{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:17:05Z","timestamp":1785802625094,"version":"3.56.0"},"reference-count":89,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,3,9]],"date-time":"2020-03-09T00:00:00Z","timestamp":1583712000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["PG 1087407"],"award-info":[{"award-number":["PG 1087407"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/K006584\/1"],"award-info":[{"award-number":["MR\/K006584\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/L011859\/1"],"award-info":[{"award-number":["MR\/L011859\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/L023091\/1"],"award-info":[{"award-number":["MR\/L023091\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011199","name":"FP7 Ideas: European Research Council","doi-asserted-by":"publisher","award":["278535"],"award-info":[{"award-number":["278535"]}],"id":[{"id":"10.13039\/100011199","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011199","name":"FP7 Ideas: European Research Council","doi-asserted-by":"publisher","award":["305280"],"award-info":[{"award-number":["305280"]}],"id":[{"id":"10.13039\/100011199","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011199","name":"FP7 Ideas: European Research Council","doi-asserted-by":"publisher","award":["324400"],"award-info":[{"award-number":["324400"]}],"id":[{"id":"10.13039\/100011199","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011199","name":"FP7 Ideas: European Research Council","doi-asserted-by":"publisher","award":["315997"],"award-info":[{"award-number":["315997"]}],"id":[{"id":"10.13039\/100011199","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009794","name":"Breast Cancer Now","doi-asserted-by":"publisher","award":["147"],"award-info":[{"award-number":["147"]}],"id":[{"id":"10.13039\/100009794","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The pathogenesis of autoimmune thyroid diseases (AITD) is poorly understood and the association between different immune features and the germline variants involved in AITD are yet unclear. We previously observed systemic depletion of IgG core fucosylation and antennary \u03b11,2 fucosylation in peripheral blood mononuclear cells in AITD, correlated with anti-thyroid peroxidase antibody (TPOAb) levels. Fucose depletion is known to potentiate strong antibody-mediated NK cell activation and enhanced target antigen-expressing cell killing. In autoimmunity, this may translate to autoantibody-mediated immune cell recruitment and attack of self-antigen expressing normal tissues. Hence, we investigated the crosstalk between immune cell traits, secreted proteins, genetic variants and the glycosylation patterns of serum IgG, in a multi-omic and cross-sectional study of 622 individuals from the TwinsUK cohort, 172 of whom were diagnosed with AITD. We observed associations between two genetic variants (rs505922 and rs687621), AITD status, the secretion of Desmoglein-2 protein, and the profile of two IgG N-glycan traits in AITD, but further studies need to be performed to better understand their crosstalk in AITD. On the other side, enhanced afucosylated IgG was positively associated with activatory CD335- CD314+ CD158b+ NK cell subsets. Increased levels of the apoptosis and inflammation markers Caspase-2 and Interleukin-1\u03b1 positively associated with AITD. Two genetic variants associated with AITD, rs1521 and rs3094228, were also associated with altered expression of the thyrocyte-expressed ligands known to recognize the NK cell immunoreceptors CD314 and CD158b. Our analyses reveal a combination of heightened Fc-active IgG antibodies, effector cells, cytokines and apoptotic signals in AITD, and AITD genetic variants associated with altered expression of thyrocyte-expressed ligands to NK cell immunoreceptors. Together, TPOAb responses, dysregulated immune features, germline variants associated with immunoactivity profiles, are consistent with a positive autoreactive antibody-dependent NK cell-mediated immune response likely drawn to the thyroid gland in AITD.<\/jats:p>","DOI":"10.3390\/cells9030665","type":"journal-article","created":{"date-parts":[[2020,3,12]],"date-time":"2020-03-12T04:13:57Z","timestamp":1583986437000},"page":"665","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Dysregulated Antibody, Natural Killer Cell and Immune Mediator Profiles in Autoimmune Thyroid Diseases"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9990-1455","authenticated-orcid":false,"given":"Tiphaine C.","family":"Martin","sequence":"first","affiliation":[{"name":"Department of Twin Research and Genetic Epidemiology, King\u2019s College, London SE1 7EH, UK"},{"name":"School of Biomedical Sciences, University of Western Australia, Crawley, WA 6009, Australia"},{"name":"Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"},{"name":"Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina M.","family":"Ilieva","sequence":"additional","affiliation":[{"name":"St John\u2019s Institute of Dermatology, School of Basic &amp; Medical Biosciences, King\u2019s College London, Guy\u2019s Hospital, London SE1 9RT, UK"},{"name":"Breast Cancer Now Research Unit, School of Cancer &amp; Pharmaceutical Sciences, King\u2019s College London, Guy\u2019s Cancer Centre, London SE1 9RT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4144-2019","authenticated-orcid":false,"given":"Alessia","family":"Visconti","sequence":"additional","affiliation":[{"name":"Department of Twin Research and Genetic Epidemiology, King\u2019s College, London SE1 7EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Beaumont","sequence":"additional","affiliation":[{"name":"Department of Twin Research and Genetic Epidemiology, King\u2019s College, London SE1 7EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven J.","family":"Kiddle","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College, London SE5 8AF, UK"},{"name":"MRC Biostatistics Unit, University of Cambridge, Cambridge CB2 0SR, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4224-9245","authenticated-orcid":false,"given":"Richard J. B.","family":"Dobson","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College, London SE5 8AF, UK"},{"name":"Health Data Research UK (HDR UK), London Institute of Health Informatics, University College London, London NW1 2DA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Mangino","sequence":"additional","affiliation":[{"name":"Department of Twin Research and Genetic Epidemiology, King\u2019s College, London SE1 7EH, UK"},{"name":"NIHR Biomedical Research Centre at Guy\u2019s and St. Thomas\u2019s NHS Foundation Trust, London SE1 9RT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ee Mun","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia"},{"name":"Medical School, The University of Western Australia, Crawley, WA 6009, Australia"},{"name":"PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, WA 6009, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marija","family":"Pezer","sequence":"additional","affiliation":[{"name":"Genos, Glycoscience Research Laboratory, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4910-0489","authenticated-orcid":false,"given":"Claire J.","family":"Steves","sequence":"additional","affiliation":[{"name":"Department of Twin Research and Genetic Epidemiology, King\u2019s College, London SE1 7EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3858-5986","authenticated-orcid":false,"given":"Jordana T.","family":"Bell","sequence":"additional","affiliation":[{"name":"Department of Twin Research and Genetic Epidemiology, King\u2019s College, London SE1 7EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0357-1373","authenticated-orcid":false,"given":"Scott G.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Department of Twin Research and Genetic Epidemiology, King\u2019s College, London SE1 7EH, UK"},{"name":"School of Biomedical Sciences, University of Western Australia, Crawley, WA 6009, Australia"},{"name":"Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordan","family":"Lauc","sequence":"additional","affiliation":[{"name":"Genos, Glycoscience Research Laboratory, 10000 Zagreb, Croatia"},{"name":"Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Roederer","sequence":"additional","affiliation":[{"name":"ImmunoTechnology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1766-2612","authenticated-orcid":false,"given":"John P.","family":"Walsh","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia"},{"name":"Medical School, The University of Western Australia, Crawley, WA 6009, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim D.","family":"Spector","sequence":"additional","affiliation":[{"name":"Department of Twin Research and Genetic Epidemiology, King\u2019s College, London SE1 7EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4100-7810","authenticated-orcid":false,"given":"Sophia N.","family":"Karagiannis","sequence":"additional","affiliation":[{"name":"St John\u2019s Institute of Dermatology, School of Basic &amp; Medical Biosciences, King\u2019s College London, Guy\u2019s Hospital, London SE1 9RT, UK"},{"name":"Breast Cancer Now Research Unit, School of Cancer &amp; Pharmaceutical Sciences, King\u2019s College London, Guy\u2019s Cancer Centre, London SE1 9RT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,9]]},"reference":[{"key":"ref_1","first-page":"930","article-title":"Evidence for a Major Role of Heredity in Graves\u2019 Disease: A Population-Based Study of Two Danish Twin Cohorts","volume":"86","author":"Brix","year":"2001","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1111\/j.1365-2265.2005.02230.x","article-title":"The relative importance of genetic and environmental factors in the aetiology of thyroid nodularity: A study of healthy Danish twins","volume":"62","author":"Hansen","year":"2006","journal-title":"Clin. Endocrinol."},{"key":"ref_3","first-page":"536","article-title":"A population-based study of chronic autoimmune hypothyroidism in Danish twins","volume":"85","author":"Brix","year":"2000","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Martin, T.C., \u0160imurina, M., Z\u0105bczy\u0144ska, M., Martinic Kavur, M., Rydlewska, M., Pezer, M., Koz\u0142owska, K., Burri, A., Vilaj, M., and Turek-Jabrocka, R. (2020). Decreased immunoglobulin G core fucosylation, a player in antibody-dependent cell-mediated cytotoxicity, is associated with autoimmune thyroid diseases. Mol. Cell. Proteom.","DOI":"10.1074\/mcp.RA119.001860"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1093\/bmb\/ldh032","article-title":"Genetic insights into disease mechanisms of autoimmunity","volume":"71","author":"Simmonds","year":"2005","journal-title":"Br. Med. Bull."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"521","DOI":"10.3389\/fimmu.2017.00521","article-title":"Thyroid autoimmunity: Role of anti-thyroid antibodies in thyroid and extra-thyroidal diseases","volume":"8","author":"Wahl","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_7","first-page":"396","article-title":"The emerging role of epigenetics in autoimmune thyroid diseases","volume":"8","author":"Wang","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/S0002-9440(10)61762-2","article-title":"Thyroid autoimmune disease: Demonstration of thyroid antigen-specific B cells and recombination-activating gene expression in chemokine-containing active intrathyroidal germinal centers","volume":"159","author":"Armengol","year":"2001","journal-title":"Am. J. Pathol."},{"key":"ref_9","unstructured":"Braverman, L., and Wartofsky, L. (2014). Thyroid Tests, National Institute of Diabetes and Digestive and Kidney Diseases."},{"key":"ref_10","unstructured":"British Thyroid Association (2006). Adapted Summary of UK Guidelines for the Use of Thyroid Function Tests, British Thyroid Association."},{"key":"ref_11","first-page":"153","article-title":"Lymphocyte-dependent antibody-mediated cytotoxicity in Hashimoto thyroiditis","volume":"14","author":"Calder","year":"1973","journal-title":"Clin. Exp. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"574","DOI":"10.4103\/2230-8210.137524","article-title":"Immunoregulatory T cells, LFA-3 and HLA-DR in autoimmune thyroid diseases","volume":"18","author":"Nada","year":"2014","journal-title":"Indian J. Endocrinol. Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"466","DOI":"10.3109\/08916934.2014.914175","article-title":"The clinical role of serum concentrations of selected cytokines: IL-1beta, TNF-alpha and IL-6 in diagnosis of autoimmune thyroid disease (AITD) in children","volume":"47","author":"Mikos","year":"2014","journal-title":"Autoimmunity"},{"key":"ref_14","first-page":"2595","article-title":"Antibody-dependent cell-mediated cytotoxicity in autoimmune thyroid disease: Relationship to antithyroperoxidase antibodies","volume":"81","author":"Rodien","year":"1996","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"65","DOI":"10.3109\/08916939708996272","article-title":"Analysis of antibody-dependent cell-mediated cytotoxicity in autoimmune thyroid disease","volume":"25","author":"Metcalfe","year":"1997","journal-title":"Autoimmunity"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jaut.2014.12.002","article-title":"Glycans in the immune system and The Altered Glycan Theory of Autoimmunity: A critical review","volume":"57","author":"Maverakis","year":"2015","journal-title":"J. Autoimmun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1038\/nri2417","article-title":"Mammalian glycosylation in immunity","volume":"8","author":"Marth","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1093\/glycob\/cwl057","article-title":"Comparison of biological activity among nonfucosylated therapeutic IgG1 antibodies with three different N-linked Fc oligosaccharides: The high-mannose, hybrid, and complex types","volume":"17","author":"Kanda","year":"2007","journal-title":"Glycobiology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"26733","DOI":"10.1074\/jbc.M202069200","article-title":"Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human Fc\u03b3RIII and antibody-dependent cellular toxicity","volume":"277","author":"Shields","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6248","DOI":"10.1158\/1078-0432.CCR-04-0850","article-title":"Enhancement of the antibody-dependent cellular cytotoxicity of low-fucose IgG1 Is independent of FcgammaRIIIa functional polymorphism","volume":"10","author":"Niwa","year":"2004","journal-title":"Clin. Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3466","DOI":"10.1074\/jbc.M210665200","article-title":"The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity","volume":"278","author":"Shinkawa","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"12669","DOI":"10.1073\/pnas.1108455108","article-title":"Unique carbohydrate-carbohydrate interactions are required for high affinity binding between FcgammaRIII and antibodies lacking core fucose","volume":"108","author":"Ferrara","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3492","DOI":"10.1172\/JCI130029","article-title":"Functional diversification of IgGs through Fc glycosylation","volume":"129","author":"Wang","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2327","DOI":"10.1158\/1078-0432.CCR-04-2263","article-title":"Enhanced natural killer cell binding and activation by low-fucose IgG1 antibody results in potent antibody-dependent cellular cytotoxicity induction at lower antigen density","volume":"11","author":"Niwa","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"129464","DOI":"10.1016\/j.bbagen.2019.129464","article-title":"Altered N-glycan profile of IgG-depleted serum proteins in Hashimoto\u2019s thyroiditis","volume":"1864","author":"Novokmet","year":"2020","journal-title":"Biochim. Biophys. Acta Gen. Subj."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"eaax0301","DOI":"10.1126\/sciadv.aax0301","article-title":"Glycosylation of immunoglobulin G is regulated by a large network of genes pleiotropic with inflammatory diseases","volume":"6","author":"Tsepilov","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/ncomms13850","article-title":"Innate and adaptive immune traits are differentially affected by genetic and environmental factors","volume":"8","author":"Mangino","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.cell.2015.02.046","article-title":"The genetic architecture of the human immune system: A bioresource for autoimmunity and disease pathogenesis","volume":"161","author":"Roederer","year":"2015","journal-title":"Cell"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Lauc, G., Huffman, J.E., Pu\u010di\u0107, M., Zgaga, L., Adamczyk, B., Mu\u017eini\u0107, A., Novokmet, M., Pola\u0161ek, O., Gornik, O., and Kri\u0161ti\u0107, J. (2013). Loci Associated with N-Glycosylation of Human Immunoglobulin G Show Pleiotropy with Autoimmune Diseases and Haematological Cancers. PLoS Genet., 9.","DOI":"10.1371\/journal.pgen.1003225"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1093\/nar\/gkt1229","article-title":"The NHGRI GWAS Catalog, a curated resource of SNP-trait associations","volume":"42","author":"Welter","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41586-018-0175-2","article-title":"Genomic atlas of the human plasma proteome","volume":"558","author":"Sun","year":"2018","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1126\/science.1262110","article-title":"The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans","volume":"348","author":"Ardlie","year":"2015","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/nature24277","article-title":"Genetic effects on gene expression across human tissues","volume":"550","author":"Aguet","year":"2017","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Aguet, F., Barbeira, A.N., Bonazzola, R., Brown, A., Castel, S.E., Jo, B., Kasela, S., Kim-Hellmuth, S., Liang, Y., and Oliva, M. (2019). The GTEx Consortium atlas of genetic regulatory effects across human tissues. bioRxiv.","DOI":"10.1101\/787903"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Westra, H.J., Arends, D., Esko, T., Peters, M.J., Schurmann, C., Schramm, K., Kettunen, J., Yaghootkar, H., Fairfax, B.P., and Andiappan, A.K. (2015). Cell Specific eQTL Analysis without Sorting Cells. PLoS Genet., 11.","DOI":"10.1371\/journal.pgen.1005223"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1375\/twin.9.6.899","article-title":"The UK Adult Twin Registry (TwinsUK)","volume":"9","author":"Spector","year":"2006","journal-title":"Twin Res. Hum. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1017\/thg.2012.89","article-title":"The UK Adult Twin Registry (TwinsUK Resource)","volume":"16","author":"Moayyeri","year":"2013","journal-title":"Twin Res. Hum. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1210\/jcem.87.2.8182","article-title":"Serum TSH, T 4, and Thyroid Antibodies in the United States Population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III)","volume":"87","author":"Hollowell","year":"2002","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2646","DOI":"10.1056\/NEJMra021194","article-title":"Thyroiditis","volume":"348","author":"Pearce","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_40","unstructured":"Elhomsy, G. (2020, January 08). Antithyroid Antibody. Available online: https:\/\/emedicine.medscape.com\/article\/2086819-overview."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1093\/gerona\/glu121","article-title":"Circulating proteomic signatures of chronological age","volume":"70","author":"Menni","year":"2014","journal-title":"J. Gerontol. Ser. A Biol. Sci. Med. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e584","DOI":"10.1038\/tp.2015.78","article-title":"Plasma protein biomarkers of Alzheimer\u2019s disease endophenotypes in asymptomatic older twins: Early cognitive decline and regional brain volumes","volume":"5","author":"Kiddle","year":"2015","journal-title":"Transl. Psychiatry"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v067.i01","article-title":"Fitting Linear Mixed-Exffects Models Using lme4","volume":"67","author":"Bates","year":"2015","journal-title":"J. Stat. Softw."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"914","DOI":"10.12688\/f1000research.8733.1","article-title":"The GenABEL Project for statistical genomics","volume":"5","author":"Karssen","year":"2016","journal-title":"F1000Research"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/s41467-017-00453-3","article-title":"Multivariate discovery and replication of five novel loci associated with Immunoglobulin G N-glycosylation","volume":"8","author":"Shen","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/nature13835","article-title":"Genetic and epigenetic fine mapping of causal autoimmune disease variants","volume":"518","author":"Farh","year":"2015","journal-title":"Nature"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"D877","DOI":"10.1093\/nar\/gkv1340","article-title":"HaploReg v4: Systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease","volume":"44","author":"Ward","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.it.2017.02.004","article-title":"The Immunoregulatory Roles of Antibody Glycosylation","volume":"38","author":"Jennewein","year":"2017","journal-title":"Trends Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.bbagen.2007.06.012","article-title":"The N-linked sugar chains of human immunoglobulin G: Their unique pattern, and their functional roles","volume":"1780","author":"Kobata","year":"2008","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1146\/annurev.immunol.25.022106.141702","article-title":"The impact of glycosylation on the biological function and structure of human immunoglobulins","volume":"25","author":"Arnold","year":"2007","journal-title":"Annu. Rev. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1016\/j.str.2015.06.015","article-title":"The Structural Role of Antibody N-Glycosylation in Receptor Interactions","volume":"23","author":"Subedi","year":"2015","journal-title":"Structure"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.1080\/19420862.2016.1218586","article-title":"The immunoglobulin G1 N-glycan composition affects binding to each low affinity Fc \u03b3 receptor","volume":"8","author":"Subedi","year":"2016","journal-title":"mAbs"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/sj.hdy.6800717","article-title":"Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix","volume":"95","author":"Li","year":"2005","journal-title":"Heredity"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1084\/jem.186.7.1129","article-title":"P46, a Novel Natural Killer Cell-Specific Surface Molecule That Mediates Cell Activation","volume":"186","author":"Sivori","year":"1997","journal-title":"J. Exp. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1084\/jem.188.5.953","article-title":"Molecular cloning of NKp46: A novel member of the immunoglobulin superfamily involved in triggering of natural cytotoxicity","volume":"188","author":"Pessino","year":"1998","journal-title":"J. Exp. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1038\/ni1581","article-title":"Up on the tightrope: Natural killer cell activation and inhibition","volume":"9","author":"Lanier","year":"2008","journal-title":"Nat. Immunol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/ni929","article-title":"NKG2D-DAP10 triggers human NK cell-mediated killing via a Syk-independent regulatory pathway","volume":"4","author":"Billadeau","year":"2003","journal-title":"Nat. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"18692","DOI":"10.1073\/pnas.0906051106","article-title":"Co-evolution of KIR2DL3 with HLA-C in a human population retaining minimal essential diversity of KIR and HLA class I ligands","volume":"106","author":"Gendzekhadze","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"6719","DOI":"10.4049\/jimmunol.173.11.6719","article-title":"Phenotypic and functional characterization of CD4 T cells expressing killer Ig-like receptors","volume":"173","author":"Thompson","year":"2004","journal-title":"J. Immunol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1038\/ng.898","article-title":"A genome-wide association study identifies two new risk loci for Graves\u2019 disease","volume":"43","author":"Chu","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Medici, M., Porcu, E., Pistis, G., Teumer, A., Brown, S.J., Jensen, R.A., Rawal, R., Roef, G.L., Plantinga, T.S., and Vermeulen, S.H. (2014). Identification of Novel Genetic Loci Associated with Thyroid Peroxidase Antibodies and Clinical Thyroid Disease. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004123"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Cho, W.K., Jung, M.H., Park, S.H., Baek, I.C., Choi, H.B., Kim, T.G., and Suh, B.K. (2012). Association of MICA alleles with autoimmune thyroid disease in Korean children. Int. J. Endocrinol., 2012.","DOI":"10.1155\/2012\/235680"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1111\/cen.12640","article-title":"The association of thyroid peroxidase antibody risk loci with susceptibility to and phenotype of Graves\u2019 disease","volume":"83","author":"Peeters","year":"2015","journal-title":"Clin. Endocrinol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1038\/ng.2756","article-title":"Systematic identification of trans eQTLs as putative drivers of known disease associations","volume":"45","author":"Westra","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1093\/nar\/gks1284","article-title":"Integrative annotation of chromatin elements from ENCODE data","volume":"41","author":"Hoffman","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1530\/JOE-17-0145","article-title":"Characterization of the human thyroid epigenome","volume":"235","author":"Siu","year":"2017","journal-title":"J. Endocrinol."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Martin, T.C., Yet, I., Tsai, P.-C., and Bell, J.T. (2015). coMET: Visualisation of regional epigenome-wide association scan results and DNA co-methylation patterns. BMC Bioinform., 16.","DOI":"10.1186\/s12859-015-0568-2"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e201","DOI":"10.1038\/mtna.2014.49","article-title":"Nucleic acid ligands with protein-like side chains: Modified aptamers and their use as diagnostic and therapeutic agents","volume":"3","author":"Rohloff","year":"2014","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1210\/jcem-46-6-859","article-title":"Association of serum antithyroid antibodies with lymphocytic infiltration of the thyroid gland: Studies of seventy autopsied cases","volume":"46","author":"Yoshida","year":"1978","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1089\/thy.1996.6.445","article-title":"Clinical significance of measurements of antithyroid antibodies in the diagnosis of Hashimoto\u2019s thyroiditis: Comparison with histological findings","volume":"6","author":"Kasagi","year":"1996","journal-title":"Thyroid"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1080\/08916930600907913","article-title":"Thyroid peroxidase and thyroglobulin auto-antibodies in patients with newly diagnosed overt hypothyroidism","volume":"39","author":"Laurberg","year":"2006","journal-title":"Autoimmunity"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"McInnes, L., Healy, J., and Melville, J. (2018). UMAP: Uniform Manifold Approximation and Projection for Dimension Reduction. arXiv.","DOI":"10.21105\/joss.00861"},{"key":"ref_73","unstructured":"Li, A., Kim, J., Smith, M., Hughes, S., and Laderas, T. (2020, February 12). umapr. Available online: https:\/\/github.com\/ropenscilabs\/umapr."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"4565","DOI":"10.1091\/mbc.e07-05-0426","article-title":"Desmoglein-2: A novel regulator of apoptosis in the intestinal epithelium","volume":"18","author":"Nava","year":"2007","journal-title":"Mol. Biol. Cell"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"R241","DOI":"10.1530\/EJE-14-0047","article-title":"Mechanisms in endocrinology: Autoimmune thyroid disease: Old and new players","volume":"170","author":"Effraimidis","year":"2014","journal-title":"Eur. J. Endocrinol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1210\/jc.2007-2042","article-title":"Antithyroperoxidase antibody-dependent cytotoxicity in autoimmune thyroid disease","volume":"93","author":"Rebuffat","year":"2008","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1038\/sj.bjc.6605464","article-title":"Human recombinant anti-thyroperoxidase autoantibodies: In vitro cytotoxic activity on papillary thyroid cancer expressing TPO","volume":"102","author":"Rebuffat","year":"2010","journal-title":"Br. J. Cancer"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1038\/cdd.2014.216","article-title":"Old, new and emerging functions of caspases","volume":"22","author":"Shalini","year":"2015","journal-title":"Cell Death Differ."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"20684","DOI":"10.1073\/pnas.1116848108","article-title":"Sterile inflammation of endothelial cell-derived apoptotic bodies is mediated by interleukin-1alpha","volume":"108","author":"Robert","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_80","first-page":"324","article-title":"Analysis of intrathyroidal cytokine production in thyroid autoimmune disease: Thyroid follicular cells produce interleukin-1 alpha and interleukin-6","volume":"77","author":"Buchan","year":"1989","journal-title":"Clin. Exp. Immunol."},{"key":"ref_81","first-page":"945","article-title":"Cytokines and thyroid epithelial integrity: Interleukin-1\u03b1 induces dissociation of the junctional complex and paracellular leakage in filter- cultured human thyrocytes","volume":"83","author":"Nilsson","year":"1998","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/1074-7613(95)90069-1","article-title":"Killer cell inhibitory receptors specific for HLA-C and HLA-B identified by direct binding and by functional transfer","volume":"3","author":"Wagtmann","year":"1995","journal-title":"Immunity"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"336","DOI":"10.3389\/fimmu.2012.00336","article-title":"Diverse functionality among human NK cell receptors for the C1 epitope of HLA-C: KIR2DS2, KIR2DL2, and KIR2DL3","volume":"3","author":"Moesta","year":"2012","journal-title":"Front. Immunol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1002\/bit.20151","article-title":"Establishment of FUT8 knockout Chinese hamster ovary cells: An ideal host cell line for producing completely defucosylated antibodies with enhanced antibody-dependent cellular cytotoxicity","volume":"87","author":"Kinoshita","year":"2004","journal-title":"Biotechnol. Bioeng."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"786","DOI":"10.15252\/msb.20145728","article-title":"Quantitative variability of 342 plasma proteins in a human twin population","volume":"11","author":"Liu","year":"2015","journal-title":"Mol. Syst. Biol."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Z\u0105bczy\u0144ska, M., Polak, K., Koz\u0142owska, K., Soko\u0142owski, G., and Poche\u0107, E. (2020). The contribution of igg glycosylation to antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in hashimoto\u2019s thyroiditis: An in vitro model of thyroid autoimmunity. Biomolecules, 10.","DOI":"10.3390\/biom10020171"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1210\/jc.2011-2178","article-title":"Evidence of a Combined Cytotoxic Thyroglobulin and Thyroperoxidase Epitope-Specific Cellular Immunity in Hashimoto\u2019s Thyroiditis","volume":"97","author":"Ehlers","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1126\/science.1103478","article-title":"Natural killer cell signaling pathways","volume":"306","author":"Vivier","year":"2004","journal-title":"Science"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"e26097","DOI":"10.4161\/onci.26097","article-title":"New prospects on the NKG2D\/NKG2DL system for oncology","volume":"2","author":"Ullrich","year":"2013","journal-title":"Oncoimmunology"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/3\/665\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:05:36Z","timestamp":1760173536000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/3\/665"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,9]]},"references-count":89,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2020,3]]}},"alternative-id":["cells9030665"],"URL":"https:\/\/doi.org\/10.3390\/cells9030665","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/662957","asserted-by":"object"}]},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,9]]}}}