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鉴定克罗恩病和溃疡性结肠炎中共同的免疫相关基因
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Abstract:
目的：筛选出UC和CD患者的共有的表达异常的免疫相关基因，并比较UC和CD患者的免疫浸润的异同；
方法：从GEO获取2个肠粘膜基因表达矩阵GSE87473和GSE102133，对其进行差异分析，以及WGCNA
获取关键基因，并对获得的基因进行GO和KEGG分析，最后用CIBERSORT获取UC和CD患者的免疫浸润
情况，并分析免疫相关基因与免疫细胞的相关性。结果：UC和CD患者中共有8个差异表达的免疫相关共
同基因，分别是：DUOX2，LCN2，PI3，CXCL1，IDO1，STAT1，CXCL2和PLAUR。UC和CD患者具有
相似的免疫细胞浸润结果和轻微的免疫细胞浸润差异。识别的免疫相关共同基因或多或少与同时失调的
免疫细胞显著相关。结论：本研究利用生物信息学方法，筛选出8个UC和CD患者共有的表达异常的免疫
相关基因，为深入研究IBD患者的发病机制、诊断以及靶向治疗带来了新的思路。
Objective: To screen for immune-related genes with abnormal expression common to patients with
UC and CD and to compare the similarities and differences in immune infiltration in patients with UC
and CD. Methods: Two intestinal mucosal gene expression matrices, GSE87473 and GSE102133,
were obtained from GEO for differential analysis, as well as WGCNA to obtain essential genes and
GO and KEGG analysis of the obtained genes, and finally, CIBERSORT was used to obtain immune
infiltration in UC and CD patients and to analyze the correlation between immune-related genes
and immune cells. Results: There were eight differentially expressed immune-associated common
genes in UC and CD patients: DUOX2, LCN2, PI3, CXCL1, IDO1, STAT1, CXCL2 and PLAUR. UC and CD
patients had similar immune cell infiltration results and slight differences in immune cell infiltration.
Identified immune-related common genes were more or less significantly associated with
concurrently dysregulated immune cells. Conclusion: Using a bioinformatics approach, this study
screened for eight immune-related genes with abnormal expression common to UC and CD patients,
bringing new ideas for an in-depth study of pathogenesis, diagnosis and targeted therapy in
IBD patients.
| [1] | Matsuoka, K. and Kanai, T. (2015) The Gut Microbiota and Inflammatory Bowel Disease. Seminars in Immunopatholo-gy, 37, 47-55. https://doi.org/10.1007/s00281-014-0454-4 |
| [2] | Ungaro, R., Mehandru, S., Allen, P.B., et al. (2017) Ulcerative Colitis. The Lancet, 389, 1756-1770.
https://doi.org/10.1016/S0140-6736(16)32126-2 |
| [3] | Roda, G., Chien Ng, S., Kotze, P.G., et al. (2020) Crohn’s Disease. Nature Reviews Disease Primers, 6, Article No. 22.
https://doi.org/10.1038/s41572-020-0156-2 |
| [4] | Ng, S.C., Shi, H.Y., Hamidi, N., et al. (2017) Worldwide Inci-dence and Prevalence of Inflammatory Bowel Disease in the 21st Century: A Systematic Review of Population-Based Studies. The Lancet, 390, 2769-2778.
https://doi.org/10.1016/S0140-6736(17)32448-0 |
| [5] | Lu, Y., Li, X., Liu, S., et al. (2018) Toll-Like Receptors and Inflammatory Bowel Disease. Frontiers in Immunology, 9, Article No. 72. https://doi.org/10.3389/fimmu.2018.00072 |
| [6] | Pan, X., Zhu, Q., Pan, L.-L., et al. (2022) Macrophage Im-munometabolism in Inflammatory Bowel Diseases: From Pathogenesis to Therapy. Pharmacology & Therapeutics, 238, Article ID: 108176.
https://doi.org/10.1016/j.pharmthera.2022.108176 |
| [7] | Neumann, C., Scheffold, A. and Rutz, S. (2019) Functions and Regulation of T Cell-Derived Interleukin-10. Seminars in Immunology, 44, Article ID: 101344. https://doi.org/10.1016/j.smim.2019.101344 |
| [8] | Sharifinejad, N., Zaki-Dizaji, M., Sepahvandi, R., et al. (2022) The Clinical, Molecular, and Therapeutic Features of Patients with IL10/IL10R Deficiency: A Systematic Review. Clini-cal & Experimental Immunology, 208, 281-291.
https://doi.org/10.1093/cei/uxac040 |
| [9] | Yu, B., Yin, Y.-X., Tang, Y.-P., et al. (2021) Diagnostic and Predictive Value of Immune-Related Genes in Crohn’s Disease. Frontiers in Immunology, 12, Article ID: 643036. https://doi.org/10.3389/fimmu.2021.643036 |
| [10] | Xu, M., Kong, Y., Chen, N., et al. (2022) Identification of Im-mune-Related Gene Signature and Prediction of CeRNA Network in Active Ulcerative Colitis. Frontiers in Immunology, 13, Article ID: 855645.
https://doi.org/10.3389/fimmu.2022.855645 |
| [11] | Langfelder, P. and Horvath, S. (2008) WGCNA: An R Package for Weighted Correlation Network Analysis. BMC Bioinformatics, 9, Article No. 559. https://doi.org/10.1186/1471-2105-9-559 |
| [12] | Newman, A.M., Liu, C.L., Green, M.R., et al. (2015) Robust Enu-meration of Cell Subsets from Tissue Expression Profiles. Nature Methods, 12, 453-457. https://doi.org/10.1038/nmeth.3337 |
| [13] | Sham, H.P., Bazett, M., Bosiljcic, M., et al. (2018) Immune Stimulation Using a Gut Microbe-Based Immunotherapy Reduces Disease Pathology and Improves Barrier Function in Ulcerative Colitis. Frontiers in Immunology, 9, Article No. 2211. https://doi.org/10.3389/fimmu.2018.02211 |
| [14] | Di Jiang, C. and Raine, T. (2020) IBD Considerations in Spondyloarthritis. Therapeutic Advances in Musculoskeletal Disease, 12. https://doi.org/10.1177/1759720X20939410 |
| [15] | Malik, T. and Mannon, P. (2012) Inflammatory Bowel Diseases: Emerging Therapies and Promising Molecular Targets. Frontiers in Bioscience (Scholar Edition), 4, 1172-1189. https://doi.org/10.2741/s324 |
| [16] | Grasberger, H., Gao, J., Nagao-Kitamoto, H., et al. (2015) Increased Expression of DUOX2 Is an Epithelial Response to Mucosal Dysbiosis Required for Immune Homeostasis in Mouse Intestine. Gastroenterology, 149, 1849-1859.
https://doi.org/10.1053/j.gastro.2015.07.062 |
| [17] | Haberman, Y., Tickle, T.L., Dexheimer, P.J., et al. (2014) Pediat-ric Crohn Disease Patients Exhibit Specific Ileal Transcriptome and Microbiome Signature. Journal of Clinical Investiga-tion, 124, 3617-3633.
https://doi.org/10.1172/JCI75436 |
| [18] | Grasberger, H., Magis, A.T., Sheng, E., et al. (2021) DUOX2 Variants Associate with Preclinical Disturbances in Microbiota-Immune Homeostasis and Increased Inflammatory Bowel Disease Risk. Journal of Clinical Investigation, 131, e141676. https://doi.org/10.1172/JCI141676 |
| [19] | He, P., Yu, L., Tian, F., et al. (2022) Dietary Patterns and Gut Microbiota: The Crucial Actors in Inflammatory Bowel Disease. Advances in Nutrition, 13, 1628-1651. https://doi.org/10.1093/advances/nmac029 |
| [20] | Thorsvik, S., Dam？s, J.K., Granlund, A.V., et al. (2017) Fecal Neutrophil Gelatinase-Associated Lipocalin as a Biomarker for Inflammatory Bowel Disease. Journal of Gastroenterology and Hepatology, 32, 128-135.
https://doi.org/10.1111/jgh.13598 |
| [21] | Thorsvik, S., Bakke, I., van Beelen Granlund, A., et al. (2018) Expression of Neutrophil Gelatinase-Associated Lipocalin (NGAL) in the Gut in Crohn’s Disease. Cell and Tissue Research, 374, 339-348.
https://doi.org/10.1007/s00441-018-2860-8 |
| [22] | Zollner, A., Schmiderer, A., Reider, S.J., et al. (2021) Faecal Bi-omarkers in Inflammatory Bowel Diseases: Calprotectin versus Lipocalin-2—A Comparative Study. Journal of Crohn’s and Colitis, 15, 43-54.
https://doi.org/10.1093/ecco-jcc/jjaa124 |
| [23] | Chakraborty, S., Kaur, S., Guha, S., et al. (2012) The Multifaceted Roles of Neutrophil Gelatinase Associated Lipocalin (NGAL) in Inflammation and Cancer. Biochimica et Biophysica Ac-ta, 1826, 129-169.
https://doi.org/10.1016/j.bbcan.2012.03.008 |
| [24] | Behnsen, J., Jellbauer, S., Wong, C.P., et al. (2014) The Cytokine IL-22 Promotes Pathogen Colonization by Suppressing Related Commensal Bacteria. Immunity, 40, 262-273. https://doi.org/10.1016/j.immuni.2014.01.003 |
| [25] | Xiao, X., Yeoh, B.S. and Vijay-Kumar, M. (2017) Lipocalin 2: An Emerging Player in Iron Homeostasis and Inflammation. Annual Review of Nutrition, 37, 103-130. https://doi.org/10.1146/annurev-nutr-071816-064559 |
| [26] | Kortman, G.A.M., Mulder, M.L.M., Richters, T.J.W., et al. (2015) Low Dietary Iron Intake Restrains the Intestinal Inflammatory Response and Pathology of Enteric Infection by Food-Borne Bacterial Pathogens. European Journal of Immunology, 45, 2553-2567. https://doi.org/10.1002/eji.201545642 |
| [27] | Playford, R.J., Belo, A., Poulsom, R., et al. (2006) Effects of Mouse and Human Lipocalin Homologues 24p3/lcn2 and Neutrophil Gelatinase-Associated Lipocalin on Gastrointestinal Mu-cosal Integrity and Repair. Gastroenterology, 131, 809-817. https://doi.org/10.1053/j.gastro.2006.05.051 |
| [28] | Toyonaga, T., Matsuura, M., Mori, K., et al. (2016) Lipocalin 2 Prevents Intestinal Inflammation by Enhancing Phagocytic Bacterial Clearance in Macrophages. Scientific Reports, 6, Ar-ticle No. 35014.
https://doi.org/10.1038/srep35014 |
| [29] | Mori, K., Suzuki, T., Minamishima, S., et al. (2016) Neutrophil Gelati-nase-Associated Lipocalin Regulates Gut Microbiota of Mice. Journal of Gastroenterology and Hepatology, 31, 145-154. https://doi.org/10.1111/jgh.13042 |
| [30] | Yan, L., Borregaard, N., Kjeldsen, L., et al. (2001) The High Molecular Weight Urinary Matrix Metalloproteinase (MMP) Activity Is a Complex of Gelatinase B/MMP-9 and Neutrophil Gelati-nase-Associated Lipocalin (NGAL). Modulation of MMP-9 Activity by NGAL. Journal of Biological Chemistry, 276, 37258-3765.
https://doi.org/10.1074/jbc.M106089200 |
| [31] | Makhezer, N., Ben Khemis, M., Liu, D., et al. (2019) NOX1-Derived ROS Drive the Expression of Lipocalin-2 in Colonic Epithelial Cells in Inflammatory Conditions. Mu-cosal Immunology, 12, 117-131.
https://doi.org/10.1038/s41385-018-0086-4 |
| [32] | Rajarathnam, K., Schnoor, M., Richardson, R.M., et al. (2019) How Do Chemokines Navigate Neutrophils to the Target Site: Dissecting the Structural Mechanisms and Signaling Pathways. Cell Signal, 54, 69-80.
https://doi.org/10.1016/j.cellsig.2018.11.004 |
| [33] | Relton, C.L. and Davey Smith, G. (2010) Epigenetic Epidemiol-ogy of Common Complex Disease: Prospects for Prediction, Prevention, and Treatment. PLOS Medicine, 7, e1000356. https://doi.org/10.1371/journal.pmed.1000356 |
| [34] | S？terstad, S., ？stvik, A.E., R？yset, E.S., et al. (2022) Pro-found Gene Expression Changes in the Epithelial Monolayer of Active Ulcerative Colitis and Crohn’s Disease. PLOS ONE, 17, e0265189.
https://doi.org/10.1371/journal.pone.0265189 |
| [35] | Ball, H.J., Jusof, F.F., Bakmiwewa, S.M., et al. (2014) Trypto-phan-Catabolizing Enzymes—Party of Three. Frontiers in Immunology, 5, Article No. 485. https://doi.org/10.3389/fimmu.2014.00485 |
| [36] | Mellor, A.L. and Munn, D.H. (2004) IDO Expression by Dendrit-ic Cells: Tolerance and Tryptophan Catabolism. Nature Reviews Immunology, 4, 762-774. https://doi.org/10.1038/nri1457 |
| [37] | Nikolaus, S., Schulte, B., Al-Massad, N., et al. (2017) Increased Tryptophan Metabolism Is Associated with Activity of Inflammatory Bowel Diseases. Gastroenterology, 153, 1504-1516.e2. https://doi.org/10.1053/j.gastro.2017.08.028 |
| [38] | Chen, W., Liang, X., Peterson, A.J., et al. (2008) The Indoleam-ine 2,3-Dioxygenase Pathway Is Essential for Human Plasmacytoid Dendritic Cell-Induced Adaptive T Regulatory Cell Generation. The Journal of Immunology, 181, 5396-5404. https://doi.org/10.4049/jimmunol.181.8.5396 |
| [39] | Lin, Y., Yang, X., Yue, W., et al. (2014) Chemerin Aggravates DSS-Induced Colitis by Suppressing M2 Macrophage Polar-ization. Cellular & Molecular Immunology, 11, 355-366. https://doi.org/10.1038/cmi.2014.15 |
| [40] | Shon, W.-J., Lee, Y.-K., Shin, J.H., et al. (2015) Severity of DSS-Induced Colitis Is Reduced in Ido1-Deficient Mice with Down-Regulation of TLR-MyD88-NF-κB Transcriptional Networks. Scientific Reports, 5, Article No. 17305.
https://doi.org/10.1038/srep17305 |
| [41] | Bai, X., Liu, W., Chen, H., et al. (2022) Immune Cell Landscaping Reveals Distinct Immune Signatures of Inflammatory Bowel Disease. Frontiers in Immunology, 13, Article ID: 861790. https://doi.org/10.3389/fimmu.2022.861790 |
| [42] | Wéra, O., Lancellotti, P. and Oury, C. (2016) The Dual Role of Neutrophils in Inflammatory Bowel Diseases. Journal of Clinical Medicine, 5, Article No. 118. https://doi.org/10.3390/jcm5120118 |
| [43] | Roda, G., Jharap, B., Neeraj, N., et al. (2016) Loss of Response to An-ti-TNFs: Definition, Epidemiology, and Management. Clinical and Translational Gastroenterology, 7, e135. https://doi.org/10.1038/ctg.2015.63 |
| [44] | Vos, A.C.W., Wildenberg, M.E., Arijs, I., et al. (2012) Regulatory Mac-rophages Induced by Infliximab Are Involved in Healing in Vivo and in Vitro. Inflammatory Bowel Diseases, 18, 401-408. https://doi.org/10.1002/ibd.21818 |
| [45] | Du, Y., Rong, L., Cong, Y., et al. (2021) Macrophage Polarization: An Effective Approach to Targeted Therapy of Inflammatory Bowel Disease. Expert Opinion on Therapeutic Targets, 25, 191-209.
https://doi.org/10.1080/14728222.2021.1901079 |
| [46] | Endharti, A.T., Okuno, Y., Shi, Z., et al. (2011) CD8+CD122+ Regulatory T Cells (Tregs) and CD4+ Tregs Cooperatively Prevent and Cure CD4+ Cell-Induced Colitis. The Journal of Immunology, 186, 41-52.
https://doi.org/10.4049/jimmunol.1000800 |
| [47] | Rabe, H., Malmquist, M., Barkman, C., et al. (2019) Distinct Pat-terns of Naive, Activated and Memory T and B Cells in Blood of Patients with Ulcerative Colitis or Crohn’s Disease. Clinical & Experimental Immunology, 197, 111-129.
https://doi.org/10.1111/cei.13294 |
| [48] | Clough, J.N., Omer, O.S., Tasker, S., et al. (2020) Regulatory T-Cell Ther-apy in Crohn’s Disease: Challenges and Advances. Gut, 69, 942-952. https://doi.org/10.1136/gutjnl-2019-319850 |
| [49] | Mottet, C., Uhlig, H.H. and Powrie, F. (2003) Cutting Edge: Cure of Colitis by CD4+CD25+ Regulatory T Cells. The Journal of Immunology, 170, 3939-3943. https://doi.org/10.4049/jimmunol.170.8.3939 |
