Department of Twin Research and Genetic Epidemiology, King's College, London SE1 7EH, UK.
School of Biomedical Sciences, University of Western Australia, Crawley, WA 6009, Australia.
Cells. 2020 Mar 9;9(3):665. doi: 10.3390/cells9030665.
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.
自身免疫性甲状腺疾病（AITD）的发病机制尚不清楚，不同免疫特征与涉及 AITD 的种系变异之间的关联尚不清楚。我们之前观察到 AITD 患者外周血单个核细胞中 IgG 核心岩藻糖基化和触角α1,2 岩藻糖基化的系统性耗竭，与抗甲状腺过氧化物酶抗体（TPOAb）水平相关。已知岩藻糖缺失可增强抗体介导的 NK 细胞的强烈激活和增强靶抗原表达细胞的杀伤。在自身免疫中，这可能转化为自身抗体介导的免疫细胞募集和自身抗原表达正常组织的攻击。因此，我们在 TwinsUK 队列的 622 名个体的多组学和横断面研究中研究了免疫细胞特征、分泌蛋白、遗传变异和血清 IgG 糖基化模式之间的相互作用，其中 172 名个体被诊断为 AITD。我们观察到两个遗传变异（rs505922 和 rs687621）、AITD 状态、桥粒蛋白-2 的分泌以及 AITD 中两种 IgG N-糖基化特征的模式之间存在关联，但需要进一步研究以更好地了解它们在 AITD 中的相互作用。另一方面，增强的去岩藻糖基 IgG 与激活的 CD335+CD314+CD158b+NK 细胞亚群呈正相关。凋亡和炎症标志物 Caspase-2 和白细胞介素-1α 的水平升高与 AITD 呈正相关。与 AITD 相关的两个遗传变异 rs1521 和 rs3094228 也与已知识别 NK 细胞免疫受体 CD314 和 CD158b 的甲状腺细胞表达配体的表达改变相关。我们的分析揭示了 AITD 中升高的 Fc 活性 IgG 抗体、效应细胞、细胞因子和凋亡信号的组合，以及与 NK 细胞免疫受体的甲状腺细胞表达配体表达改变相关的 AITD 遗传变异。总的来说，TPOAb 反应、失调的免疫特征、与免疫活性谱相关的种系变异，与可能吸引 AITD 甲状腺的阳性自身反应性抗体依赖的 NK 细胞介导的免疫反应一致。
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