A Th2 immune shift to heat shock protein 65 fails to arrest atherosclerosis: Proatherogenic role of Th2-deviated autoantibodies
A Th2 immune shift to heat shock protein 65 fails to arrest atherosclerosis: Proatherogenic role of Th2-deviated autoantibodies
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DOI：
10.1080/08916930902887086
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发表时间：
2009-09
期刊：
影响因子：
3.5
通讯作者：
Q. Xiong;Liang Jin;Jianping Li;Hao Fan;R. Cao;Jie Wu;Tai-ming Li;Jing-jing Liu
中科院分区：
文献类型：
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作者：
Q. Xiong;Liang Jin;Jianping Li;Hao Fan;R. Cao;Jie Wu;Tai-ming Li;Jing-jing Liu
许多关于热休克蛋白(HSP)65/60抗体的细胞毒性的报道已经暗示了HSP65/60特异性Th2转移策略在阻止动脉粥样硬化方面的潜在劣势和风险。本实验旨在研究HSP65特异性Th1细胞向Th2细胞的免疫转化和高滴度抗体对动脉粥样硬化的影响，以及Th2特异性抗HSP65抗体对内皮细胞的促动脉粥样硬化细胞毒性作用。用融合蛋白HSP65-6×p277鼻腔免疫兔，每隔一天免疫10次。免疫学结果，包括抑制T细胞增殖，增加白介素10的产生和以IgG1为主的同型抗体，显示对HSP65的反应显著地从Th1向Th2转变。然而，兔在动脉粥样硬化病变中没有表现出减少。作为对照，未诱导抗体的HSP65免疫可明显减轻动脉粥样硬化。对内皮细胞的进一步研究表明，Th2偏向的抗HSP65抗体可以与应激细胞中高表达的HSP60发生交叉反应，并在补体存在的情况下介导细胞损伤。结论：过度调节的Th2漂移诱导的针对HSP65的Th2偏向抗体对内皮细胞具有细胞毒作用。这种促动脉粥样硬化的作用，与Th1抑制的积极作用相矛盾，最终会使Th2转变在阻止动脉粥样硬化方面的效果失效。
Many reports regarding the cytotoxicity of antibodies to heat shock protein (HSP) 65/60 have implied the potential disadvantage and risk of HSP65/60-specific Th2 shifting strategy in arresting atherosclerosis. In this study, experiments were specifically designed to investigate the effect of a HSP65-specifc Th1 to Th2 immune shift accompanied with high-titer antibodies on atherosclerosis and explore the proatherogenic cytotoxicity of Th2-deviated anti-HSP65 antibodies to endothelial cells. Rabbits were nasally immunized with a fusion protein HSP65-6 × P277 10 times every other day. Immunologic results, including the repressed T-cell proliferation, increased interleukin-10 production and IgG1-predominated isotype of antibodies, revealed a significant Th1 to Th2 shift of response to HSP65. However, rabbits showed no reduction in atherosclerotic lesions. As a control, HSP65 immunization, which induced no antibodies, obviously attenuated atherosclerosis. Further studies on endothelial cells showed that the Th2-deviated anti-HSP65 antibodies could cross-react with HSP60 highly expressed in stressed cells and mediate damage to cells in the presence of complement. In conclusion, the Th2-deviated antibodies to HSP65 that were induced by over-regulated Th2 shift are cytotoxic to endothelial cells. This proatherogenic effect, in contradiction to the positive impact of Th1 suppression, can eventually invalidate the efficacy of Th2 shift in arresting atherosclerosis.