{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:00:32Z","timestamp":1753891232419,"version":"3.41.2"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,7,31]],"date-time":"2024-07-31T00:00:00Z","timestamp":1722384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Uveitis refers to a group inflammation affecting the uvea, retina, retinal blood vessels as well as vitreous body, which is one of the common causes of blindness. There is growing evidence linking different types of immune cells to uveitis, although it remains uncertain if these associations imply causal relationships. Recent advancements in high-density genetic markers like SNPs or CNVs for genotyping, along with the progress in genome-wide association studies (GWAS) technologies, have improved our understanding of the immunological mechanisms involved in ocular diseases. Therefore, our objective was to investigate the potential causal link between immune cells and uveitis using a Mendelian randomization study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The exposure and outcome GWAS data for this study were sourced from an open-access database (<jats:ext-link>https:\/\/gwas.mrcieu.ac.uk\/<\/jats:ext-link>). Two-sample MR analysis was utilized to evaluate the causal relationship between 731 immune cell features and uveitis. Various MR methods were employed to reduce bias and obtain dependable estimates of the causal link between the immune cell variables and the outcomes. Instrumental variable selection criteria were carefully chosen to enhance the accuracy and efficacy of the causal relationship between different immune cell types and the risk of uveitis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Using two-sample MR, IVW modeling showed that GAD had significant effect on immunophenotypes. CD3 levels on CD45RA\u2212 CD4+ T cells (OR\u2009=\u20091.087, 95%CI\u2009=\u20091.029\u2009~\u20091.147, <jats:italic>p<\/jats:italic>\u2009=\u20090.003) and CD3 levels on CM CD4+ T cells (OR\u2009=\u20091.086, 95%CI\u2009=\u20091.033\u2009~\u20091.141, <jats:italic>p<\/jats:italic>\u2009=\u20090.001) were found to be elevated in cases of uveitis. HLA DR levels in CD14\u2212 CD16+ monocyte cells (OR\u2009=\u20090.735, 95% CI\u2009=\u20090.635\u2009~\u20090.850, <jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.001) and HLA DR levels in NK cells (OR\u2009=\u20090.910, 95% CI\u2009=\u20090.851\u2009~\u20090.972, <jats:italic>p<\/jats:italic>\u2009=\u20090.005) were observed to be reduced in individuals with uveitis. Furthermore, Two cells were identified to be significantly associated with uveitis risk: HLA DR on in NK cells (OR\u2009=\u20090.938, 95%CI\u2009=\u20090.899\u2009~\u20090.979, <jats:italic>p<\/jats:italic>\u2009=\u20090.003), HLA DR on CD14\u2212 CD16+ monocytes (OR\u2009=\u20090.924, 95%CI\u2009=\u20090.878\u2009~\u20090.972, <jats:italic>p<\/jats:italic>\u2009=\u20090.002).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study highlights the intricate relationship between immune cells and generalized anxiety disorder using genetic methods, offering valuable insights for future clinical investigations.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmed.2024.1445775","type":"journal-article","created":{"date-parts":[[2024,7,31]],"date-time":"2024-07-31T08:01:44Z","timestamp":1722412904000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Causal role of immune cells in uveitis: a Mendelian randomization study"],"prefix":"10.3389","volume":"11","author":[{"given":"Jianping","family":"Pu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhuanghong","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanping","family":"Duan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuchen","family":"Yao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuxin","family":"Wen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanxun","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fengyu","family":"Ye","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,7,31]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"758240","DOI":"10.3389\/fcell.2021.758240","article-title":"Epigenetic modifications and therapy in uveitis","volume":"9","author":"Zou","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1007\/s40265-020-01314-y","article-title":"Uveitis therapy: the corticosteroid options","volume":"80","author":"Valdes","year":"2020","journal-title":"Drugs"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1111\/jdv.15963","article-title":"Early-onset granulomatous arthritis, uveitis and skin rash: characterization of skin involvement in Blau syndrome","volume":"34","author":"Poline","year":"2020","journal-title":"J Europ Acad Dermatol Venereol"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/j.ophtha.2020.06.052","article-title":"Collaborative ocular tuberculosis study consensus guidelines on the Management of Tubercular Uveitis-Report 2: guidelines for initiating Antitubercular therapy in anterior uveitis, intermediate uveitis, Panuveitis, and retinal Vasculitis","volume":"1282","author":"Agrawal","year":"2021","journal-title":"Ophthalmology"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"601619","DOI":"10.3389\/fimmu.2021.601619","article-title":"Altered metabolic phenotype of immune cells in a spontaneous autoimmune uveitis model","volume":"12","author":"Barf\u00fc\u00dfer","year":"2021","journal-title":"Front Immunol"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1016\/j.survophthal.2021.07.006","article-title":"The association between vitamin D and uveitis: a comprehensive review","volume":"672","author":"Pillar","year":"2022","journal-title":"Surv Ophthalmol"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1080\/09273948.2016.1196713","article-title":"A focus on the epidemiology of uveitis","volume":"26","author":"Tsirouki","year":"2018","journal-title":"Ocul Immunol Inflamm"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.survophthal.2015.07.001","article-title":"The ocular immunology and uveitis foundation preferred practice patterns of uveitis management","volume":"61","author":"Foster","year":"2016","journal-title":"Surv Ophthalmol"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1711","DOI":"10.1186\/s12889-023-16591-x","article-title":"Association between uveitis onset and economic development in mainland China","volume":"231","author":"Tan","year":"2023","journal-title":"BMC Public Health"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1016\/j.jaci.2011.07.008","article-title":"Regulation of TH17 and regulatory T cells in patients with Beh\u00e7et disease","volume":"128","author":"Direskeneli","year":"2011","journal-title":"J Allergy Clin Immunol"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1016\/j.immuni.2020.06.022","article-title":"The cytokine IL-17A limits Th17 pathogenicity via a negative feedback loop driven by autocrine induction of IL-24","volume":"532","author":"Chong","year":"2020","journal-title":"Immunity"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1016\/j.celrep.2019.06.021","article-title":"Type I interferon therapy limits CNS autoimmunity by inhibiting CXCR3-mediated trafficking of pathogenic effector T cells","volume":"282","author":"Wang","year":"2019","journal-title":"Cell Rep"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"5866","DOI":"10.1038\/s41467-022-33502-7","article-title":"Multicellular immune dynamics implicate PIM1 as a potential therapeutic target for uveitis","volume":"13","author":"Li","year":"2022","journal-title":"Nat Commun"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1016\/j.it.2017.06.004","article-title":"The ambiguous role of \u03b3\u03b4 T lymphocytes in antitumor immunity","volume":"38","author":"Chitadze","year":"2017","journal-title":"Trends Immunol"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"2389","DOI":"10.3389\/fimmu.2018.02389","article-title":"\u03b3\u03b4 T lymphocytes: an effector cell in autoimmunity and infection","volume":"9","author":"Shiromizu","year":"2018","journal-title":"Front Immunol"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"115629","DOI":"10.1016\/j.bcp.2023.115629","article-title":"\u03b3\u03b4 T cells in autoimmune uveitis pathogenesis: a promising therapeutic target","volume":"213","author":"Zhang","year":"2023","journal-title":"Biochem Pharmacol"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"1925","DOI":"10.1001\/jama.2017.17219","article-title":"Mendelian randomization","volume":"31819","author":"Emdin","year":"2017","journal-title":"JAMA"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.ajhg.2022.12.017","article-title":"Using genetic association data to guide drug discovery and development: review of methods and applications","volume":"110","author":"Burgess","year":"2023","journal-title":"Am J Hum Genet"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1093\/ije\/dyac149","article-title":"Tools for assessing quality and risk of bias in Mendelian randomization studies: a systematic review","volume":"52","author":"Spiga","year":"2023","journal-title":"Int J Epidemiol"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1038\/s41586-020-2528-x","article-title":"Global reference mapping of human transcription factor footprints","volume":"5837818","author":"Vierstra","year":"2020","journal-title":"Nature"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1985","DOI":"10.1093\/ije\/dyx102","article-title":"Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption","volume":"46","author":"Hartwig","year":"2017","journal-title":"Int J Epidemiol"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"1338083","DOI":"10.3389\/fimmu.2023.1338083","article-title":"Causal role of immune cells in generalized anxiety disorder: Mendelian randomization study","volume":"14","author":"Ma","year":"2023","journal-title":"Front Immunol"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"1196","DOI":"10.1038\/s41588-018-0164-2","article-title":"Publisher correction: detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases","volume":"50","author":"Verbanck","year":"2018","journal-title":"Nat Genet"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1132","DOI":"10.1016\/j.immuni.2019.04.011","article-title":"T follicular helper cell biology: a decade of discovery and diseases","volume":"50","author":"Crotty","year":"2019","journal-title":"Immunity"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1146\/annurev-immunol-041015-055605","article-title":"Follicular helper T cells","volume":"34","author":"Vinuesa","year":"2016","journal-title":"Annu Rev Immunol"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"883","DOI":"10.3389\/fimmu.2018.00883","article-title":"Emerging functions of regulatory T cells in tissue homeostasis","volume":"9","author":"Sharma","year":"2018","journal-title":"Front Immunol"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"e1006349","DOI":"10.1371\/journal.ppat.1006349","article-title":"Skin-resident CD4+ T cells protect against Leishmania major by recruiting and activating inflammatory monocytes","volume":"13","author":"Glennie","year":"2017","journal-title":"PLoS Pathog"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"2025","DOI":"10.3389\/fimmu.2020.02025","article-title":"T helper (Th) cell profiles in pregnancy and recurrent pregnancy losses: Th1\/Th2\/Th9\/Th17\/Th22\/Tfh cells","volume":"11","author":"Wang","year":"2020","journal-title":"Front Immunol"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"2611","DOI":"10.1002\/art.39228","article-title":"Interactions between amino acid-defined major histocompatibility complex class II variants and smoking in seropositive rheumatoid arthritis","volume":"67","author":"Kim","year":"2015","journal-title":"Arthritis Rheumatol"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1038\/jhg.2015.36","article-title":"Human leukocyte antigen polymorphisms and personalized medicine for rheumatoid arthritis","volume":"60","author":"Furukawa","year":"2015","journal-title":"J Hum Genet"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1016\/j.bbi.2020.01.018","article-title":"Peripheral innate immune and bacterial signals relate to clinical heterogeneity in Parkinson's disease","volume":"87","author":"Wijeyekoon","year":"2020","journal-title":"Brain Behav Immun"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1186\/s12974-018-1286-2","article-title":"Targeting of the class II transactivator attenuates inflammation and neurodegeneration in an alpha-synuclein model of Parkinson's disease","volume":"15","author":"Williams","year":"2018","journal-title":"J Neuroinflammation"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"9592","DOI":"10.1523\/JNEUROSCI.5610-12.2013","article-title":"MHCII is required for \u03b1-synuclein-induced activation of microglia, CD4 T cell proliferation, and dopaminergic neurodegeneration","volume":"33","author":"Harms","year":"2013","journal-title":"J Neurosci Off J Soc Neurosci"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1002\/iid3.416","article-title":"Current research status of HLA in immune-related diseases","volume":"9","author":"Liu","year":"2021","journal-title":"Immunity Inflammation Dis"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.imlet.2011.10.012","article-title":"Maturation profiles of peripheral blood dendritic cells in patients with endogenous uveitis","author":"Kim","year":"2012","journal-title":"Immunol Lett"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/s41421-024-00671-2","article-title":"Sex-specific circulating unconventional neutrophils determine immunological outcome of auto-inflammatory Beh\u00e7et's uveitis","volume":"10","author":"Wang","year":"2024","journal-title":"Cell Discov"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2024.1445775\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,31]],"date-time":"2024-07-31T08:01:49Z","timestamp":1722412909000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2024.1445775\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,31]]},"references-count":36,"alternative-id":["10.3389\/fmed.2024.1445775"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2024.1445775","relation":{},"ISSN":["2296-858X"],"issn-type":[{"type":"electronic","value":"2296-858X"}],"subject":[],"published":{"date-parts":[[2024,7,31]]},"article-number":"1445775"}}