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Open AccessArticle

Dysregulated Antibody, Natural Killer Cell and Immune Mediator Profiles in Autoimmune Thyroid Diseases

1
Department of Twin Research and Genetic Epidemiology, King’s College, London SE1 7EH, UK
2
School of Biomedical Sciences, University of Western Australia, Crawley, WA 6009, Australia
3
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
4
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
5
St John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London, Guy’s Hospital, London SE1 9RT, UK
6
Breast Cancer Now Research Unit, School of Cancer & Pharmaceutical Sciences, King’s College London, Guy’s Cancer Centre, London SE1 9RT, UK
7
Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King’s College, London SE5 8AF, UK
8
MRC Biostatistics Unit, University of Cambridge, Cambridge CB2 0SR, UK
9
Health Data Research UK (HDR UK), London Institute of Health Informatics, University College London, London NW1 2DA, UK
10
NIHR Biomedical Research Centre at Guy’s and St. Thomas’s NHS Foundation Trust, London SE1 9RT, UK
11
Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia
12
Medical School, The University of Western Australia, Crawley, WA 6009, Australia
13
PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, WA 6009, Australia
14
Genos, Glycoscience Research Laboratory, 10000 Zagreb, Croatia
15
Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia
16
ImmunoTechnology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA
*
Author to whom correspondence should be addressed.
Equal contribution as joint senior authors.
Cells 2020, 9(3), 665; https://doi.org/10.3390/cells9030665
Received: 12 February 2020 / Revised: 4 March 2020 / Accepted: 5 March 2020 / Published: 9 March 2020
(This article belongs to the Special Issue Molecular and Cellular Basis of Autoimmune Diseases)
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 α1,2 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-1α 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. View Full-Text
Keywords: multi-omic; autoimmune thyroid diseases (AITD); genetic variants; apoptosis; antibody-dependent cell-mediated cytotoxicity (ADCC); anti-thyroid peroxidase antibody (TPOAb) multi-omic; autoimmune thyroid diseases (AITD); genetic variants; apoptosis; antibody-dependent cell-mediated cytotoxicity (ADCC); anti-thyroid peroxidase antibody (TPOAb)
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MDPI and ACS Style

Martin, T.C.; Ilieva, K.M.; Visconti, A.; Beaumont, M.; Kiddle, S.J.; Dobson, R.J.B.; Mangino, M.; Lim, E.M.; Pezer, M.; Steves, C.J.; Bell, J.T.; Wilson, S.G.; Lauc, G.; Roederer, M.; Walsh, J.P.; Spector, T.D.; Karagiannis, S.N. Dysregulated Antibody, Natural Killer Cell and Immune Mediator Profiles in Autoimmune Thyroid Diseases. Cells 2020, 9, 665. https://doi.org/10.3390/cells9030665

AMA Style

Martin TC, Ilieva KM, Visconti A, Beaumont M, Kiddle SJ, Dobson RJB, Mangino M, Lim EM, Pezer M, Steves CJ, Bell JT, Wilson SG, Lauc G, Roederer M, Walsh JP, Spector TD, Karagiannis SN. Dysregulated Antibody, Natural Killer Cell and Immune Mediator Profiles in Autoimmune Thyroid Diseases. Cells. 2020; 9(3):665. https://doi.org/10.3390/cells9030665

Chicago/Turabian Style

Martin, Tiphaine C.; Ilieva, Kristina M.; Visconti, Alessia; Beaumont, Michelle; Kiddle, Steven J.; Dobson, Richard J.B.; Mangino, Massimo; Lim, Ee M.; Pezer, Marija; Steves, Claire J.; Bell, Jordana T.; Wilson, Scott G.; Lauc, Gordan; Roederer, Mario; Walsh, John P.; Spector, Tim D.; Karagiannis, Sophia N. 2020. "Dysregulated Antibody, Natural Killer Cell and Immune Mediator Profiles in Autoimmune Thyroid Diseases" Cells 9, no. 3: 665. https://doi.org/10.3390/cells9030665

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