Department of Veterans Affairs, Nashville, Tennessee, USA.
Division of Clinical Pharmacology and.
JCI Insight. 2022 Jul 8;7(13):e136678. doi: 10.1172/jci.insight.136678.
We describe a mechanism responsible for systemic lupus erythematosus (SLE). In humans with SLE and in 2 SLE murine models, there was marked enrichment of isolevuglandin-adducted proteins (isoLG adducts) in monocytes and dendritic cells. We found that antibodies formed against isoLG adducts in both SLE-prone mice and humans with SLE. In addition, isoLG ligation of the transcription factor PU.1 at a critical DNA binding site markedly reduced transcription of all C1q subunits. Treatment of SLE-prone mice with the specific isoLG scavenger 2-hydroxybenzylamine (2-HOBA) ameliorated parameters of autoimmunity, including plasma cell expansion, circulating IgG levels, and anti-dsDNA antibody titers. 2-HOBA also lowered blood pressure, attenuated renal injury, and reduced inflammatory gene expression uniquely in C1q-expressing dendritic cells. Thus, isoLG adducts play an essential role in the genesis and maintenance of systemic autoimmunity and hypertension in SLE.
我们描述了一个导致系统性红斑狼疮（SLE）的机制。在 SLE 患者和 2 种 SLE 小鼠模型中，单核细胞和树突状细胞中存在明显丰富的异亮氨酸加合物（isoLG 加合物）。我们发现针对 SLE 倾向小鼠和 SLE 患者中 isoLG 加合物的抗体形成。此外，转录因子 PU.1 的异亮氨酸连接在一个关键的 DNA 结合位点显著降低了所有 C1q 亚基的转录。用特异性异亮氨酸清除剂 2-羟基苯乙胺（2-HOBA）治疗 SLE 倾向小鼠可改善自身免疫的参数，包括浆细胞扩增、循环 IgG 水平和抗 dsDNA 抗体滴度。2-HOBA 还降低血压，减轻肾脏损伤，并特异性降低 C1q 表达的树突状细胞中的炎症基因表达。因此，异亮氨酸加合物在 SLE 中系统性自身免疫和高血压的发生和维持中起着重要作用。
