Institute for Immunobiology, Shanghai Medical College of Fudan University, Shanghai 200032, China.
J Immunol. 2013 Jun 1;190(11):5411-22. doi: 10.4049/jimmunol.1203301. Epub 2013 Apr 24.
Anti-dsDNA Ab is reported to be the central pathogenic autoantibody involved in systemic lupus erythematosus (SLE) pathogenesis. However, the mechanisms involved in anti-dsDNA Ab production remain unclear. Recent evidence indicated that DNA-containing immune complexes (ICs) in circulation (termed "circulating DNA-containing ICs"), which are one of the hallmarks of SLE, might be involved in autoantibody production. In this study, we explored their potential role in anti-dsDNA Ab production and the underlying mechanisms in patients with SLE. We demonstrated that circulating DNA-containing ICs were able to induce anti-dsDNA Ab. Of note, HMGB1 in circulating DNA-containing ICs was crucial for anti-dsDNA Ab induction. The HMGB1 content of circulating DNA-containing ICs also correlated positively with anti-dsDNA Ab production in patients with SLE. Further, we revealed that the TLR2/MyD88/microRNA-155 (miR-155) pathway was pivotal for HMGB1 to confer anti-dsDNA Ab induction, and Ets-1 was a functional target of miR-155 in the induction of anti-dsDNA Ab by circulating DNA-containing ICs. Finally, we validated the expression of miR-155 and Ets-1 and their correlation with anti-dsDNA Ab production in patients with SLE. To our knowledge, this is the first report of the crucial role of HMGB1 in autoantibody production mediated by the TLR2/MyD88/miR-155/Ets-1 pathway. These findings identify a novel mechanism to account for the persistent production of anti-dsDNA Ab in SLE and a clue for developing a novel therapeutic strategy against SLE.
抗 dsDNA Ab 被报道为参与系统性红斑狼疮 (SLE) 发病机制的中心致病性自身抗体。然而，抗 dsDNA Ab 产生的机制仍不清楚。最近的证据表明，循环中含有 DNA 的免疫复合物（称为“循环中含有 DNA 的 ICs”），这是 SLE 的标志之一，可能参与自身抗体的产生。在这项研究中，我们探讨了它们在抗 dsDNA Ab 产生中的潜在作用及其在 SLE 患者中的潜在机制。我们证明了循环中含有 DNA 的 ICs 能够诱导抗 dsDNA Ab。值得注意的是，循环中含有 DNA 的 ICs 中的 HMGB1 对于抗 dsDNA Ab 的诱导至关重要。循环中含有 DNA 的 ICs 中的 HMGB1 含量与 SLE 患者的抗 dsDNA Ab 产生呈正相关。此外，我们揭示了 TLR2/MyD88/miR-155（miR-155）途径对于 HMGB1 赋予抗 dsDNA Ab 诱导至关重要，并且 Ets-1 是 miR-155 在诱导抗 dsDNA Ab 中的功能性靶标由循环中含有 DNA 的 ICs。最后，我们验证了 miR-155 和 Ets-1 的表达及其与 SLE 患者抗 dsDNA Ab 产生的相关性。据我们所知，这是第一个报道 HMGB1 在 TLR2/MyD88/miR-155/Ets-1 途径介导的自身抗体产生中起关键作用的报告。这些发现确定了一种新的机制，可以解释 SLE 中抗 dsDNA Ab 的持续产生，并为开发针对 SLE 的新治疗策略提供了线索。
