Crosstalk between neutrophils, B-1a cells and plasmacytoid dendritic cells initiates autoimmune diabetes
Crosstalk between neutrophils, B-1a cells and plasmacytoid dendritic cells initiates autoimmune diabetes
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DOI：
10.1038/nm.3042
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发表时间：
2013-01-01
期刊：
影响因子：
82.9
通讯作者：
Lehuen, Agnes
中科院分区：
文献类型：
--
作者：
Diana, Julien;Simoni, Yannick;Lehuen, Agnes
1型糖尿病发展多年，其特征最终在于自身反应性T细胞对产生胰岛素的胰腺β细胞的破坏。尽管如此，先天细胞在这种疾病的起始中的作用仍然知之甚少。在这里，我们表明，在年轻的女性非肥胖糖尿病小鼠，生理性β细胞死亡诱导的招聘和激活的B-la细胞，中性粒细胞和浆细胞样树突状细胞（pDC）的胰腺。活化的B-1a细胞分泌对双链DNA具有特异性的IgG。IgG激活中性粒细胞释放DNA结合的cathelicidin相关抗菌肽（CRAMP），其结合自身DNA。然后，自身DNA、DNA特异性IgG和CRAMP肽通过Toll样受体9-髓样分化因子88途径激活pDC，导致胰岛中产生干扰素-α。我们通过使用消耗治疗进一步证明，B-1a细胞、中性粒细胞和产生IFN-α的pDC是引发致糖尿病性T细胞应答和1型糖尿病发展所必需的。这些发现揭示了先天免疫细胞串扰发生在年轻NOD小鼠的胰腺中，并导致T1 D的启动。
Type 1 diabetes develops over many years and is characterized ultimately by the destruction of insulin-producing pancreatic beta cells by autoreactive T cells. Nonetheless, the role of innate cells in the initiation of this disease remains poorly understood. Here, we show that in young female nonobese diabetic mice, physiological beta cell death induces the recruitment and activation of B-la cells, neutrophils and plasmacytoid dendritic cells (pDCs) to the pancreas. Activated B-1a cells secrete IgGs specific for double-stranded DNA. IgGs activate neutrophils to release DNA-binding cathelicidin-related antimicrobial peptide (CRAMP), which binds self DNA. Then, self DNA, DNA-specific IgG and CRAMP peptide activate pDCs through the Toll-like receptor 9-myeloid differentiation factor 88 pathway, leading to interferon-alpha production in pancreatic islets. We further demonstrate through the use of depleting treatments that B-1a cells, neutrophils and IFN-alpha-producing pDCs are required for the initiation of the diabetogenic T cell response and type 1 diabetes development. These findings reveal that an innate immune cell crosstalk takes place in the pancreas of young NOD mice and leads to the initiation of T1D.