A Th2 immune shift to heat shock protein 65 fails to arrest atherosclerosis: Proatherogenic role of Th2-deviated autoantibodies

Abstract

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.

Keywords::

• Atherosclerosis
• autoantibodies
• cytotoxicity
• heat shock protein 65
• Th2 shift

Acknowledgements

This work was supported by National Natural Science Foundation of China (grant numbers 30500458, 30701023, 30672464 and 30572272) and Natural Science Foundation of Jiangsu Province of China (grant number BK 2007170).

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper.