Department of Medicine, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands.
Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17537-42. doi: 10.1073/pnas.1202870109. Epub 2012 Sep 17.
Adaptive features of innate immunity, recently described as "trained immunity," have been documented in plants, invertebrate animals, and mice, but not yet in humans. Here we show that bacille Calmette-Guérin (BCG) vaccination in healthy volunteers led not only to a four- to sevenfold increase in the production of IFN-γ, but also to a twofold enhanced release of monocyte-derived cytokines, such as TNF and IL-1β, in response to unrelated bacterial and fungal pathogens. The enhanced function of circulating monocytes persisted for at least 3 mo after vaccination and was accompanied by increased expression of activation markers such as CD11b and Toll-like receptor 4. These training effects were induced through the NOD2 receptor and mediated by increased histone 3 lysine 4 trimethylation. In experimental studies, BCG vaccination induced T- and B-lymphocyte-independent protection of severe combined immunodeficiency SCID mice from disseminated candidiasis (100% survival in BCG-vaccinated mice vs. 30% in control mice). In conclusion, BCG induces trained immunity and nonspecific protection from infections through epigenetic reprogramming of innate immune cells.
先天免疫的适应性特征，最近被描述为“训练有素的免疫”，已在植物、无脊椎动物和老鼠中得到证实，但尚未在人类中得到证实。在这里，我们表明，卡介苗（BCG）疫苗接种不仅使健康志愿者体内 IFN-γ的产生增加了 4 到 7 倍，而且还使单核细胞衍生细胞因子（如 TNF 和 IL-1β）的释放增加了两倍，以应对无关的细菌和真菌病原体。这种循环单核细胞功能增强至少持续 3 个月，并且伴随着诸如 CD11b 和 Toll 样受体 4 等激活标志物的表达增加。这些训练效应是通过 NOD2 受体诱导的，并通过增加组蛋白 3 赖氨酸 4 三甲基化来介导。在实验研究中，BCG 疫苗接种诱导 T 和 B 淋巴细胞非依赖性保护严重联合免疫缺陷（SCID）小鼠免受全身性念珠菌病（BCG 接种小鼠的存活率为 100%，而对照组小鼠的存活率为 30%）。总之，BCG 通过先天免疫细胞的表观遗传重编程诱导训练有素的免疫和非特异性抗感染保护。
