Background

The cause of severe nasal polyposis in aspirin-exacerbated respiratory disease (AERD) is unknown. Elevated antibody levels have been associated with disease severity in nasal polyps, but upstream drivers of local antibody production in nasal polyps are undetermined.

Objective

We sought to identify upstream drivers and phenotypic properties of local antibody-expressing cells in nasal polyps from subjects with AERD.

Methods

Sinus tissue was obtained from subjects with AERD, chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), CRS without nasal polyps, and controls without CRS. Tissue antibody levels were quantified via ELISA and immunohistochemistry and were correlated with disease severity. Antibody-expressing cells were profiled with single-cell RNA sequencing, flow cytometry, and immunofluorescence, with IL-5Rα function determined through IL-5 stimulation and subsequent RNA sequencing and quantitative PCR.

Results

Tissue IgE and IgG4 levels were elevated in AERD compared with in controls (P < .01 for IgE and P < .001 for IgG4 vs CRSwNP). Subjects with AERD whose nasal polyps recurred rapidly had higher IgE levels than did subjects with AERD, with slower regrowth (P = .005). Single-cell RNA sequencing revealed increased IL5RA, IGHG4, and IGHE in antibody-expressing cells from patients with AERD compared with antibody-expressing cells from patients with CRSwNP. There were more IL-5Rα⁺ plasma cells in the polyp tissue from those with AERD than in polyp tissue from those with CRSwNP (P = .026). IL-5 stimulation of plasma cells in vitro induced changes in a distinct set of transcripts.

Conclusions

Our study identifies an increase in antibody-expressing cells in AERD defined by transcript enrichment of IL5RA and IGHG4 or IGHE, with confirmed surface expression of IL-5Rα and functional IL-5 signaling. Tissue IgE and IgG4 levels are elevated in AERD, and higher IgE levels are associated with faster nasal polyp regrowth. Our findings suggest a role for IL-5Rα⁺ antibody-expressing cells in facilitating local antibody production and severe nasal polyps in AERD.

中文翻译：

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IL-5Rα标记阿司匹林加重的呼吸系统疾病中鼻息肉IgG4-和IgE表达细胞。

背景

阿司匹林加重呼吸道疾病（AERD）中严重鼻息肉的病因尚不清楚。升高的抗体水平与鼻息肉中的疾病严重程度有关，但尚不确定鼻息肉中局部抗体产生的上游驱动因素。

目的

我们试图从患有AERD的受试者的鼻息肉中鉴定出上游驱动因子和表达局部抗体的细胞的表型特性。

方法

窦组织取自患有AERD，患有鼻息肉的慢性鼻-鼻窦炎（CRS）（CRSwNP），无鼻息肉的CRS和无CRS的受试者。组织抗体水平通过ELISA和免疫组织化学定量，并与疾病严重程度相关。通过单细胞RNA测序，流式细胞仪和免疫荧光分析表达抗体的细胞，并通过IL-5刺激，随后的RNA测序和定量PCR确定IL-5Rα功能。

结果

与对照组相比，AERD中的组织IgE和IgG4水平升高（ IgE的P <0.01  ，IgG4的CR <0.001 ，P <0.001）。鼻息肉复发较快的AERD受试者的IgE水平高于AERD的受试者，其再生长较慢（P  = .005）。单细胞RNA测序显示，与来自CRSwNP患者的抗体表达细胞相比，AERD患者的抗体表达细胞中IL5RA，IGHG4和IGHE升高。AERD患者的息肉组织中的IL-5Rα ⁺浆细胞比CRSwNP患者的息肉组织中的IL-5Rα ⁺浆细胞多（P  = .026 ）。IL-5体外刺激浆细胞 导致一组独特的成绩单发生变化。

结论

我们的研究确定了IL5RA和IGHG4或IGHE的转录本富集所定义的AERD中抗体表达细胞的增加，并证实了IL-5Rα的表面表达和功能性IL-5信号传导。AERD中组织IgE和IgG4的水平升高，而较高的IgE的水平与更快的鼻息肉再生有关。我们的发现表明IL-5Rα ⁺抗体表达细胞在促进AERD中局部抗体产生和严重鼻息肉中的作用。