephen R Durham 4 , Mohamed H Shamji 5
Affiliation  

Background

Allergen-specific immunotherapy is a disease-modifying treatment that induces long-term T-cell tolerance.

Objective

We sought to evaluate the role of circulating CXCR5+PD-1+ T follicular helper (cTFH) and T follicular regulatory (TFR) cells following grass pollen subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) and the accompanying changes in their chromatin landscape.

Methods

Phenotype and function of cTFH cells were initially evaluated in the grass pollen-allergic (GPA) group (n = 28) and nonatopic healthy controls (NAC, n = 13) by mathematical algorithms developed to manage high-dimensional data and cell culture, respectively. cTFH and TFR cells were further enumerated in NAC (n = 12), GPA (n = 14), SCIT- (n = 10), and SLIT- (n = 8) treated groups. Chromatin accessibility in cTFH and TFR cells was assessed by assay for transposase-accessible chromatin sequencing (ATAC-seq) to investigate epigenetic mechanisms underlying the differences between NAC, GPA, SCIT, and SLIT groups.

Results

cTFH cells were shown to be distinct from TH2- and TH2A-cell subsets, capable of secreting IL-4 and IL-21. Both cytokines synergistically promoted B-cell class switching to IgE and plasma cell differentiation. Grass pollen allergen induced cTFH-cell proliferation in the GPA group but not in the NAC group (P < .05). cTFH cells were higher in the GPA group compared with the NAC group and were lower in the SCIT and SLIT groups (P < .01). Time-dependent induction of IL-4, IL-21, and IL-6 was observed in nasal mucosa following intranasal allergen challenge in the GPA group but not in SCIT and SLIT groups. TFR and IL-10+ cTFH cells were induced in SCIT and SLIT groups (all, P < .01). ATAC-seq analyses revealed differentially accessible chromatin regions in all groups.

Conclusions

For the first time, we showed dysregulation of cTFH cells in the GPA group compared to NAC, SCIT, and SLIT groups and induction of TFR and IL-10+ cTFH cells following SCIT and SLIT. Changes in the chromatin landscape were observed following allergen-specific immunotherapy in cTFH and TFR cells.



中文翻译:

草花粉皮下和舌下免疫治疗后循环 T 滤泡辅助细胞和调节细胞的染色质景观改变

背景

过敏原特异性免疫疗法是一种改善疾病的治疗方法,可诱导长期 T 细胞耐受。

客观的

我们试图评估草花粉皮下免疫治疗 (SCIT) 和舌下免疫治疗 (SLIT)后循环 CXCR5 + PD-1 + T 滤泡辅助 (cT FH ) 和 T 滤泡调节 (T FR ) 细胞的作用及其伴随的变化。染色质景观。

方法

最初通过为管理高维数据和细胞培养而开发的数学算法在草花粉过敏 (GPA) 组 (n = 28) 和非特应性健康对照 (NAC, n = 13) 中评估了 cT FH细胞的表型和功能,分别。在 NAC (n = 12)、GPA (n = 14)、SCIT- (n = 10) 和 SLIT- (n = 8) 治疗组中进一步列举了cT FH和 T FR细胞。cT FH和 T FR细胞中的染色质可及性通过测定转座酶可及染色质测序 (ATAC-seq) 进行评估,以研究 NAC、GPA、SCIT 和 SLIT 组之间差异的表观遗传机制。

结果

显示 cT FH细胞不同于 T H 2 和 T H 2A 细胞亚群,能够分泌 IL-4 和 IL-21。两种细胞因子协同促进 B 细胞类别转换为 IgE 和浆细胞分化。草花粉过敏原在 GPA 组中诱导 cT FH细胞增殖,但在 NAC 组中不诱导( P  < .05)。与 NAC 组相比,GPA 组的cT FH细胞较高,而 SCIT 和 SLIT 组的cT FH细胞较低 ( P  < .01)。在 GPA 组鼻内过敏原攻击后,在鼻粘膜中观察到 IL-4、IL-21 和 IL-6 的时间依赖性诱导,但在 SCIT 和 SLIT 组中未观察到。T FR和 IL-10 +在 SCIT 和 SLIT 组中诱导cT FH细胞(所有,P  < .01)。ATAC-seq 分析揭示了所有组中不同可及的染色质区域。

结论

我们第一次显示,与 NAC、SCIT 和 SLIT 组相比,GPA 组中 cT FH细胞的失调以及SCIT 和 SLIT 后 T FR和 IL-10 + cT FH细胞的诱导。在 cT FH和 T FR细胞中进行过敏原特异性免疫治疗后观察到染色质景观的变化。

更新日期:2020-11-06
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