Genetically driven target tissue overexpression of CD40: a novel mechanism in autoimmune disease.
Genetically driven target tissue overexpression of CD40: a novel mechanism in autoimmune disease.
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DOI：
10.4049/jimmunol.1200311
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发表时间：
2012-09-15
期刊：
影响因子：
--
通讯作者：
Tomer Y
中科院分区：
文献类型：
--
作者：
Huber AK;Finkelman FD;Li CW;Concepcion E;Smith E;Jacobson E;Latif R;Keddache M;Zhang W;Tomer Y
CD40基因是一种重要的免疫调节基因，在非髓系来源的细胞上也有表达和功能，其中许多非髓系来源的细胞是组织特异性自身免疫性疾病的靶细胞，包括1型糖尿病的β细胞，克罗恩病的肠上皮细胞，以及Graves病(GD)的甲状腺滤泡细胞。靶组织CD40的表达是否在自身免疫性疾病的病因中起作用还有待确定。在这里，我们表明，靶组织CD40的过度表达在自身免疫的病因学中起着关键作用。利用GD小鼠模型，我们证明了甲状腺CD40的过度表达增加了甲状腺特异性抗体的产生，导致了更严重的实验性自身免疫性Graves病(EAGD)，而甲状腺CD40的缺失抑制了疾病的发生。利用转录组和免疫途径分析，我们发现在EAGD小鼠甲状腺和人类原代甲状腺细胞中，CD40通过激活下游细胞因子和趋化因子，最明显的是IL-6来介导这一效应。为了将这些发现转化为治疗，我们在EAGD诱导期间在甲状腺CD40过度表达的情况下阻断了IL-6，并显示TSHR刺激性抗体水平和疾病发生率降低。我们认为靶组织中CD40的过度表达在器官特异性自身免疫性疾病的发病机制中起着关键作用。
The CD40 gene, an important immune regulatory gene, is also expressed and functional on non-myeloid derived cells, many of which are targets for tissue specific autoimmune diseases, including beta cells in type 1 diabetes, intestinal epithelial cells in Crohn’s disease, and thyroid follicular cells in Graves’ disease (GD). Whether target tissue CD40 expression plays a role in autoimmune disease etiology has yet to be determined. Here we show, that target-tissue over-expression of CD40 plays a key role in the etiology of autoimmunity. Using a murine model of GD, we demonstrated that thyroidal CD40 over-expression augmented the production of thyroid specific antibodies, resulting in more severe experimental autoimmune Graves’ disease (EAGD), whereas deletion of thyroidal CD40 suppressed disease. Using transcriptome and immune-pathway analyses we showed that in both EAGD mouse thyroids and human primary thyrocytes, CD40 mediates this effect by activating downstream cytokines and chemokines, most notably IL-6. To translate these findings into therapy, we blocked IL-6 during EAGD induction in the setting of thyroidal CD40 over-expression, and showed decreased levels of TSHR stimulating antibodies and frequency of disease. We conclude that target tissue over-expression of CD40 plays a key role in the etiology of organ specific autoimmune disease.
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影响因子：
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作者：
Min, DJ;Cho, ML;Kim, HY
通讯作者：
Kim, HY
影响因子：
4.8
作者：
Chen, CR;Pichurin, P;Rapoport, B
通讯作者：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1006/clin.1997.4391
发表时间：
1997-08-01
期刊：
CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY
影响因子：
--
作者：
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通讯作者：
Leclere, J
影响因子：
5
作者：
Jacobson, E. M.;Huber, A. K.;Tomer, Y.
通讯作者：
Tomer, Y.