METHODS: Patients from 6 EoE centers with symptoms of esophageal dysfunction, but peak eosinophil counts of <15/hpf in esophageal biopsies and absence of gastroesophageal reflux disease with at least one follow-up visit were included. Clinical, (immuno)histological, and molecular features were determined and compared with EoE and healthy controls.
RESULTS: We included 54 patients with EoE variants (EoE-like esophagitis 53.7%; lymphocytic esophagitis 13.0%; and nonspecific esophagitis 33.3%). In 8 EoE-like esophagitis patients, EoE developed after a median of 14 months (interquartile range 3.6-37.6). Such progression increased over time (17.6% year 1, 32.0% year 3, and 62.2% year 6). Sequential RNA sequencing analyses revealed only 7 genes associated with this progression (with TSG6 and ALOX15 among the top 3 upregulated genes) with upregulation of a previously attenuated Th2 pathway. Immunostaining confirmed the involvement of eosinophil-associated proteins (TSG6 and ALOX15) and revealed a significantly increased number of GATA3-positive cells during progression, indicating a Th1/Th2 switch. Transition from one EoE variant (baseline) to another variant (during follow-up) was seen in 35.2% (median observation time of 17.3 months).
CONCLUSIONS: Transition of EoE variants to EoE suggests the presence of a disease spectrum. Few genes seem to be associated with the progression to EoE with upregulation of a previously attenuated Th2 signal. These genes, including GATA3 as a Th1/Th2 switch regulator, may represent potential therapeutic targets in early disease pathogenesis.
方法:来自六个EoE中心的有食管功能障碍症状的患者,但包括食管活检中嗜酸性粒细胞峰值计数<15/hpf和至少一次随访没有胃食管反流病。临床,测定(免疫)-组织学和分子特征,并与EoE和健康对照进行比较。
结果:我们纳入了54例EoE变异型患者(EoE样食管炎53.7%;淋巴细胞性食管炎13.0%;非特异性食管炎33.3%)。在8例EoE样食管炎患者中,EoE的中位数为14个月(IQR3.6-37.6)。这种进展随着时间的推移而增加(第1年为17.6%,第3年为32.0%,第6年为62.2%)。序列RNA测序分析显示,只有7个与此进展相关的基因(TSG6和ALOX15在前三个上调基因中)与先前减弱的Th2途径上调。免疫染色证实了嗜酸性粒细胞相关蛋白(TSG6,ALOX15)的参与,并显示在进展期间GATA3阳性细胞的数量显着增加,表明Th1/Th2转换。从一个EoE变体(基线)到另一个变体(在随访期间)的转变为35.2%(中位观察时间为17.3个月)。
结论:EoE变异体转变为EoE提示存在疾病谱。似乎很少有基因与先前减弱的Th2信号的上调与EoE的进展有关。这些基因,包括GATA3作为Th1/Th2开关调节器,可能代表早期疾病发病机制的潜在治疗靶点。