S100A8/A9调控MDSC功能在桥本氏甲状腺炎免疫失衡中的作用及机制

Hashimoto’s Thyroiditis (HT) is characterized by severe infiltration of thyroid targeting immunocytes which cause the local inflammation and subsequent thyroid gland destruction and hypothyroidism. Immune imbalance is considered to participate and play an important role in the pathogenesis of HT. However, the underlining mechanism remains elusive. Myeloid-derived suppressor cells (MDSC) is a cell group with highly plastic and pleiotropic immune regulatory function. In our previous study, we found that the expressions of inflammation-associated S100 protein were significantly higher in thyroid gland of HT compared with that of simple goiter. Additionally, we detected MDSC expansion in peripheral blood of HT patients. Recent investigations suggested that MDSC had the receptors for S100A8/A9, which is a member of S100 family, and its accumulation and expansion can be activated by this S100 subtype. Combining our findings in HT and recent research progress of MDSC, we hypothesize that: In Hashimoto’s Thyroiditis, the high expressions of S100A8/A9 in thyroid gland regulate the function of MDSC, and this may involve in the immune imbalance of Hashimoto’s Thyroiditis. To verify this hypothesis, we will use experimental autoimmune thyroiditis mice (EAT mice) as HT murine model for investigation. In vivo imaging, cellular immunological and molecular biological techniques will be used for assessing how S100A8/A9 works on MDSC by modifying its phenotypes，differentiation, accumulation, expansion and T cell regulatory capacity. Accordingly the effect of “S100A8/A9-MDSC interaction” on immune imbalance of HT and relevant mechanisms will be studied. Furthermore, experiments will be performed with HT patients’ specimens to verify this hypothesis in human. Our study will elucidate the role of “S100A8/A9-MDSC” in immune imbalance of Hashimoto’s Thyroiditis, which will contribute to novel therapeutic strategies for Hashimoto’s Thyroiditis.

桥本氏甲状腺炎(HT)为甲状腺免疫细胞浸润及其介导的腺体炎症破坏，致甲状腺功能低下，多认为与免疫失衡相关，其确切机制尚未阐明。髓系来源免疫抑制细胞(MDSC)为一具多向免疫调节功能细胞。我们在研究中发现，HT患者甲状腺中炎症相关因子S100蛋白表达增加，而外周血MDSC出现扩增。结合国际上“MDSC具有S100A8/A9亚型受体并被其诱导扩增”的研究进展，我们推测：在桥本氏甲状腺炎中，甲状腺高表达S100A8/A9，通过调控MDSC聚集扩增及其免疫功能，参与HT免疫失衡的发生发展。为证实这一假说，我们将以自身免疫性甲状腺炎小鼠为HT动物模型，采用体内成像、细胞免疫学、分子生物学等技术，从整体-细胞-分子三个层面，探讨S100A8/A9通过调控MDSC功能对HT免疫失衡的影响及机制。再在HT患者标本上进行验证。本课题将阐明桥本氏甲状腺炎免疫失衡的分子-细胞新机制，为其治疗提供新思路和新靶点。

桥本氏甲状腺炎(HT)为最常见的自身免疫性甲状腺疾病之一，近年来其发病率显著上升。HT的免疫致病机制目前尚未被完全阐明，缺乏具有针对性的有效治疗方法。髓系来源免疫抑制细胞(MDSC)为一多向性免疫调节细胞。我们在前期研究中发现，HT患者甲状腺中炎症相关因子S100蛋白表达增加，外周血MDSC出现扩增。结合国际上“MDSC具有S100A8/A9受体并被其诱导扩增”的研究进展，推测在HT中，S100A8/A9高表达并介导MDSC扩增及功能调控，为HT免疫失衡的机制之一。本项目研究中，我们检测了HT动物模型及HT患者外周血及甲状腺组织中S100A8、S100A9、MDSC的表达情况并行相关性分析，并对MDSC进行亚型分析；对不同治疗阶段、不同甲状腺功能的HT患者的以上项目进行分组比较；最后，初步探究了HT患者外周血MDSC的功能。在该研究中，我们首次阐明了在HT动物模型及HT患者中，均存在MDSC扩增、S100蛋白表达增多。外周血以Mo-MDSC亚群及S100A8蛋白升高更为明显。在HT患者中，治疗前组外周血Mo-MDSC亚群表达明显高于治疗中组及痊愈组，而治疗中组Mo-MDSC表达高于痊愈组；甲亢组外周血Mo-MDSC表达高于甲功正常组及甲减组。HT患者甲状腺组织中，MDSC相关抗原部分表达增多，S100A8、S100A9蛋白表达增多。S100A8/A9蛋白与MDSC各亚群表达未显示明显相关性。HT患者外周血MDSC的功能实验初步显示其具有免疫抑制功能，需扩大例数进一步明确。目前研究结果提示S100A8、S100A9、MDSC在HT的疾病发生发展过程中可能起调控作用。初步实验提示HT患者外周血MDSC具有免疫抑制功能，这可能是HT疾病发生发展中的免疫调节机制之一。本项目研究成果将揭示桥本氏甲状腺炎免疫失衡致病中的新机制，为其治疗提供科学基础和新思路。