Changes in gene expression profile and development of autoimmunity in the thyroid following infection.

自身免疫性甲状腺疾病的病理基础仍然很大程度上是未知的。虽然有研究表明感染和/或组织损伤先于自身免疫的发生，但这种情况与自身免疫反应的触发之间的关系尚不清楚。在本研究中，我们发现从病原体或宿主基因组释放的双链DNA （ds）作用于甲状腺细胞，产生I型干扰素、促炎细胞因子和趋化因子，以及抗原加工和递呈所必需的主要组织相容性复合体（MHC）和相关分子。这种效应是dsdna特异性的，独立于toll样受体（TLRs）或rig - 1，已知的病原体相关分子模式（PAMPs）的细胞受体。我们分别表明，传统的tlr依赖途径也在甲状腺中起作用，并参与先天免疫反应的启动。tlr确实在甲状腺滤泡上皮和腺体肥大细胞中表达。有趣的是，dsDNA或TLR配体对甲状腺细胞的刺激不仅激活了先天免疫反应，而且抑制了甲状腺的碘吸收和激素合成，这与病毒感染和非甲状腺疾病前驱期的甲状腺功能障碍相对应。这些证据表明，感染和/或组织损伤可激活甲状腺的先天免疫，增强辅助作用，从而可能引发自身免疫反应。此外，这些事件可能是甲状腺功能障碍的直接原因。

Pathological basis of autoimmune thyroid diseases are still largely unknown. Although it has been suggested that infection and/or tissue damage precede the onset of autoimmunity, the relationship between such incidences and the triggering of autoimmune reactions was not clear. In the present study, we have shown that double-stranded (ds) DNA released from pathogen or host genome acts on thyroid cells to produce type I interferons, proinflammatory cytokines and chemokines as well as major histocompatibility complex (MHC) and related molecules necessary for antigen processing and presentation. This effect was dsDNA-specific and independent of toll-like receptors (TLRs) or RIG-I, known cellular receptors for pathogen-associated molecular patterns (PAMPs). We separately showed that conventional TLR-dependent pathways are also operating in the thyroid and involved in the initiation of innate immune reaction. TLRs are indeed expressed in the thyroid follicular epithelium and in mast cells in the gland. Interestingly, stimulation of thyroid cells by dsDNA or TLR ligands not only activated innate immune reactions, but resulted in suppression of iodide uptake and hormone synthesis of the thyroid, which is corresponding to the thyroid dysfunction seen in the prodromal period of viral infection and non-thyroid illness. These evidence suggest that infection and/or tissue damage can activate innate immunity in the thyroid and enhance the adjuvant effect, which may trigger autoimmune reactions. Additionally, such events may be a direct cause of thyroid dysfunction.