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Analyzing the role of thyroidal CD40 expression in the pathogenesis of Graves' disease.

机译：分析甲状腺CD40表达在Graves病发病机理中的作用。

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摘要

Graves' disease (GD) is characterized by the production of high levels of thyroid stimulating hormone receptor (TSHR) auto-antibodies which activate the TSHR and cause goiter and thyrotoxicosis. A C/T single nucleotide polymorphism (SNP) in the CD40 gene at the -1 position of the 5'UTR, in the Kozak sequence, was shown to be associated with GD, increasing the risk for GD by 30-80%. Functionally, the C allele of this SNP has been shown to drive increased CD40 gene translation, and cellular CD40 protein expression. In one study, we showed a statistical association of the CC genotype in GD with high titers of thyroid specific antibodies, more precisely, pathogenic, disease causing antibodies.;In another study, we analyzed a known CD40 copy number variant (CNV) for association with Graves' disease, since duplications in the CD40 gene could also result in an increased protein expression of CD40. We found no duplications or deletions in the locus of a known CD40 CNV, suggesting that CNVs in this region are rare, and that the entire genetic risk seen with CD40 in GD is likely to be attributed to non-CNV genomic variations, mostly the CD40 5'UTR Kozak sequence SNP we have identified.;Based on these findings, my hypothesis is that thyroidal CD40, through tissue specific mechanisms, is involved in the pathogenesis of Graves' disease, specifically in the process of pathogenic antibody production. To test this, I created transgenic (TG) mice that over-express CD40 in the thyroid, and then induced the currently accepted experimental autoimmune Graves' disease (EAGD) model, first developed by Nagayama. I demonstrate that thyroid specific expression is not necessary for onset of EAGD, it is important in augmenting the production of thyroid specific antibodies, as there was a significant increase in THSR antibodies (TRAb) in TG mice compared to WT. Moreover, these antibodies were stimulatory in nature, as there was also a significant increase in the serum thyroid hormone levels in TG mice compared to WT. This suggests that tissue specific CD40 mediates stimulatory, pathogenic antibody production in GD. In addition, when EAGD was induced in mice that lacked CD40 expression in non-bone marrow derived cells, including thyrocytes, fewer mice developed thyroid specific antibodies, levels of these antibodies were decreased in the mice that did develop antibodies, and in the percentage of mice developing EAGD was decreased. In total, these observations support the hypothesis that CD40 augments the production of pathogenic, tissue specific thyroidal antibodies in GD. Mechanistically, cytokine analysis demonstrated that transgenic mice had significantly higher levels of IL-6, and CD40 activation in human primary thyroid cells also resulted in secretion of IL-6. Additionally, blocking IL-6 action in EAGD mice resulted in decreased levels of TRAb in both WT and TG mice, although only this decrease was significant in TG mice, but not in the WT mice. Therefore, CD40 stimulation during times of local inflammation (i.e. by excess iodine or infection) could trigger a bystander mechanism through thyroidal cytokine release and recruitment of immune cells to the target tissue, resulting in tissue specific antibody production. This, when other predisposing factors are present, can lead to the onset of GD.
机译：格雷夫斯病（GD）的特征是高水平的甲状腺刺激激素受体（TSHR）自身抗体的产生，这些抗体会激活TSHR并引起甲状腺肿和甲状腺毒症。已显示，在Kozak序列中5'UTR -1位置的CD40基因中的C / T单核苷酸多态性（SNP）与GD相关，使GD的风险增加了30-80％。从功能上讲，该SNP的C等位基因已显示出驱动CD40基因翻译和细胞CD40蛋白表达增加的能力。在一项研究中，我们显示了GD中CC基因型与高滴度的甲状腺特异性抗体（更确切地说是致病性，致病性抗体）的统计关联。在另一项研究中，我们分析了已知的CD40拷贝数变异体（CNV）的关联性与Graves病有关，因为CD40基因重复也可能导致CD40的蛋白质表达增加。我们在已知的CD40 CNV的基因座中未发现重复或缺失，这表明该区域的CNV很罕见，GD中CD40所见的整个遗传风险很可能归因于非CNV基因组变异，主要是CD40根据这些发现，我们确定了5'UTR Kozak序列SNP。我的假设是，甲状腺CD40通过组织特异性机制参与了Graves病的发病机理，特别是在致病性抗体产生过程中。为了测试这一点，我创建了在甲状腺中过表达CD40的转基因（TG）小鼠，然后诱导了由长山最初开发的目前公认的实验性自身免疫性Graves病（EAGD）模型。我证明甲状腺特异性表达对于EAGD的发作不是必需的，它对增加甲状腺特异性抗体的产生很重要，因为与野生型相比，TG小鼠中THSR抗体（TRAb）显着增加。此外，这些抗体本质上是刺激性的，因为与WT相比，TG小鼠的血清甲状腺激素水平也显着增加。这表明组织特异性CD40介导GD中刺激性，致病性抗体的产生。此外，当在非骨髓来源的细胞（包括甲状腺细胞）中缺乏CD40表达的小鼠中诱导EAGD时，更少的小鼠会产生甲状腺特异性抗体，在产生抗体的小鼠中这些抗体的水平会降低，并且百分比发育EAGD的小鼠减少。总体而言，这些观察结果支持CD40增加GD中病原性，组织特异性甲状腺抗体产生的假说。从机理上讲，细胞因子分析表明转基因小鼠的IL-6水平明显升高，而人原发性甲状腺细胞中CD40的激活也导致IL-6的分泌。此外，在EAGD小鼠中阻断IL-6的作用导致WT和TG小鼠的TRAb水平降低，尽管只有这种降低在TG小鼠中很明显，而在WT小鼠中却没有。因此，在局部发炎（即过量的碘或感染）期间的CD40刺激可通过甲状腺细胞因子释放和免疫细胞募集到靶组织而触发旁观者机制，从而产生组织特异性抗体。当存在其他诱发因素时，这可能导致GD发作。

著录项

  • 作者

    Huber, Amanda Katherine.;

  • 作者单位

    Mount Sinai School of Medicine.;

  • 授予单位 Mount Sinai School of Medicine.;
  • 学科 Biology Endocrinology.;Health Sciences Immunology.;Health Sciences Medicine and Surgery.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 151 p.
  • 总页数 151
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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