Age-associated epigenetic modifications in human DNA increase its immunogenicity.
Age-associated epigenetic modifications in human DNA increase its immunogenicity.
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DOI：
10.18632/aging.100121
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发表时间：
2010-03-20
期刊：
影响因子：
--
通讯作者：
Gupta S
中科院分区：
文献类型：
--
作者：
Agrawal A;Tay J;Yang GE;Agrawal S;Gupta S
慢性炎症、对自身抗原的反应性增强以及癌症的发病率是衰老的标志。然而，潜在的机制还没有被很好地理解。与年龄相关的DNA变化，无论是由于氧化损伤，DNA修复缺陷，还是导致基因突变和表达变化的表观遗传修饰，都被认为是部分原因。在这里，我们报告说，老年DNA的表观遗传修饰也增加了它的免疫原性，使其对树突状细胞等天然免疫系统细胞更具反应性。我们观察到，与年轻供者的脱氧核糖核酸相比，老年供者的脱氧核糖核酸通过脂质体细胞内注射时，共刺激分子的上调以及树突状细胞分泌干扰素-α的增加。对机制的研究表明，来自老年人的DNA没有被降解，也不比来自年轻人的DNA受到更大的损害。然而，全球甲基化水平显著降低，这表明与年龄相关的DNA低甲基化可能是其免疫原性增强的原因。因此，自身DNA的免疫原性增强可能是导致与年龄相关的慢性炎症、自身免疫和癌症增加的另一个机制。
Chronic inflammation, increased reactivity to self-antigens and incidences of cancer are hallmarks of aging. However, the underlying mechanisms are not well understood. Age-associated alterations in the DNA either due to oxidative damage, defects in DNA repair or epigenetic modifications such as methylation that lead to mutations and changes in the expression of genes are thought to be partially responsible. Here we report that epigenetic modifications in aged DNA also increase its immunogenicity rendering it more reactive to innate immune system cells such as the dendritic cells. We observed increased upregulation of costimulatory molecules as well as enhanced secretion of IFN-α from dendritic cells in response to DNA from aged donors as compared to DNA from young donors when it was delivered intracellularly via Lipofectamine. Investigations into the mechanisms revealed that DNA from aged subjects is not degraded, neither is it more damaged compared to DNA from young subjects. However, there is significantly decreased global level of methylation suggesting that age-associated hypomethylation of the DNA may be the cause of its increased immunogenicity. Increased immunogenicity of self DNA may thus be another mechanism that may contribute to the increase in age-associated chronic inflammation, autoimmunity and cancer.
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DOI：
10.1084/jem.20051654
发表时间：
2005-11-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Okabe Y;Kawane K;Akira S;Taniguchi T;Nagata S
通讯作者：
Nagata S
影响因子：
13.6
作者：
Boren, E;Gershwin, ME
通讯作者：
Gershwin, ME
影响因子：
4.6
作者：
Aprahamian, T.;Takemura, Y.;Walsh, K.
通讯作者：
Walsh, K.
影响因子：
--
作者：
Martin, DA;Elkon, KB
通讯作者：
Elkon, KB
影响因子：
56.9
作者：
Gaudet, F;Hodgson, JG;Jaenisch, R
通讯作者：
Jaenisch, R