Esophageal type 2 cytokine expression heterogeneity in eosinophilic esophagitis in a multisite cohort.,Journal of Allergy and Clinical Immunology

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Esophageal type 2 cytokine expression heterogeneity in eosinophilic esophagitis in a multisite cohort.
Journal of Allergy and Clinical Immunology ( IF 11.4 ) Pub Date : 2020-03-19 , DOI: 10.1016/j.jaci.2020.01.051
Julia L M Dunn ₁ , Tetsuo Shoda ₁ , Julie M Caldwell ₁ , Ting Wen ₁ , Seema S Aceves ₂ , Margaret H Collins ₃ , Evan S Dellon ₄ , Gary W Falk ₅ , John Leung ₆ , Lisa J Martin ₇ , Paul Menard-Katcher ₈ , Amanda K Rudman-Spergel ₉ , Jonathan M Spergel ₁₀ , Joshua B Wechsler ₁₁ , Guang-Yu Yang ₁₂ , Glenn T Furuta ₁₃ , Marc E Rothenberg ₁ ,

Affiliation

Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio.
Division of Allergy Immunology, University of California, San Diego, Calif; Rady Children's Hospital, San Diego, Calif.
Division of Pathology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati.
Center for Esophageal Diseases and Swallowing and Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC.
Division of Gastroenterology, Hospital of the University of Pennsylvania, Philadelphia, Pa.
Division of Gastroenterology, Tufts Medical Center, Boston, Mass.
Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio.
Division of Gastroenterology & Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colo.
Allergy, Asthma and Airway Biology Branch Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Md.
Division of Allergy and Immunology, Children's Hospital of Philadelphia, School of Medicine, University of Pennsylvania, Philadelphia, Pa.
Division of Gastroenterology, Hepatology and Nutrition, Lurie Children's Hospital of Chicago, Chicago, Ill.
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Ill.
Digestive Health Institute, Children's Hospital Colorado, Gastrointestinal Eosinophilic Diseases Program, University of Colorado School of Medicine, Aurora, Colo.

Background

There is strong evidence for a role of type 2 cytokines in the pathogenesis of eosinophilic esophagitis (EoE); however, heterogeneity in type 2 gene expression has not been examined.

Objective

We examined type 2 immunity–associated gene expression in esophageal biopsy specimens, aiming to determine the degree of cytokine heterogeneity and its potential clinical significance.

Methods

Patients (n = 312) were recruited from 10 sites associated with the Consortium of Eosinophilic Gastrointestinal Disease Researchers. In addition to histologic and endoscopic assessment, esophageal biopsy specimens were examined for expression of 96 genes within the EoE diagnostic panel.

Results

Five subgroups of patients with active EoE were identified by unsupervised clustering based on expression of IL4, IL5, IL13, C-C motif chemokine ligand 26 (CCL26), thymic stromal lymphopoietin (TSLP), Charcot-Leyden crystal (CLC), C-C motif chemokine receptor 3 (CCR3), and CPA3. These groups differed in age (P < .02) and EoE diagnostic panel score (P < 1.08E–30) but not in eosinophil levels. The group V patients had the highest expression of IL5, TSLP, and CCL26 and genes associated with tissue remodeling, such as COL8A1, actin γ-2 (ACTG2), and tetraspanin 12 (TSPAN12). IL5 and IL13 were highly expressed in group IV; however, groups IV and V differed in age (34 vs 14 years [P < .05]). Groups II and III, which exhibited intermediate expression of IL5 and CPA3, were differentiated by high TSLP and IL13 in group III.

Conclusion

We observed heterogeneous type 2 gene expression among patients with active EoE. Type 2 gene overexpression was not directly proportional to disease features; this was especially true for tissue remodeling events. These findings highlight a clinical opportunity for leveraging molecular endotypes to implement personalized medicine in EoE.

中文翻译：

多部位队列嗜酸性食管炎中食管2型细胞因子表达异质性。

背景

有充分的证据表明2型细胞因子在嗜酸性食管炎（EoE）的发病机制中起作用；但是，尚未检查2型基因表达的异质性。

目的

我们研究了食管活检标本中与2型免疫相关的基因表达，旨在确定细胞因子异质性的程度及其潜在的临床意义。

方法

从嗜酸性胃肠道疾病研究人员联合会的10个地点招募患者（n = 312）。除了组织学和内窥镜检查之外，还检查了食管活检标本在EoE诊断组内是否存在96个基因的表达。

结果

根据IL4，IL5，IL13，CC型趋化因子配体26（CCL26），胸腺间质淋巴生成素（TSLP），夏科-莱登晶体（CLC），CC型趋化因子受体的表达，通过无监督聚类鉴定出具有活动性EoE的5个亚组。3（CCR3）和CPA3。这些组的年龄（P <.02）和EoE诊断组评分（P <1.08E–30）不同，但嗜酸性粒细胞水平无差异。V组患者IL5，TSLP和CCL26的表达最高。并与组织重塑，例如相关的基因COL8A1，肌动蛋白γ-2（ACTG2），和四次跨膜蛋白12（TSPAN12）。IL5和IL13在IV组中高表达。但是，IV和V组的年龄有所不同（34岁对14岁[ P <.05]）。II组和III组表现出IL5和CPA3的中间表达，在III组中高TSLP和IL13对其进行区分。