Tian Jane, Avalos Ana Maria, Mao Su-Yau, Chen Bo, Senthil Kannaki, Wu Herren, Parroche Peggy, Drabic Stacey, Golenbock Douglas, Sirois Cherilyn, Hua Jing, An Ling Ling, Audoly Laurent, La Rosa Greg, Bierhaus Angelika, Naworth Peter, Marshak-Rothstein Ann, Crow Mary K, Fitzgerald Katherine A, Latz Eicke, Kiener Peter A, Coyle Anthony J
Inflammation and Autoimmune Group, Research Department, MedImmune, Gaithersburg, Maryland 20878, USA.
Nat Immunol. 2007 May;8(5):487-96. doi: 10.1038/ni1457. Epub 2007 Apr 8.
Increased concentrations of DNA-containing immune complexes in the serum are associated with systemic autoimmune diseases such as lupus. Stimulation of Toll-like receptor 9 (TLR9) by DNA is important in the activation of plasmacytoid dendritic cells and B cells. Here we show that HMGB1, a nuclear DNA-binding protein released from necrotic cells, was an essential component of DNA-containing immune complexes that stimulated cytokine production through a TLR9-MyD88 pathway involving the multivalent receptor RAGE. Moreover, binding of HMGB1 to class A CpG oligodeoxynucleotides considerably augmented cytokine production by means of TLR9 and RAGE. Our data demonstrate a mechanism by which HMGB1 and RAGE activate plasmacytoid dendritic cells and B cells in response to DNA and contribute to autoimmune pathogenesis.
血清中含DNA免疫复合物浓度的升高与系统性自身免疫疾病（如狼疮）相关。DNA对Toll样受体9（TLR9）的刺激在浆细胞样树突状细胞和B细胞的激活中起重要作用。在此我们表明，HMGB1（一种从坏死细胞释放的核DNA结合蛋白）是含DNA免疫复合物的重要组成部分，该复合物通过涉及多价受体RAGE的TLR9-MyD88途径刺激细胞因子产生。此外，HMGB1与A类CpG寡脱氧核苷酸的结合通过TLR9和RAGE显著增强了细胞因子的产生。我们的数据证明了一种机制，即HMGB1和RAGE响应DNA激活浆细胞样树突状细胞和B细胞，并促成自身免疫发病机制。
