Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, USA.
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
Immunol Cell Biol. 2018 Apr;96(4):426-438. doi: 10.1111/imcb.12018. Epub 2018 Mar 6.
Eosinophilic esophagitis (EoE) is an increasingly recognized allergic disease associated with dysphagia and esophageal fibrosis. We aimed to determine expression patterns of specific eosinophil integrins that promote eosinophilic infiltration of the esophageal epithelium, and to determine how key EoE-related cytokines influence eosinophil activation and survival. Esophageal and peripheral eosinophils were isolated from 20 adult subjects with EoE for immunophenotyping and integrin profiling using multicolor flow cytometry and immunohistochemistry. Expression signatures of eosinophil integrins were further assessed by immunohistochemistry using serial sections of esophageal biopsy specimens. Purified eosinophils were used to assess the effect of EoE-relevant cytokines and recombinant periostin on expression of known eosinophil integrins and eosinophil survival and activation. We found that resting eosinophils express high levels of the β2-pairing integrins αL and αM, and lower levels of α4, α6 and α4β7. The migration of peripheral eosinophils to the esophagus is characterized by the specific induction of αM, and a significant increase in the proportion of αM in high-activity conformation. Periostin, a secreted extracellular matrix protein that is significantly overexpressed in EoE, enhances eosinophil survival, and this effect is mediated by αM interaction. Integrin αM is a specific marker of activated tissue eosinophils in EoE, and promotes eosinophil survival through interactions with periostin. The ability of αMβ2 to mediate eosinophil tissue residency via periostin represents a key mechanism for disease development and a potential therapeutic target in EoE.
嗜酸性食管炎（EoE）是一种日益被认识的与吞咽困难和食管纤维化相关的过敏性疾病。我们旨在确定促进食管上皮嗜酸性浸润的特定嗜酸性粒细胞整合素的表达模式，并确定关键的 EoE 相关细胞因子如何影响嗜酸性粒细胞的激活和存活。我们从 20 名成人 EoE 患者中分离出食管和外周嗜酸性粒细胞，用于免疫表型分析和使用多色流式细胞术和免疫组织化学分析整合素谱。通过对食管活检标本的连续切片进行免疫组织化学分析，进一步评估嗜酸性粒细胞整合素的表达特征。使用纯化的嗜酸性粒细胞评估与 EoE 相关的细胞因子和重组骨桥蛋白对已知嗜酸性粒细胞整合素的表达以及嗜酸性粒细胞存活和激活的影响。我们发现静止的嗜酸性粒细胞表达高水平的β2 配对整合素αL 和 αM，以及较低水平的α4、α6 和α4β7。外周嗜酸性粒细胞向食管的迁移特征是αM 的特异性诱导，以及高活性构象中αM 的比例显著增加。骨桥蛋白是一种在 EoE 中显著过表达的分泌细胞外基质蛋白，可增强嗜酸性粒细胞的存活，这种作用是通过αM 相互作用介导的。整合素αM 是 EoE 中活化组织嗜酸性粒细胞的特异性标志物，通过与骨桥蛋白的相互作用促进嗜酸性粒细胞的存活。αMβ2 通过骨桥蛋白介导嗜酸性粒细胞组织驻留的能力是疾病发展的关键机制，也是 EoE 的潜在治疗靶点。
