Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06519, USA.
Immunity. 2013 Mar 21;38(3):528-40. doi: 10.1016/j.immuni.2012.11.017. Epub 2013 Mar 14.
Detection of self nucleic acids by Toll-like receptors (TLR) preciptates autoimmune diseases, including systemic lupus erythematosus (SLE). It remains unknown how TLR signals in specific cell types contribute to distinct manifestations of SLE. Here, we demonstrate that formation of anti-nuclear antibodies in MRL.Fas(lpr) mice entirely depends on the TLR signaling adaptor MyD88 in B cells. Further, MyD88 deficiency in B cells ameliorated nephritis, including antibody-independent interstitial T cell infiltrates, suggesting that nucleic acid-specific B cells activate nephrotoxic T cells. Surprisingly, MyD88 deletion in dendritic cells (DCs) did not affect nephritis, despite the importance of DCs in renal inflammation. In contrast, MyD88 in DCs was critical for dermatitis, revealing a separate pathogenetic mechanism. DC-expressed MyD88 promoted interferon-α production by plasmacytoid DCs, which was associated with Death domain-associated protein 6 upregulation and B lymphopenia. Our findings thus reveal unique immunopathological consequences of MyD88 signaling in B cells and DCs in lupus.
Toll 样受体（TLR）检测自身核酸可引发自身免疫性疾病，包括系统性红斑狼疮（SLE）。目前尚不清楚特定细胞类型中的 TLR 信号如何导致 SLE 的不同表现。在这里，我们证明了 MRL.Fas(lpr) 小鼠中抗核抗体的形成完全依赖于 B 细胞中的 TLR 信号接头 MyD88。此外，B 细胞中 MyD88 的缺失改善了肾炎，包括抗体非依赖性间质 T 细胞浸润，这表明核酸特异性 B 细胞激活了肾毒性 T 细胞。令人惊讶的是，树突状细胞（DC）中 MyD88 的缺失并未影响肾炎，尽管 DC 在肾脏炎症中很重要。相比之下，DC 中的 MyD88 对皮炎至关重要，揭示了一种单独的发病机制。DC 表达的 MyD88 促进了浆细胞样 DC 产生干扰素-α，这与死亡结构域相关蛋白 6 的上调和 B 淋巴细胞减少有关。因此，我们的研究结果揭示了 MyD88 信号在狼疮中 B 细胞和 DC 中的独特免疫病理后果。
