1. Dysregulated Antibody, Natural Killer Cell and Immune Mediator Profiles in Autoimmune Thyroid Diseases
- Author
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John P. Walsh, Scott Wilson, Michelle Beaumont, Alessia Visconti, Mario Roederer, Massimo Mangino, Marija Pezer, Steven J. Kiddle, Tiphaine Martin, Jordana T. Bell, Ee Mun Lim, Richard Dobson, Sophia N. Karagiannis, Claire J. Steves, Gordan Lauc, Tim D. Spector, Kristina M. Ilieva, Martin, Tiphaine C [0000-0001-9990-1455], Visconti, Alessia [0000-0003-4144-2019], Dobson, Richard JB [0000-0003-4224-9245], Steves, Claire J [0000-0002-4910-0489], Bell, Jordana T [0000-0002-3858-5986], Wilson, Scott G [0000-0002-0357-1373], Walsh, John P [0000-0002-1766-2612], Karagiannis, Sophia N [0000-0002-4100-7810], and Apollo - University of Cambridge Repository
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anti-thyroid peroxidase antibody (TPOAb) ,Inflammation ,medicine.disease_cause ,antibody-dependent cell-mediated cytotoxicity (ADCC) ,Peripheral blood mononuclear cell ,Iodide Peroxidase ,Article ,Autoimmunity ,Natural killer cell ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Humans ,lcsh:QH301-705.5 ,Fucosylation ,030304 developmental biology ,Autoantibodies ,Fucose ,autoimmune thyroid diseases (AITD) ,0303 health sciences ,multi-omic ,anti-thyroid peroxidase antibody ,TPOAb ,antibody-dependent cell-mediated cytotoxicity ,ADCC ,apoptosis ,autoimmune thyroid diseases ,AITD ,genetic variants ,biology ,General Medicine ,Thyroid Diseases ,3. Good health ,Killer Cells, Natural ,Cell killing ,medicine.anatomical_structure ,Cross-Sectional Studies ,lcsh:Biology (General) ,030220 oncology & carcinogenesis ,Immunology ,biology.protein ,Leukocytes, Mononuclear ,medicine.symptom ,Antibody - Abstract
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 &alpha, 1,2 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&alpha, 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.
- Published
- 2020
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