Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes

Autoimmune thyroid diseases (AITD) and Type 1 diabetes (T1D) frequently occur in the same individual pointing to a strong shared genetic susceptibility. Indeed, the co-occurrence of T1D and AITD in the same individual is classified as a variant of the autoimmune polyglandular syndrome type 3 (designated APS3v). Our aim was to identify new genes and mechanisms causing the co-occurrence of T1D + AITD (APS3v) in the same individual using a genome-wide approach. For our discovery set we analyzed 346 Caucasian APS3v patients and 727 gender and ethnicity matched healthy controls. Genotyping was performed using the Illumina Human660W-Quad.v1. The replication set included 185 APS3v patients and 340 controls. Association analyses were performed using the PLINK program, and pathway analyses were performed using the MAGENTA software. We identified multiple signals within the HLA region and conditioning studies suggested that a few of them contributed independently to the strong association of the HLA locus with APS3v. Outside the HLA region, variants in GPR103, a gene not suggested by previous studies of APS3v, T1D, or AITD, showed genome-wide significance (p < 5 × 10⁻⁸). In addition, a locus on 1p13 containing the PTPN22 gene showed genome-wide significant associations. Pathway analysis demonstrated that cell cycle, B-cell development, CD40, and CTLA-4 signaling were the major pathways contributing to the pathogenesis of APS3v. These findings suggest that complex mechanisms involving T-cell and B-cell pathways are involved in the strong genetic association between AITD and T1D.     

甲状腺乳头状癌伴发桥本甲状腺炎的临床研究

背景与目的：甲状腺乳头状癌（papillary thyroid carcinoma，PTC）和桥本甲状腺炎（Hashimoto’s thyroiditis，HT）的发病率均呈上升趋势，两者之间的关系已成为目前研究的热点。探讨PTC和HT之间的关系。方法：回顾性分析2014—2015年期间在中国科学院大学附属肿瘤医院头颈肿瘤外科行甲状腺癌手术治疗的首诊患者306例，术后病理学检查均明确诊断为PTC，其中术后病理学确诊伴发HT者42例，比较伴发HT与未伴发HT患者的临床病理学特征。结果：PTC患者女性发病年龄高于男性（46.2岁 vs 41.9岁）。相较于与未伴发HT的PTC患者，伴发HT的患者中女性比例更高（93% vs77%），中央区淋巴结数目较多［（5.0±3.4）枚 vs （2.5±2.7）枚］，术前促甲状腺激素（thyroid-stimulating hormone，TSH）水平较高［（3.28±1.91）μU/mL vs （2.12±1.29）μU/mL］，术前抗甲状腺过氧化物酶抗体（thyroid peroxidaseantibody，TPOAb）阳性率较高（55% vs 14%），术前甲状腺球蛋白抗体（thyroglobulin antibodies，TgAb）阳性率较高（69% vs 13%）。发生中央区淋巴结转移的患者中，中央区淋巴结转移数目与中央区淋巴结总数显著相关（Pearson相关系数=0.582）。多因素logistic回归分析发现，男性、低龄、被膜侵犯是PTC患者中央区淋巴结转移的独立危险因素。结论：伴发HT对PTC患者的预后无显著影响。伴发HT的PTC患者TSH水平显著偏高，提示HT可能是PTC发病风险因素之一。中央区淋巴结转移数目与中央区淋巴结总数相关，推测PTC淋巴结转移可能与淋巴结炎症反应相关。     

Therapeutic effect of mesenchymal stem cell on Hashimoto’s thyroiditis in a rat model by modulating Th17/Treg cell balance

Abstract

The autoimmune condition Hashimoto’s thyroiditis (HT) is a disease wherein lymphocytes mediate the autoimmune damage and destruction of the thyroid gland. There are currently no effective means of treating HT, with the primary strategies of thyroid hormone therapy, surgery, or immunomodulatory therapy being associated with serious risks and side effects. There is thus a clear and urgent need to identify novel treatments for HT. In this study, we utilize female SD rats induced HT to evaluated the ability of transplanted MSCs to regulate Th17/Treg interactions in a rat Hashimoto’s thyroiditis (HT) model system. The results showed that Rats in the HT model group exhibited increased thyroid autoantibody levels consistent with successful model development, whereas these levels were lower in rats treated with MSCs. There were also fewer thyroid lesions and less lymphoid infiltration of the thyroid in MSC-treated rats relative to HT model rats, as well as fewer Th17 cells and more Treg cells – an observation consistent with the cytokine analyses. All of these showed that MSCs can regulate Th17/Treg interactions in a rat Hashimoto’s thyroiditis (HT) model system. It suggested that transplanted MSCs could be a potential immunotherapy strategy for the treatment of Hashimoto’s thyroiditis.     

环孢菌素A和1,2 5(OH)2D3防治实验性自身免疫性甲状腺炎的研究

将猪的甲状腺球蛋白（pTG)100μg/只分别于第0d,第14d皮下注入CBA小鼠体内，制作实验性自身免疫性甲状腺炎（EAT）的动物模型。免免疫干预组从0－28d，治疗组从10－38d单独或者联合应用环孢菌素A（CsA,10mg/kg)灌胃和（或）1,25(OH)2D3(0.2μg/kg）腹腔注射，pTG免疫后第28d，第38d处死小鼠，取甲状腺组织作病理学检查，并检测血清中猪的甲状腺球蛋白抗体（pTGAb)、猪的甲状腺微粒体抗体（pTMAb)。免疫干预组和治疗组联合应用小剂量CsA和1，25（OH）2D3分别使EAT发病率降低44．44％和37．50％。严重病例分别降低71．43％和60．32％，免疫干预组的血清pTGAb,pTMAb的值均降低。提示：小剂量免疫抑制剂CsA和1，25（OH）2D2联合防治EAT有效，并具有协同作用。     

亚急性甲状腺炎的CT诊断

目的:探讨亚急性甲状腺炎的CT表现和特点,提高对该病影像表现的认识。材料和方法:回顾性分析10例亚急性甲状腺炎CT影像特征及临床资料,共16个病灶,其中9例经手术病理证实,1例临床证实。同时抽取局限型甲状腺癌65例,就部分征象作对照分析。结果:亚急性甲状腺炎局限性3例,弥漫性7例。CT表现分3型:①局限于甲状腺一侧叶的低密度病变,病变甲状腺肿大,峡部可受累,3例;②甲状腺两叶各有一低密度病变,呈不对称肿大,病灶之间有正常甲状腺组织,6例共12个病灶;③甲状腺两叶及岬部均匀肿大,略不对称,1例。CT平扫病变为低密度,增强扫描后呈轻到中度均匀强化(15/16),腺内更低密度结节少见(1/16)。病变处甲状腺边缘模糊(16/16),与正常甲状腺组织界限不清(15/16),而局限型甲状腺癌病灶与正常甲状腺腺组织分界清楚(62/65),两者极不一样(P<0.01)。结论:亚急性甲状腺炎CT表现有一定特点,熟悉这些特点对于诊断及鉴别诊断很有帮助。     

碘和甲状腺球蛋白诱导大鼠自身免疫性甲状腺炎的研究

目的　研究碘与自身免疫性甲状腺炎 (EAT)的关系。方法　用碘和甲状腺球蛋白 (TG)诱导SD大鼠建立甲状腺炎模型 ,随机分为 5组 ,每组 10只。正常对照组 (NC组 ) ;少量碘组 (LI组 ) :饮 5 0 0 μg/L碘化钠水 ;大量碘组 (HI组 ) :饮 5 0 0mg/L碘化钠水 ;TG组 :于实验第 15天大鼠接受皮内多点注射完全福氏佐剂乳化的TG各 10 0 μg作为初次免疫 ,2周后以不完全福氏佐剂乳化的TG加强免疫 ,以后每周加强免疫 1次至第 6周末实验结束 ;TG HI组 :TG及HI给药方法同上。至第 6周末实验结束处死所有动物 ,用放免法检测血清TG抗体 (TGAb)及甲状腺过氧化物酶抗体 (TPOAb)效价 ,并于光镜下观察甲状腺组织淋巴细胞浸润程度。结果　TG HI组、HI组及TG组甲状腺滤泡破坏及淋巴细胞浸润均较明显 ,TG HI组及HI组与NC组比较 ,P<0 .0 5 ,TG组与NC组比较有增高趋势 ,但无统计学意义。 3组TGAb、TPOAb均明显高于NC组及LI组 (P<0 .0 1;仅HI组TPOAbP<0 .0 5 )。各组TGAb及TPOAb水平与甲状腺病理分级呈正相关关系 (r =0 .9,P<0 .0 5 )。结论　高碘可诱发SD鼠EAT发生 ,TG与高碘结合诱导SD大鼠EAT的作用更明显