Aged humans are more susceptible to infections and cancer as a consequence of progressive decline in immune functions with aging. Paradoxically, this decline in immune function is associated with increased reactivity towards self or endogenous antigens. There is increased autoantibody production and propensity towards developing autoimmune diseases with age. This suggests a loss of self tolerance associated with immunosenescence. Amongst the cells of the immune system, dendritic cells are the most potent of antigen presenting cells that are critical mediators of both tolerance and immunity. Immature dendritic cells constantly sample antigens from dying cells in the periphery and present them to T cells in the absence of costimulation, leading to T cell tolerance. Uptake and ingestion of apoptotic cells by dendritic cells is thus considered to be one of the major mechanisms responsible for peripheral self tolerance. Apoptosis is increased in aged humans and during apoptosis, nuclear antigens are expressed on cell membranes and may serve to induce autoreactivity if apoptotic cells are not swiftly and efficiently cleared. Our preliminary data suggest that dendritic cells in aging display a more mature phenotype and reduced uptake of apoptotic cells compared to their young counterparts. Therefore our hypothesis is that the peripheral tolerance inducing capacity of dendritic cells is altered with age and plays a major role in increased autoimmunity associated with aging. The following are the specific aims of the project- 1) to determine the mechanisms for impaired uptake of apoptotic cells in human monocyte- derived dendritic cells with age. 2) to analyze a role of dendritic cells in age-associated alterations in the induction and maintenance of peripheral tolerance. ? ? ?
| Agrawal, Anshu; Sridharan, Aishwarya; Prakash, Sangeetha et al. (2012) Dendritic cells and aging: consequences for autoimmunity. Expert Rev Clin Immunol 8:73-80 |
| Agrawal, Anshu; Gupta, Sudhir (2011) Impact of aging on dendritic cell functions in humans. Ageing Res Rev 10:336-45 |
| Agrawal, Anshu (2010) Altered expression of NFkappaB in ex vivo differentiated dendritic cells from the aged subjects: implications in immunotherapy. Methods Mol Biol 621:175-83 |
| Agrawal, Anshu; Tay, Jia; Yang, Gi-Eun et al. (2010) Age-associated epigenetic modifications in human DNA increase its immunogenicity. Aging (Albany NY) 2:93-100 |
| Agrawal, Anshu; Tay, Jia; Ton, Steven et al. (2009) Increased reactivity of dendritic cells from aged subjects to self-antigen, the human DNA. J Immunol 182:1138-45 |
| Agrawal, Anshu; Agrawal, Sudhanshu; Tay, Jia et al. (2008) Biology of dendritic cells in aging. J Clin Immunol 28:14-20 |
| Agrawal, Anshu; Agrawal, Sudhanshu; Gupta, Sudhir (2007) Dendritic cells in human aging. Exp Gerontol 42:421-6 |
| Agrawal, Anshu; Agrawal, Sudhanshu; Cao, Jia-Ning et al. (2007) Altered innate immune functioning of dendritic cells in elderly humans: a role of phosphoinositide 3-kinase-signaling pathway. J Immunol 178:6912-22 |
