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 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.
Highlights
Autoimmune thyroid diseases (AITD) are a class of chronic, organ-specific disorders of the thyroid gland with a high genetic heritability (55–75%) [1,2,3,4] affecting approximately 5% of the population and with a gender disparity [5,6,7]
(5) We identified genetic variants that alter the expression of genes, proteins and cell-bound immune receptors using the previous genome-wide association study (GWAS) performed in the TwinsUK cohort or from GWAS
As genetic variants detected by GWASs could be lead genetic variants but not necessarily causal genetic variants [46], we extended the list of genetic variants to other variants in linkage disequilibrium (LD) with an r2 threshold of 0.8 from 1000 G Phase 1
Summary
Autoimmune thyroid diseases (AITD) are a class of chronic, organ-specific disorders of the thyroid gland with a high genetic heritability (55–75%) [1,2,3,4] affecting approximately 5% of the population and with a gender disparity (i.e., women: 5–15%; men: 1–5%) [5,6,7]. AITD are characterized by autoantibodies against three main thyroid proteins (thyroid peroxidase (TPO), thyroglobulin (Tg), and the thyroid-stimulating hormone (TSH) receptor (TSH-R)), infiltration of the thyroid gland by immune cells (e.g., lymphocytes, NK cells, monocytes, and macrophages), the formation of germinal centers in the thyroid gland [8] and dysregulated TSH levels [9,10]. Thyroid autoantibodies, and secreted proteins including cytokines may play critical roles in AITD development [13] and in immune responses, including in antibody-dependent cell-mediated cytotoxicity (ADCC) pathways [14,15]. ADCC is triggered via antigen/antibody/Fc receptor complex formation, bringing the effector cell (macrophages, NK cells) and the target cell (expressing the antigen) in close contact. Afucosylated antibodies have a higher affinity (~100-fold) for the immunoglobulin
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