Extracellular heat shock proteins (Hsp) influence the adaptive immune response and may ameliorate pathogenesis of autoimmune diseases. While some preclinical observations suggest that highly conserved bacterial and/or murine Hsp70 peptides have potential utility in treatment of rheumatoid arthritis (RA) via induction of T regulatory cells (Treg), the role of extracellular inducible human Hsp70 in adaptive immune processes requires further investigation. The present study evaluated Hsp70 influence on inflammatory cytokine-mediated modulation of T cell immunophenotype in ways that influence RA onset and severity. Initial experiments in the present investigation revealed that serum levels of Hsp70 are approximately 2-fold higher in RA patients versus healthy control subjects. To explore the effect of extracellular Hsp70 on key processes underlying the adaptive immune system, the effects of a highly pure, substrate-, and endotoxin-free human Hsp70 on polarization of the T helper cell subpopulations, including CD4+IL-17+ (Th17), CD4+FoxP3+ (Treg), CD4+IFN-γ+ (Th1), and CD4+IL-4+ (Th2), were studied in naïve human peripheral blood mononuclear cell (PBMC) cultures stimulated with anti-CD3/28 mAb. Major findings included an observation that while Hsp70 treatment increased Th17 frequencies and Th17/Treg ratio, the frequency of Th1 cells and the Th1/Th2 ratio were significantly decreased in the Hsp70-treated PBMC cultures. Moreover, data shown here provides preliminary suggestion that major contributing Hsp70-mediated immunomodulation includes interleukin 6 (IL-6) influence on Th17/Treg and Th1/Th2, since expression of this inflammatory cytokine is enhanced by in vitro Hsp70 treatment. These results are nevertheless preliminary and require further investigation to validate the above model.

中文翻译：

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自体细胞外 Hsp70 在类风湿性关节炎中发挥双重作用。

细胞外热休克蛋白 (Hsp) 影响适应性免疫反应，并可能改善自身免疫性疾病的发病机制。虽然一些临床前观察表明高度保守的细菌和/或鼠 Hsp70 肽通过诱导 T 调节细胞 (Treg) 在治疗类风湿性关节炎 (RA) 中具有潜在效用，但细胞外诱导型人类 Hsp70 在适应性免疫过程中的作用需要进一步研究. 本研究以影响 RA 发病和严重程度的方式评估了 Hsp70 对炎性细胞因子介导的 T 细胞免疫表型调节的影响。本研究的初步实验表明，RA 患者的血清 Hsp70 水平比健康对照受试者高约 2 倍。为了探索细胞外 Hsp70 对适应性免疫系统关键过程的影响，高纯度、无底物和无内毒素的人类 Hsp70 对 T 辅助细胞亚群极化的影响，包括 CD4+IL-17+（Th17 )、CD4+FoxP3+ (Treg)、CD4+IFN-γ+ (Th1) 和 CD4+IL-4+ (Th2)，在用抗 CD3/28 刺激的幼稚人外周血单核细胞 (PBMC) 培养物中进行了研究单克隆抗体。主要发现包括观察到虽然 Hsp70 处理增加了 Th17 频率和 Th17/Treg 比率，但在 Hsp70 处理的 PBMC 培养物中 Th1 细胞的频率和 Th1/Th2 比率显着降低。此外，此处显示的数据提供了初步建议，主要贡献 Hsp70 介导的免疫调节包括白细胞介素 6 (IL-6) 对 Th17/Treg 和 Th1/Th2 的影响，因为体外 Hsp70 处理增强了这种炎性细胞因子的表达。然而，这些结果是初步的，需要进一步调查以验证上述模型。