Nucleosome, the main autoantigen in systemic lupus erythematosus, induces direct dendritic cell activation via a MyD88-independent pathway:: Consequences on inflammation
Nucleosome, the main autoantigen in systemic lupus erythematosus, induces direct dendritic cell activation via a MyD88-independent pathway:: Consequences on inflammation
复制标题
DOI：
10.4049/jimmunol.174.6.3326
复制
发表时间：
2005-03-15
影响因子：
4.4
通讯作者：
Rammensee, HG
中科院分区：
文献类型：
--
作者：
Decker, P;Singh-Jasuja, H;Rammensee, HG
核小体是系统性红斑狼疮的主要自身抗原。它是在患者血清中发现的循环复合体，似乎在疾病发展中起关键作用。在这项研究中，我们首次通过刺激同种异体细胞的MLR、细胞因子分泌和CD86上调，发现生理浓度的纯化核小体直接诱导小鼠骨髓源性DC、人单核细胞源性DC和纯化人髓系DC的体外树突状细胞（DC）成熟。重要的是，核小体作为自由复合物而不需要形成免疫复合物或存在未甲基化的CpG DNA基序，因此我们确定了核小体激活DC的新机制。我们已经清楚地证明，这种激活是核小体特异性和内毒素无关的。特别是，核小体诱导MDDC分泌已知在患者血清中高浓度检测到的细胞因子。此外，活化的MDDC分泌IL-8，这是一种在患者血清中检测到的中性粒细胞趋化剂，因此可能有利于患者观察到的炎症。正常和狼疮MDDC对核小体诱导的激活都很敏感。最后，将纯化的核小体注射到正常小鼠体内诱导DC成熟。总之，这些结果加强了核小体在系统性红斑狼疮中的关键作用，并可能解释了患者的外周耐受性是如何被打破的。
Nucleosome is the major autoantigen in systemic lupus erythematosus. It is found as a circulating complex in the sera of patients and seems to play a key role in disease development. In this study, we show for the first time that physiologic concentrations of purified nucleosomes directly induce in vitro dendritic cell (DC) maturation of mouse bone marrow-derived DC, human monocyte-derived DC (MDDC), and purified human myeloid DC as observed by stimulation of allogenic cells in MLR, cytokine secretion, and CD86 up-regulation. Importantly, nucleosomes act as free complexes without the need for immune complex formation or for the presence of unmethylated CpG DNA motifs, and we thus identified a new mechanism of DC activation by nucleosomes. We have clearly demonstrated that this activation is nucleosome-specific and endotoxin-independent. Particularly, nucleosomes induce MDDC to secrete cytokines known to be detected in high concentrations in the sera of patients. Moreover, activated MDDC secrete IL-8, a neutrophil chemoattractant also detected in patient sera, and thus might favor the inflammation observed in patients. Both normal and lupus MDDC are sensitive to nucleosome-induced activation. Finally, injection of purified nucleosomes to normal mice induces in vivo DC maturation. Altogether, these results strengthen the key role of nucleosomes in systemic lupus erythematosus and might explain how peripheral tolerance is broken in patients.