Characterization of eosinophils and natural killer cells in nasal polyps and peripheral blood in eosinophilic chronic rhinosinusitis patients
Characterization of eosinophils and natural killer cells in nasal polyps and peripheral blood in eosinophilic chronic rhinosinusitis patients
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嗜酸性粒细胞慢性鼻窦炎患者鼻息肉和外周血中嗜酸性粒细胞和自然杀伤细胞的特征
DOI：
10.1016/j.alit.2022.11.009
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发表时间：
2023
影响因子：
6.8
通讯作者：
Hirahara Kiyoshi
中科院分区：
文献类型：
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作者：
Tsuji Kaori;Aoki Ami;Onodera Atsushi;Kiuchi Masahiro;Kokubo Kota;Morimoto Yuki;Iinuma Tomohisa;Hanazawa Toyoyuki;Nakayama Toshinori;Hirahara Kiyoshi
白细胞介素-5（IL-5）是嗜酸性粒细胞分化、生长和募集的关键细胞因子，主要由辅助性T细胞2（Th 2）或2型先天性淋巴细胞（ILC 2）在过敏原暴露后产生，在嗜酸性粒细胞炎症中起重要作用。1，2 IL-5通过与各种免疫细胞上的IL-5受体（IL-5 R）结合来发挥其功能。IL-5 R是由IL-5特异性α亚基（IL-5 Ra）和非特异性B亚基组成的异源二聚体，其与IL-3和粒细胞巨噬细胞集落刺激因子（GM-CSF）的受体共享。3贝那利珠单抗是一种人源化单克隆抗体，可结合IL-5 Ra表位并阻断IL-5信号传导途径。4 IL-5 Ra在嗜酸性粒细胞和嗜碱性粒细胞上表达，贝那利珠单抗能够通过两种不同的机制减少嗜酸性粒细胞：阻断IL-5信号传导途径，这对嗜酸性粒细胞的存活很重要;诱导自然杀伤（NK）细胞介导的抗体依赖性细胞毒性（ADCC）。5 ADCC涉及Fcg受体III-表达NK细胞，其识别贝那利珠单抗的片段可结晶（Fc）区与嗜酸性粒细胞上的IL-5 Ra结合。NK细胞通过Fcg受体III活化，释放细胞毒性细胞因子，并诱导嗜酸性粒细胞凋亡。6贝那利珠单抗治疗被认为是嗜酸性粒细胞性哮喘的有效疗法，通过阻断IL-5信号传导和随之而来的嗜酸性粒细胞减少来发挥其作用。2在外周血中，已经报道贝那利珠单抗介导ADCC并减少循环嗜酸性粒细胞数量。4然而，贝那利珠单抗是否对发炎组织有任何影响仍然未知。在本研究中，我们描述了嗜酸性慢性鼻窦炎（ECRS）患者鼻息肉中免疫细胞的特征，并探讨了贝那利珠单抗治疗作为ECRS患者潜在治疗方法的实用性。为了评估免疫细胞浸润到局部炎症组织中，我们评估了ECRS患者鼻息肉，7其特征是嗜酸性炎症。我们特别试图检查嗜酸性粒细胞和NK细胞，这两者都参与嗜酸性粒细胞炎症。因此，进行Siglec-8和CD 56的免疫荧光染色以分别检测鼻息肉中的嗜酸性粒细胞和NK细胞（图1A、B）。如预期的那样，我们观察到嗜酸性粒细胞和NK细胞在ECRS患者鼻息肉中的浸润。IL-5 Ra是贝那利珠单抗抑制的靶分子，与IL-5 Ra表达细胞的结合对于贝那利珠单抗抑制IL-5 Ra是必不可少的。
Interleukin-5 (IL-5), a key cytokine in the differentiation, growth, and recruitment of eosinophils, is mainly produced by T helper 2 (Th2) cells or type 2 innate lymphoid cells (ILC2) after exposure to allergens and plays an important role in eosinophilic inflammation. 1, 2 IL-5 exerts its function by binding to the IL-5 receptor (IL-5R) on various kinds of immune cells. IL-5R is a heterodimer, consisting of an IL-5-specific a subunit (IL-5Ra) and nonspecific b subunit, which is shared with receptors of IL-3 and granulocyte macrophage colony-stimulating factor (GM-CSF). 3 Benralizumab is a humanized monoclonal antibody that binds to the IL-5Ra epitope and blocks the IL-5 signaling pathway. 4 IL-5Ra is expressed on eosinophils and basophils, and benralizumab has the ability to reduce eosinophils by two distinct mechanisms: blocking the IL-5 signaling pathway, which is important for the survival of eosinophils; and inducing antibody-dependent cellular cytotoxicity (ADCC) mediated by natural killer (NK) cells. 5 ADCC involves Fcg receptor III-expressing NK cells that recognize the fragment crystallizable (Fc) region of benralizumab binding to IL-5Ra on eosinophils. NK cells are activated through the Fcg receptor III, release cytotoxic cytokines, and induce apoptosis of eosinophils. 6 Benralizumab treatment is recognized as an effective therapy for eosinophilic asthma, exerting its effects via blockade of IL-5 signaling and the consequent reduction of eosinophils. 2 In the peripheral blood, it has already been reported that benralizumab mediates ADCC and reduces circulating eosinophil cell numbers. 4 However, whether or not benralizumab has any effect on the inflamed tissues remains unknown. In the present study, we characterized the immune cells in nasal polyps derived from eosinophilic chronic rhinosinusitis (ECRS) patients and addressed the utility of benralizumab treatment as a potential therapy for ECRS patients.To assess the infiltration of immune cells into the local inflamed tissue, we evaluated nasal polyps derived from patients with ECRS, 7 which is characterized by eosinophilic inflammation. We particularly sought to examine eosinophils and NK cells, both of which are involved in eosinophilic inflammation. Thus, immunofluorescent staining of Siglec-8 and CD56 was performed to detect eosinophils and NK cells, respectively, in nasal polyps (Fig. 1 A, B). As expected, we observed the infiltration of eosinophils and NK cells in nasal polyps of ECRS patients. IL-5Ra is the target molecule inhibited by benralizumab, and binding to IL-5Ra-expressing cells is essential for benralizumab to