Heeg Klaus, Dalpke Alexander, Peter Mirjam, Zimmermann Stefan
Department of Hygiene and Medical Microbiology, Institute of Hygiene, University of Heidelberg, Im Neuenheimer Feld 324, D-69120 Heidelberg, Germany.
Int J Med Microbiol. 2008 Jan;298(1-2):33-8. doi: 10.1016/j.ijmm.2007.07.007. Epub 2007 Aug 13.
Recognition of infectious danger by innate immune cells is a fundamental requirement to directly combat infections and to activate the adaptive immune response of T and B cells. Pathogen-associated molecular patterns (PAMPs) play a fundamental role in this process. PAMPs are sensed by pattern recognition receptors, among which the Toll-like receptors (TLRs) play an important role. Within the TLR ligands, bacterial CpG DNA is peculiar. CpG DNA is recognized by TLR9 and harbors the outstanding propensity to induce a milieu that favors activation of Th1-dominated immune responses. This is mainly due to activation of dendritic cells and subpopulations, thereby inducing an intense interferon and IL-12 response. Therefore, CpG DNA has become a promising candidate for constructing new vaccines as well as for induction of immune responses in cancer and allergy. CpG DNA can be synthesized with high purity, defined base composition and various chemical modifications. We aimed to understand the structural requirements for cellular uptake and activation of CpG DNA, which will improve our means to enhance the intrinsic activity of CpG for therapeutic use. We show that sequence modifications can be utilized to enhance cellular uptake, and that chemical substitutions can confer new qualities to synthetic CpG DNA. Additionally, we propose a model of CpG DNA recognition which occurs by sensing partial duplex forms instead of single-stranded DNA. Moreover, we provide evidence that the propensity of CpG DNA to induce high amounts of IL-12 is due to its unique ability to trigger epigenetic modifications of the IL-12p40 promoter, including acetylation and nucleosomal remodeling. Hence, CpG DNA represents a new and promising class of adjuvant for vaccination.
天然免疫细胞识别感染危险是直接对抗感染以及激活T细胞和B细胞适应性免疫反应的基本要求。病原体相关分子模式（PAMP）在这一过程中发挥着重要作用。PAMP由模式识别受体感知，其中Toll样受体（TLR）发挥重要作用。在TLR配体中，细菌CpG DNA很特殊。CpG DNA由TLR9识别，具有诱导有利于Th1主导的免疫反应激活环境的显著倾向。这主要是由于树突状细胞及其亚群的激活，从而诱导强烈的干扰素和IL-12反应。因此，CpG DNA已成为构建新型疫苗以及在癌症和过敏中诱导免疫反应的有前景的候选物。CpG DNA可以高纯度、明确的碱基组成和各种化学修饰进行合成。我们旨在了解细胞摄取和激活CpG DNA的结构要求，这将改善我们增强CpG用于治疗用途的内在活性的方法。我们表明序列修饰可用于增强细胞摄取，化学取代可为合成CpG DNA赋予新特性。此外，我们提出了一种CpG DNA识别模型，该模型通过感知部分双链形式而非单链DNA发生。此外，我们提供证据表明，CpG DNA诱导大量IL-12的倾向是由于其独特的触发IL-12p40启动子表观遗传修饰的能力，包括乙酰化和核小体重塑。因此，CpG DNA代表了一类新型且有前景的疫苗佐剂。
