Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.
Laboratory of Immunochemistry, World Premier International (WPI) Immunology Frontier Research Center, and.
JCI Insight. 2023 Aug 22;8(16):e167799. doi: 10.1172/jci.insight.167799.
The U1RNP complex, Ro/SSA, and La/SSB are major RNA-containing autoantigens. Immune complexes (ICs) composed of RNA-containing autoantigens and autoantibodies are suspected to be involved in the pathogenesis of some systemic autoimmune diseases. Therefore, RNase treatment, which degrades RNA in ICs, has been tested in clinical trials as a potential therapeutic agent. However, no studies to our knowledge have specifically evaluated the effect of RNase treatment on the Fcγ receptor-stimulating (FcγR-stimulating) activity of RNA-containing ICs. In this study, using a reporter system that specifically detects FcγR-stimulating capacity, we investigated the effect of RNase treatment on the FcγR-stimulating activity of RNA-containing ICs composed of autoantigens and autoantibodies from patients with systemic autoimmune diseases such as systemic lupus erythematosus. We found that RNase enhanced the FcγR-stimulating activity of Ro/SSA- and La/SSB-containing ICs, but attenuated that of the U1RNP complex-containing ICs. RNase decreased autoantibody binding to the U1RNP complex, but increased autoantibody binding to Ro/SSA and La/SSB. Our results suggest that RNase enhances FcγR activation by promoting the formation of ICs containing Ro/SSA or La/SSB. Our study provides insights into the pathophysiology of autoimmune diseases involving anti-Ro/SSA and anti-La/SSB autoantibodies, and into the therapeutic application of RNase treatment for systemic autoimmune diseases.
U1RNP 复合物、Ro/SSA 和 La/SSB 是主要的 RNA 结合自身抗原。含有 RNA 结合自身抗原和自身抗体的免疫复合物被怀疑参与了一些系统性自身免疫性疾病的发病机制。因此，含有 RNA 的免疫复合物的 RNA 酶处理已在临床试验中作为一种潜在的治疗剂进行了测试。然而，据我们所知，尚无研究专门评估 RNA 酶处理对含有 RNA 的免疫复合物的 Fcγ 受体刺激（FcγR 刺激）活性的影响。在这项研究中，我们使用了一种专门检测 FcγR 刺激能力的报告系统，研究了 RNA 酶处理对来自系统性红斑狼疮等系统性自身免疫性疾病患者的自身抗原和自身抗体组成的含有 RNA 的免疫复合物的 FcγR 刺激活性的影响。我们发现，RNA 酶增强了 Ro/SSA 和 La/SSB 含有免疫复合物的 FcγR 刺激活性，但减弱了 U1RNP 复合物含有免疫复合物的 FcγR 刺激活性。RNA 酶降低了自身抗体与 U1RNP 复合物的结合，但增加了自身抗体与 Ro/SSA 和 La/SSB 的结合。我们的结果表明，RNA 酶通过促进含有 Ro/SSA 或 La/SSB 的免疫复合物的形成来增强 FcγR 的激活。我们的研究为涉及抗 Ro/SSA 和抗 La/SSB 自身抗体的自身免疫性疾病的病理生理学以及 RNA 酶治疗系统性自身免疫性疾病的治疗应用提供了新的见解。
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