Decreased Immunoglobulin G Core Fucosylation, A Player in Antibody-dependent Cell-mediated Cytotoxicity, is Associated with Autoimmune Thyroid Diseases

• Published in: Molecular & cellular proteomics 2020-05, Vol.19 (5), p.774-792
• Main Authors: Martin, Tiphaine C., Šimurina, Mirna, Ząbczyńska, Marta, Martinic Kavur, Marina, Rydlewska, Magdalena, Pezer, Marija, Kozłowska, Kamila, Burri, Andrea, Vilaj, Marija, Turek-Jabrocka, Renata, Krnjajić-Tadijanović, Milena, Trofimiuk-Müldner, Małgorzata, Ugrina, Ivo, Lityńska, Anna, Hubalewska-Dydejczyk, Alicja, Trbojevic-Akmacic, Irena, Lim, Ee Mun, Walsh, John P., Pocheć, Ewa, Spector, Tim D., Wilson, Scott G., Lauc, Gordan
• Format: Article
• Language: English
• Subjects: Adult; antibodies; Antibody-Dependent Cell Cytotoxicity; antibody-dependent cell-mediated cytotoxicity (ADCC); Autoimmune Diseases - immunology; autoimmune thyroid disease; Blood Cells - metabolism; Cohort Studies; Fucose - metabolism; fucosylation; Gene Expression Regulation; Glycomics; glycoproteins; Glycosylation; Humans; IgG; Immunoglobulin G - genetics; Immunoglobulin G - metabolism; Immunology; Iodide Peroxidase - immunology; Linkage Disequilibrium - genetics; Models, Biological; patient cohorts; Polymorphism, Single Nucleotide - genetics; Polysaccharides - metabolism; Thyroid Diseases - immunology; thyroid peroxidase antibodies (TPOAb)
• ISSN: 1535-9476; 1535-9484; 1535-9484
• DOI: 10.1074/mcp.RA119.001860

The glycosylation profile for IgG and PBMC and their associations with AITD and one of its biomarkers, TPOAb, have been determined in three independent European cohorts by applying couple of different assays, including HILIC-UPLC, Lectin-probed Western blotting, tandem mass-spectrometer, RNA-Seq, GWAS. The results reported reveal a decreased level of IgG core-fucosylation and PBMC antennary α1,2 fucosylation with TPOAb level and AITD and a possible role of the glycosylation of TPOAb driven by tissue-specific FUT8 and IKZF1 expression in AITD patients. [Display omitted] Highlights •Core fucosylation of IgG and antennary α1,2 fucosylation of peripheral blood mononuclear cells (PBMCs) is negatively associated with AITD and TPOAb positivity.•An association of the decrease in the core fucosylation with two enzymes: IKZF1 and FUT8.•No relevant gene mutation falling within the genes for those enzymes or general transcription deregulation in plasma of patients were observed.•Suggestion that alteration of gene expression happens in subgroup of cells, such as cells from thyroid germinal centers previously identified in patients with AITD. Autoimmune thyroid diseases (AITD) are the most common group of autoimmune diseases, associated with lymphocyte infiltration and the production of thyroid autoantibodies, like thyroid peroxidase antibodies (TPOAb), in the thyroid gland. Immunoglobulins and cell-surface receptors are glycoproteins with distinctive glycosylation patterns that play a structural role in maintaining and modulating their functions. We investigated associations of total circulating IgG and peripheral blood mononuclear cells glycosylation with AITD and the influence of genetic background in a case-control study with several independent cohorts and over 3,000 individuals in total. The study revealed an inverse association of IgG core fucosylation with TPOAb and AITD, as well as decreased peripheral blood mononuclear cells antennary α1,2 fucosylation in AITD, but no shared genetic variance between AITD and glycosylation. These data suggest that the decreased level of IgG core fucosylation is a risk factor for AITD that promotes antibody-dependent cell-mediated cytotoxicity previously associated with TPOAb levels.