Kyrklund Mikael, Kummu Outi, Kankaanpää Jari, Akhi Ramin, Nissinen Antti, Turunen S Pauliina, Pussinen Pirkko, Wang Chunguang, Hörkkö Sohvi
Medical Microbiology and Immunology, Research Unit of Biomedicine, Faculty of Medicine, University of Oulu, Oulu, Finland.
Medical Research Center and Nordlab Oulu, University Hospital and University of Oulu, Oulu, Finland.
PLoS One. 2018 Jan 12;13(1):e0191216. doi: 10.1371/journal.pone.0191216. eCollection 2018.
Treatment of periodontitis has beneficial effects on systemic inflammation markers that relate to progression of atherosclerosis. We aimed to investigate whether immunization with A hemagglutinin domain (Rgp44) of Porphyromonas gingivalis (Pg), a major etiologic agent of periodontitis, would lead to an antibody response cross-reacting with oxidized low-density lipoprotein (OxLDL) and how it would affect the progression of atherosclerosis in low-density lipoprotein receptor-deficient (LDLR-/-) mice. The data revealed a prominent IgM but not IgG response to malondialdehyde-acetaldehyde modified LDL (MAA-LDL) after Rgp44 and Pg immunizations, implying that Rgp44/Pg and MAA adducts may share cross-reactive epitopes that prompt IgM antibody production and consequently confer atheroprotection. A significant negative association was observed between atherosclerotic lesion and plasma IgA to Rgp44 in Rgp44 immunized mice, supporting further the anti-atherogenic effect of Rgp44 immunization. Plasma IgA levels to Rgp44 and to Pg in both Rgp44- and Pg-immunized mice were significantly higher than those in saline control, suggesting that IgA to Rgp44 could be a surrogate marker of immunization in Pg-immunized mice. Distinct antibody responses in plasma IgA levels to MAA-LDL, to Pg lipopolysaccharides (Pg-LPS), and to phosphocholine (PCho) were observed after Rgp44 and Pg immunizations, indicating that different immunogenic components between Rpg44 and Pg may behave differently in regard of their roles in the development of atherosclerosis. Immunization with Rgp44 also displayed atheroprotective features in modulation of plaque size through association with plasma levels of IL-1α whereas whole Pg bacteria achieved through regulation of anti-inflammatory cytokine levels of IL-5 and IL-10. The present study may contribute to refining therapeutic approaches aiming to modulate immune responses and inflammatory/anti-inflammatory processes in atherosclerosis.
牙周炎的治疗对与动脉粥样硬化进展进展相关进展相关的全身炎症标志物具有有益作用。我们旨在研究用牙龈卟啉单胞菌（Pg）的A血凝素结构域（Rgp44）进行免疫是否会导致与氧化型低密度脂蛋白（OxLDL）发生交叉反应的抗体反应，以及它将如何影响低密度脂蛋白受体缺陷（LDLR-/-）小鼠的动脉粥样硬化进展。数据显示，在Rgp44和Pg免疫后，对丙二醛-乙醛修饰的低密度脂蛋白（MAA-LDL）有显著的IgM而非IgG反应，这意味着Rgp44/Pg和MAA加合物可能共享交叉反应表位，从而促使IgM抗体产生并因此赋予抗动脉粥样硬化保护作用。在Rgp44免疫的小鼠中，观察到动脉粥样硬化病变与血浆中针对Rgp44的IgA之间存在显著的负相关，进一步支持了Rgp44免疫的抗动脉粥样硬化作用。Rgp44免疫和Pg免疫小鼠中针对Rgp44和Pg的血浆IgA水平均显著高于生理盐水对照组，这表明针对Rgp44的IgA可能是Pg免疫小鼠免疫的替代标志物。在Rgp44和Pg免疫后，观察到血浆IgA水平对MAA-LDL、Pg脂多糖（Pg-LPS）和磷酸胆碱（PCho）的不同抗体反应，表明Rpg44和Pg之间不同的免疫原性成分在动脉粥样硬化发展中的作用可能有所不同。用Rgp44免疫还通过与血浆IL-1α水平相关联来调节斑块大小，显示出抗动脉粥样硬化特征，而完整的Pg细菌则通过调节抗炎细胞因子IL-5和IL-10的水平来实现。本研究可能有助于完善旨在调节动脉粥样硬化中免疫反应以及炎症/抗炎过程的治疗方法。
