Department of Immunology, Erasmus Medical Center, Erasmus University, Rotterdam, The Netherlands.
J Clin Endocrinol Metab. 2013 Jun;98(6):2460-8. doi: 10.1210/jc.2012-4122. Epub 2013 Apr 4.
The target glands in spontaneous animal models of endocrine autoimmune disease show, prior to the autoimmune reaction, growth and connective tissue abnormalities, whereas the autoimmune reaction is initiated by an early accumulation of macrophages and dendritic cells in the target glands.
The aim of the study was to test the hypothesis that serum factors related to these growth and connective tissue abnormalities and the early accumulation of immune cells, ie, tissue growth/remodeling factors, adhesion molecules, chemokines, and pro- and anti-inflammatory cytokines, are related to thyroid peroxidase autoantibodies (TPO-Abs) seroconversion in subjects at risk to develop autoimmune thyroid disease (AITD).
A controlled study on 64 TPO-Ab-negative euthyroid female relatives with at least 1 first- or second-degree relative with documented autoimmune hyper- or hypothyroidism, 32 of whom did and 32 who did not seroconvert to TPO-Ab positivity in 5-year follow-up. The relatives were compared with 32 healthy controls. In all subjects we measured serum levels of chemokine (C-C motif) ligand (CCL)-2, CCL3, CCL4, soluble vascular cell adhesion molecule, soluble intercellular adhesion molecule-1, thrombospondin-1, vascular endothelial growth factor-A, angiopoietin 1 receptor-2, metalloproteinase-13, platelet-derived growth factor-BB, fibronectin, IL-1β, IL-6, TNF-α, IL-10, and growth differentiation factor-15 by multiplex (cytometric bead array) or a single commercial ELISA.
Both seroconverting and nonseroconverting family members showed an up-regulation of fibronectin and a down-regulation of platelet-derived growth factor-BB and the adhesion and migration factors CCL2, CCL4, soluble vascular cell adhesion molecule-1, angiopoietin 1 receptor-2, and metalloproteinase-13. The seroconverters differed from the nonseroconverters by an up-regulation of the proinflammatory compounds Il-1β, IL-6, and CCL3.
This study shows that euthyroid females within AITD families show a characteristic pattern of abnormalities in serum levels of tissue remodeling factors, growth factors, chemokines, (vascular) adhesion molecules, and cytokines prior to the occurrence of TPO-Abs in serum. The results provide proof of principle that preseroconversion stages and seroconversion to AITD might be predicted using serum analytes related to growth/connective tissue abnormalities and migration/accumulation abnormalities of macrophages and dendritic cells.
自发性内分泌自身免疫性疾病动物模型的靶腺在发生自身免疫反应之前，表现出生长和结缔组织异常，而自身免疫反应是由靶腺中早期巨噬细胞和树突状细胞的积累引发的。
本研究旨在验证以下假设，即与这些生长和结缔组织异常以及免疫细胞早期积累相关的血清因子，即组织生长/重塑因子、黏附分子、趋化因子、前炎症和抗炎细胞因子，与发生自身免疫性甲状腺疾病（AITD）风险的受试者中甲状腺过氧化物酶自身抗体（TPO-Ab）血清转换有关。
对 64 名 TPO-Ab 阴性的甲状腺功能正常的女性亲属进行了一项对照研究，这些亲属至少有 1 位一级或二级亲属患有已确诊的自身免疫性甲状腺功能亢进或甲状腺功能减退，其中 32 名亲属在 5 年随访中发生了 TPO-Ab 阳性血清转换，而 32 名亲属未发生血清转换。将这些亲属与 32 名健康对照进行了比较。在所有受试者中，我们通过多重（细胞因子珠阵列）或单个商业 ELISA 测量了趋化因子（C-C 基序）配体（CCL）-2、CCL3、CCL4、可溶性血管细胞黏附分子、可溶性细胞间黏附分子-1、血小板反应蛋白-1、血管内皮生长因子-A、血管生成素 1 受体-2、基质金属蛋白酶-13、血小板衍生生长因子-BB、纤维连接蛋白、IL-1β、IL-6、TNF-α、IL-10 和生长分化因子 15 的血清水平。
发生血清转换和未发生血清转换的家族成员均表现出纤维连接蛋白上调，血小板衍生生长因子-BB 以及黏附与迁移因子 CCL2、CCL4、可溶性血管细胞黏附分子-1、血管生成素 1 受体-2 和基质金属蛋白酶-13 下调。与未发生血清转换的个体相比，血清转换者的促炎化合物 IL-1β、IL-6 和 CCL3 上调。
本研究表明，AITD 家族中的甲状腺功能正常女性在血清 TPO-Ab 出现之前，就表现出组织重塑因子、生长因子、趋化因子（血管）、黏附分子和细胞因子血清水平异常的特征模式。这些结果提供了初步证据，表明使用与生长/结缔组织异常和巨噬细胞和树突状细胞迁移/积累异常相关的血清分析物，可能预测 preseroconversion 阶段和向 AITD 的血清转换。
