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

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.

Therapeutic monoclonal antibody targeting of neuronal pentraxin receptor to control metastasis in gastric cancer

“…Both pAbs and mAbs significantly inhibited tumor formation in this model and the anti-NPTXR mAbs also enhanced the cytotoxicity of 5-FU and cisplatin in vitro, supporting the possibility that NPTXR may be a promising therapeutic target for controlling GC progression and/or for overcoming chemotherapy resistance. We also showed that the anti-cancer effects of the mAbs in vivo resulted from NPTXR antagonism rather than as mediators of ADCC [45]. Finally, we identified the precise epitope recognized by our NPTXR mAbs, which is a critical step in developing and engineering therapeutic mAbs.…”

An Intronic HCP5 Variant Is Associated With Age of Onset and Susceptibility to Graves Disease in UK and Polish Cohorts

“…Studies have demonstrated that lncRNAs are associated specifically with autoimmune thyroid disease (AITD), including GD. Indeed, it has been proposed that rs3094228 alters the expression of thyrocyte ligands ( MICA , MICB and HLA-C) of immunoreceptors on natural killer cells in those with AITD, promoting antibody-dependent natural killer cell-mediated cytotoxicity of the thyrocyte ( 46 ), making it a potentially functional variant. Furthermore, a study by Shirasawa et al demonstrated that a polymorphism in the promoter region of a B-cell-specific antisense RNA transcript, SAS-ZFAT , is associated with susceptibility to AITD ( 44 ), and the lncRNA transcript, Heg , has demonstrated negative correlation with TRAb concentrations in untreated patients with GD ( 47 ).…”

The emerging landscape of circular RNAs in immunity: breakthroughs and challenges

“…Based on the type of foreign antigen, the immune response can perform antiviral, antibacterial, and anti-tumor functions, depending on the synthesis of a wide range of immune cells that build the immune defense [40][41][42][43]. Factors (e.g., improper exposure to autoantigen, maladjustment of immune response and cross-antigen stimulation) may induce autoimmunity and facilitate the progress of several immune diseases [44][45][46]. Immunity can fall into innate and adaptive immunity.…”