{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T15:26:40Z","timestamp":1784215600567,"version":"3.55.0"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,20]],"date-time":"2022-06-20T00:00:00Z","timestamp":1655683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82070812"],"award-info":[{"award-number":["82070812"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100019081","name":"Science and Technology Program of Hunan Province","doi-asserted-by":"publisher","award":["2020RC4044"],"award-info":[{"award-number":["2020RC4044"]}],"id":[{"id":"10.13039\/501100019081","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010083","name":"Hunan Provincial Innovation Foundation for Postgraduate","doi-asserted-by":"publisher","award":["CX20210363"],"award-info":[{"award-number":["CX20210363"]}],"id":[{"id":"10.13039\/501100010083","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012476","name":"Fundamental Research Funds for Central Universities of the Central South University","doi-asserted-by":"publisher","award":["2021zzts0361"],"award-info":[{"award-number":["2021zzts0361"]}],"id":[{"id":"10.13039\/501100012476","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Type 1 diabetes (T1D) patients are at heightened risk for other autoimmune disorders, particularly Hashimoto\u2019s thyroiditis (HT) and celiac disease (CD). Recent evidence suggests that target tissues of autoimmune diseases engage in a harmful dialogue with the immune system. However, it is unclear whether shared mechanisms drive similar molecular signatures at the target tissues among T1D, HT, and CD. In our current study, microarray datasets were obtained and mined to identify gene signatures from disease-specific targeted tissues including the pancreas, thyroid, and intestine from individuals with T1D, HT, and CD, as well as their matched controls. Further, the threshold-free algorithm rank-rank hypergeometric overlap analysis (RRHO) was used to compare the genomic signatures of the target tissues of the three autoimmune diseases. Next, promising drugs that could potentially reverse the observed signatures in patients with two or more autoimmune disorders were identified using the cloud-based CLUE software platform. Finally, microarray data of auto-antibody positive individuals but not diagnosed with T1D and single cell sequencing data of patients with T1D and HT were used to validate the shared transcriptomic fingerprint. Our findings revealed significant common gene expression changes in target tissues of the three autoimmune diseases studied, many of which are associated with virus infections, including influenza A, human T-lymphotropic virus type 1, and herpes simplex infection. These findings support the importance of common environmental factors in the pathogenesis of T1D, HT, and CD.<\/jats:p>","DOI":"10.3389\/fimmu.2022.891698","type":"journal-article","created":{"date-parts":[[2022,6,20]],"date-time":"2022-06-20T07:42:16Z","timestamp":1655710936000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Gene Expression Signatures Reveal Common Virus Infection Pathways in Target Tissues of Type 1 Diabetes, Hashimoto\u2019s Thyroiditis, and Celiac Disease"],"prefix":"10.3389","volume":"13","author":[{"given":"Min","family":"Yin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"17016","DOI":"10.1038\/nrdp.2017.16","article-title":"Type 1 Diabetes Mellitus","volume":"3","author":"Katsarou","year":"2017","journal-title":"Nat Rev Dis primers"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.2337\/dc19-2429","article-title":"Every Fifth Individual With Type 1 Diabetes Suffers From an Additional Autoimmune Disease: A Finnish Nationwide Study","volume":"43","author":"M\u00e4kimattila","year":"2020","journal-title":"Diabetes Care"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.2337\/dc16-2508","article-title":"Prevalence of Celiac Disease in 52,721 Youth With Type 1 Diabetes: International Comparison Across Three Continents","volume":"40","author":"Craig","year":"2017","journal-title":"Diabetes Care"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.2337\/dc15-2117","article-title":"Celiac Disease Increases Risk of Thyroid Disease in Patients With Type 1 Diabetes: A Nationwide Cohort Study","volume":"39","author":"Kurien","year":"2016","journal-title":"Diabetes Care"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2013.161","article-title":"Clinical Implications of Shared Genetics and Pathogenesis in Autoimmune Diseases","volume":"9","author":"Zhernakova","year":"2013","journal-title":"Nat Rev Endocrinol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abd7600","article-title":"Gene Expression Signatures of Target Tissues in Type 1 Diabetes, Lupus Erythematosus, Multiple Sclerosis, and Rheumatoid Arthritis","volume":"7","author":"Szymczak","year":"2021","journal-title":"Sci Adv"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.2337\/db15-1308","article-title":"Expression-Based Genome-Wide Association Study Links Vitamin D-Binding Protein With Autoantigenicity in Type 1 Diabetes","volume":"65","author":"Kodama","year":"2016","journal-title":"Diabetes"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0234566","article-title":"Genetic Relationship Between Hashimoto`s Thyroiditis and Papillary Thyroid Carcinoma With Coexisting Hashimoto`s Thyroiditis","volume":"15","author":"Subhi","year":"2020","journal-title":"PloS One"},{"key":"B9","doi-asserted-by":"publisher","first-page":"2551","DOI":"10.3390\/ijms22052551","article-title":"Deciphering the Transcriptomic Heterogeneity of Duodenal Coeliac Disease Biopsies","volume":"22","author":"Wolf","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.2337\/db19-0058","article-title":"NIH Initiative to Improve Understanding of the Pancreas, Islet, and Autoimmunity in Type 1 Diabetes: The Human Pancreas Analysis Program (HPAP)","volume":"68","author":"Kaestner","year":"2019","journal-title":"Diabetes"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz240","article-title":"NetworkAnalyst 3.0: A Visual Analytics Platform for Comprehensive Gene Expression Profiling and Meta-Analysis","volume":"47","author":"Zhou","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1120","article-title":"The NHGRI-EBI GWAS Catalog of Published Genome-Wide Association Studies, Targeted Arrays and Summary Statistics 2019","volume":"47","author":"Buniello","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq636","article-title":"Rank-Rank Hypergeometric Overlap: Identification of Statistically Significant Overlap Between Gene-Expression Signatures","volume":"38","author":"Plaisier","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"B14","doi-asserted-by":"publisher","first-page":"P3","DOI":"10.1186\/gb-2003-4-5-p3","article-title":"DAVID: Database for Annotation, Visualization, and Integrated Discovery","volume":"4","author":"Dennis","year":"2003","journal-title":"Genome Biol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1437","DOI":"10.1016\/j.cell.2017.10.049","article-title":"A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles","volume":"171","author":"Subramanian","year":"2017","journal-title":"Cell"},{"key":"B16","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1002\/rmv.1815","article-title":"Enteroviruses, Hygiene and Type 1 Diabetes: Toward a Preventive Vaccine","volume":"25","author":"Drescher","year":"2015","journal-title":"Rev Med virology"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2018-00862","article-title":"Study of 2009 H1N1 Pandemic Influenza Virus as a Possible Causative Agent of Diabetes","volume":"103","author":"Capua","year":"2018","journal-title":"J Clin Endocrinol Metab"},{"key":"B18","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/1743-422X-6-5","article-title":"Viruses and Thyroiditis: An Update","volume":"6","author":"Desailloud","year":"2009","journal-title":"Virol J"},{"key":"B19","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1002\/dmrr.337","article-title":"A New Look at Viruses in Type 1 Diabetes","volume":"19","author":"Jun","year":"2003","journal-title":"Diabetes Metab Res Rev"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1996","DOI":"10.1007\/s00125-018-4662-7","article-title":"Pandemic Influenza and Subsequent Risk of Type 1 Diabetes: A Nationwide Cohort Study","volume":"61","author":"Ruiz","year":"2018","journal-title":"Diabetologia"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/ajg.2010.352","article-title":"Increased Risk of Hospital Admission for Influenza in Patients With Celiac Disease: A Nationwide Cohort Study in Sweden","volume":"105","author":"M\u00e5rild","year":"2010","journal-title":"Am J gastroenterol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1089\/105072502760258640","article-title":"Cytotoxic T-Lymphocyte Antigen-4 Gene Polymorphisms and Human T-Cell Lymphotrophic Virus-1 Infection: Their Associations With Hashimoto's Thyroiditis in Japanese Patients","volume":"12","author":"Tomoyose","year":"2002","journal-title":"Thyroid"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01922","article-title":"Confirmation and Identification of Biomarkers Implicating Environmental Triggers in the Pathogenesis of Type 1 Diabetes","volume":"11","author":"Harms","year":"2020","journal-title":"Front Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1210\/me.2004-0100","article-title":"Thyrocytes Express a Functional Toll-Like Receptor 3: Overexpression can be Induced by Viral Infection and Reversed by Phenylmethimazole and is Associated With Hashimoto's Autoimmune Thyroiditis","volume":"19","author":"Harii","year":"2005","journal-title":"Mol Endocrinol (Baltimore Md)"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3390\/v11080762","article-title":"Viruses and Autoimmunity: A Review on the Potential Interaction and Molecular Mechanisms","volume":"11","author":"Smatti","year":"2019","journal-title":"Viruses"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(21)00139-X","article-title":"Imatinib Therapy for Patients With Recent-Onset Type 1 Diabetes: A Multicentre, Randomised, Double-Blind, Placebo-Controlled, Phase 2 Trial","volume":"9","author":"Gitelman","year":"2021","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1016\/j.cmet.2017.03.018","article-title":"Targeting ABL-Ire1\u03b1 Signaling Spares ER-Stressed Pancreatic \u03b2 Cells to Reverse Autoimmune Diabetes","volume":"25","author":"Morita","year":"2017","journal-title":"Cell Metab"},{"key":"B28","doi-asserted-by":"publisher","first-page":"5995","DOI":"10.1128\/JVI.00034-11","article-title":"An Anti-Inflammatory Role of VEGFR2\/Src Kinase Inhibitor in Herpes Simplex Virus 1-Induced Immunopathology","volume":"85","author":"Sharma","year":"2011","journal-title":"J virology"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01969-10","article-title":"Receptor Tyrosine Kinase Inhibitors Block Multiple Steps of Influenza a Virus Replication","volume":"85","author":"Kumar","year":"2011","journal-title":"J virology"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/nm962","article-title":"Hsp70 Promotes Antigen-Presenting Cell Function and Converts T-Cell Tolerance to Autoimmunity In Vivo","volume":"9","author":"Millar","year":"2003","journal-title":"Nat Med"},{"key":"B31","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1053\/j.gastro.2015.05.013","article-title":"Distinct and Synergistic Contributions of Epithelial Stress and Adaptive Immunity to Functions of Intraepithelial Killer Cells and Active Celiac Disease","volume":"149","author":"Setty","year":"2015","journal-title":"Gastroenterology"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-8411(03)00038-6","article-title":"T Cells and Autoantibodies to Human HSP70 in Type 1 Diabetes in Children","volume":"20","author":"Abulafia-Lapid","year":"2003","journal-title":"J autoimmunity"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2796.2009.02129.x","article-title":"ANTI-HSP60 and ANTI-HSP70 Antibody Levels and Micro\/ Macrovascular Complications in Type 1 Diabetes: The EURODIAB Study","volume":"266","author":"Gruden","year":"2009","journal-title":"J Internal Med"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.3.1263-1270.2004","article-title":"Heat Shock Protein 70 Is Related to Thermal Inhibition of Nuclear Export of the Influenza Virus Ribonucleoprotein Complex","volume":"78","author":"Hirayama","year":"2004","journal-title":"J virology"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2005.01.152","article-title":"Heat-Shock Protein 70 Acts as an Effective Adjuvant in Neonatal Mice and Confers Protection Against Challenge With Herpes Simplex Virus","volume":"23","author":"Pack","year":"2005","journal-title":"Vaccine"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2010.00955.x","article-title":"Phosphatidylinositol 3-Kinase-\u03b4 Up-Regulates L-Type Ca2+ Currents and Increases Vascular Contractility in a Mouse Model of Type 1 Diabetes","volume":"161","author":"Pinho","year":"2010","journal-title":"Br J Pharmacol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0169695","article-title":"Pi3k\u03b3 Deficient NOD-Mice Are Protected From Diabetes by Restoring the Balance of Regulatory to Effector-T-Cells","volume":"12","author":"Azzi","year":"2017","journal-title":"PloS One"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.jamcollsurg.2006.12.037","article-title":"Increased Incidence of Well-Differentiated Thyroid Cancer Associated With Hashimoto Thyroiditis and the Role of the PI3k\/Akt Pathway","volume":"204","author":"Larson","year":"2007","journal-title":"J Am Coll Surgeons"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.891698\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,20]],"date-time":"2022-06-20T07:42:21Z","timestamp":1655710941000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.891698\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,20]]},"references-count":38,"alternative-id":["10.3389\/fimmu.2022.891698"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.891698","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,20]]},"article-number":"891698"}}