Multi-omic analyses reveal antibody-dependent natural killer cell-mediated cytotoxicity in autoimmune thyroid diseases

The pathogenesis of autoimmune thyroid diseases (AITD) is poorly understood. We previously observed systemic depletion of IgG core fucosylation and antennary α1,2 fucosylation of peripheral blood mononuclear cells in AITD, correlated with thyroid peroxidase antibody (TPOAb) levels. We hypothesized that deficiency in IgG core fucose enhances antibody-dependent cell-mediated cytotoxicity of thyrocytes by TPOAb, contributing to thyroid autoimmunity. Multi-omic evaluations in 622 individuals (172 with AITD) from the TwinsUK cohort showed decreased IgG core fucosylation levels associated with a subpopulation of natural killer (NK) cells featuring CD335, CD314, and CD158b immunoreceptors, and increased levels of apoptosis-associated Caspase-2 and Interleukin-1α, positively associated with AITD. AITD-associated genetic variants rs1521 and rs3094228 alter expression of thyrocyte ligands of the CD314 and CD158b immunoreceptors on NK cells. The combination of low-core fucose IgG associated with an NK cell subpopulation and genetic variant-promoted ligand activation in thyrocytes may promote antibody-dependent NK cell-mediated cytotoxicity of thyrocytes in AITD.