基于GEO数据库甲状腺相关性眼病差异基因免疫浸润机制研究

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摘要目的利用GEO数据库，对甲状腺相关性眼病基因数据进行差异分析、富集分析和免疫浸润分析，为深入了解甲状腺相关性眼病免疫相关机制提供理论依据。方法通过GEO数据库检索“Graves disease”，选定甲状腺相关性眼病前眼眶表达基因作为试验组，正常人前眼眶表达基因作为对照组，利用STRING数据库对差异基因进行蛋白质-蛋白质相互作用（PPI）分析，筛选核心基因；并利用R软件对差异基因进行GO和KEGG富集分析；同时利用CIBERSORT反卷积法对22种免疫细胞在甲状腺相关性眼病中的浸润情况进行分析。结果根据GEO数据库进行差异分析，获得差异基因315个，其中下调基因220个，上调基因95个；将差异基因进行PPI分析，筛选核心基因56个，其中前5位主要核心基因分别是FOS、JUN、CXCL8、ITGAM和CXCL12；GO富集分析显示生物过程460个，细胞成分6个，分子功能36个，主要涉及细胞趋化性、白细胞趋化性、粒细胞趋化性、白细胞迁移、单核细胞迁移等生物过程；KEGG富集分析显示信号通路20条，主要涉及细胞因子-细胞因子受体相互作用、PI3K-Akt信号通路、白细胞介素-17信号通路、NF-κB信号通路、Toll样受体信号通路、破骨细胞分化等信号通路；免疫浸润结果显示试验组中单核细胞、浆细胞、中性粒细胞显著增高，M2巨噬细胞和未活化的静息肥大细胞显著减少，免疫细胞相关性分析中，浆细胞与活化的肥大细胞呈显著正相关（r = 0.64），单核细胞、未活化的自然杀伤细胞均与中性粒细胞呈显著正相关（r = 0.61、0.62），调节性T细胞与CD8+T细胞呈显著正相关（r = 0.60）。未活化的静息肥大细胞与浆细胞、活化的肥大细胞均呈显著负相关（r = -0.71、-0.68），单核细胞与M2巨噬细胞、未活化的静息肥大细胞均呈显著负相关（r = -0.71、-0.66），未活化的自然杀伤细胞与活化的自然杀伤细胞呈显著负相关（r = -0.71）。试验组与对照组组间的免疫浸润差异分析提示，在试验组中单核细胞和中性粒细胞显著增高（P ＜ 0.05），而M2巨噬细胞和未活化的静息肥大细胞显著减少（P ＜ 0.05）。结论甲状腺相关性眼病中存在各类免疫细胞不同程度的浸润，免疫应答和炎症反应贯穿疾病始终。

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	尹谢添1
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关键词 ： GEO数据库, 甲状腺相关性眼病, 免疫浸润, CIBERSORT反卷法, 机制研究

Abstract：Objective GEO database was used to conduct differential analysis, enrichment analysis, and immune infiltration analysis of gene data of thyroid-associated ophthalmopathy, providing theoretical basis for in-depth understanding of the immune related mechanism of thyroid-associated ophthalmopathy. Methods “Graves disease” was retrieved from GEO database, and orbital expression genes before thyroid-associated ophthalmopathy were selected as experimental group, and normal anterior orbital expression genes were used as control group. PPI analysis of differential genes was performed using STRING database to screen core genes; the R software was used for GO and KEGG enrichment analysis of differential genes; meanwhile, CIBERSORT deconvolution method was used to analyze the infiltration of 22 kinds of immune cells in thyroid-associpated ophthalmopathy. Results According to GEO database, 315 differential genes were obtained, including 220 down-regulated genes and 95 up-regulated genes, 56 core genes were screened by protein-protein interaction (PPI) analysis, and the top five core genes were FOS, JUN, CXCL8, ITGAM, and CXCL12, respectively; GO enrichment analysis showed 460 biological processes, six cellular components, and 36 molecular functions, it mainly involved cell chemotaxis, leukocyte chemotaxis, granulocyte chemotaxis, leukocyte migration, monocyte migration, and other biological processes; KEGG enrichment analysis showed 20 signaling pathways, mainly involved cytokine-cytokine receptor interaction, PI3K-Akt signaling pathway, interleukin-17 signaling pathway, NF-κB signaling pathway, Toll-like receptor signaling pathway, osteoclast differentiation, and other signaling pathways; the results of immune infiltration showed that monocytes, plasma cells and neutrophils were significantly increased in the experimental group, while M2 macrophages and inactive resting mast cells were significantly decreased. Immunocell correlation analysis showed a significant positive correlation between plasma cells and activated mast cells (r = 0.64), and there was a significant positive correlation between monocytes, inactive natural killer cells and neutrophils (r = 0.61, 0.62), regulatory T cells were significant positively correlated with CD8+T cells (r = 0.60), there was a significant negative correlation between inactive resting mast cells, plasma cells and activated mast cells (r = -0.71, -0.68), there was a significant negative correlation between monocytes, M2 macrophages and inactive resting mast cells (r = -0.71, -0.66), there was a significant negative correlation between inactive and activated natural killer cells (r = -0.71), the difference analysis of immune infiltration between experimental group and control group indicated that monocytes and neutrophils in experimental group were significantly increased (P ＜ 0.05), M2 macrophages and non-activated resting mast cells were significantly decreased (P ＜ 0.05). Conclusion There are various kinds of immune cell infiltration in thyroid-associated ophthalmopathy, immune response and inflammatory reaction throughout the disease.

Key words： GEO database Thyroid associated ophthalmopathy Immune infiltration CIBERSORT reverse convolution Mechanism study

基金资助:湖北省卫健委“向楠名医工作室”项目（鄂卫生计生通报〔2018〕15号）；
湖北省高等学校优秀中青年科技创新团队项目（T201708）。

通讯作者: 向楠（1961.6-），女，博士，教授，主任医师，博士生导师；研究方向：中医内科学内分泌。

作者简介: 尹谢添（1984.12-），男，湖北中医药大学中医临床学院2018级中医内科专业在读博士研究生；研究方向：中医内科学内分泌。

引用本文:

尹谢添1,2,3 赵诗超4 向楠1,3 陈继东1,3,5 曾明星3,6 周广文3,7. 基于GEO数据库甲状腺相关性眼病差异基因免疫浸润机制研究[J]. 中国医药导报, 2021, 18(35): 32-37,57.
YIN Xietian1,2,3 ZHAO Shichao4 XIANG Nan1,3 CHEN Jidong1,3,5 ZENG Mingxing3,6 ZHOU Guangwen3,7. Immune infiltration mechanism of differential genes in thyroid-associated ophthalmopathy based on GEO database#br#. 中国医药导报, 2021, 18(35): 32-37,57.

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