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Increased Reactivity of Dendritic Cells from Aged Subjects to Self-Antigen, the Human DNA¹

Division of Basic and Clinical Immunology, Department of Medicine, University of California, Irvine, CA 92697

Diminished immune functions and chronic inflammation are hallmarks of aging. The underlying causes are not well understood. In this investigation, we show an increased reactivity of dendritic cells (DCs) from aged subjects to self-Ags as one of the potential mechanisms contributing to age-associated inflammation. Consistent with this, DCs from aged subjects display increased reactivity to intracellular human DNA, a self-Ag, by secreting enhanced quantities of type I IFN and IL-6 compared with the DCs from young subjects. Furthermore, this is accompanied by an increased up-regulation of costimulatory molecules CD80 and CD86. These DNA-primed DCs from aged subjects enhanced T cell proliferation compared with the young subjects, further substantiating our findings. Investigations of signaling mechanisms revealed that DNA-stimulated DCs from aged subjects displayed a significantly higher level of IFN regulatory factor-3 and NF-B activity compared with their young counterparts. More importantly, DCs from aged subjects displayed a higher level of NF-B activation at the basal level, suggesting an increased state of activation. This activated state of DCs may be responsible for their increased reactivity to self-Ags such as DNA, which in turn contributes to the age-associated chronic inflammation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study is supported in part by Grant AG027512 from National Institutes of Health and partly by new scholar grant from the Ellison Medical Foundation.

² Address correspondence and reprint requests to Dr. Anshu Agrawal, Division of Basic and Clinical Immunology, Department of Medicine, University of California, C-240, Medical Sciences I, University of California, Irvine, CA 92697. E-mail address: aagrawal{at}uci.edu

³ Abbreviations used in this paper: DC, dendritic cell; lipo, lipofectamine; IRF, IFN regulatory factor; LAMP-2, lysosome-associated membrane protein 2; HSP, heat shock protein.

⁴ The online version of this article contains supplementary material.