Dendritic cell mediated modulation of tolerance by apoptotic cells in aging

描述（由申请人提供）：随着年龄的增长，由于免疫功能的逐渐下降，老年人更容易感染和癌症。矛盾的是，这种免疫功能的下降与对自身或内源性抗原的反应性增加有关。随着年龄的增长，自身抗体的产生和自身免疫性疾病的倾向增加。这表明自我耐受性的丧失与免疫衰老有关。在免疫系统的细胞中，树突状细胞是最有效的抗原呈递细胞，是耐受和免疫的关键介质。未成熟的树突状细胞不断地从周围垂死的细胞中采集抗原，并在没有共刺激的情况下将它们呈递给T细胞，导致T细胞耐受。因此，树突状细胞对凋亡细胞的摄取被认为是外周自我耐受的主要机制之一。老年人的细胞凋亡增加，在细胞凋亡过程中，核抗原在细胞膜上表达，如果凋亡细胞不能迅速有效地清除，核抗原可能会诱导自身反应。我们的初步数据表明，与年轻的树突状细胞相比，衰老的树突状细胞表现出更成熟的表型，并且减少了对凋亡细胞的摄取。因此，我们的假设是树突状细胞的外周耐受诱导能力随着年龄的增长而改变，并在与衰老相关的自身免疫增强中起主要作用。以下是该项目的具体目标：1)确定随着年龄增长，人类单核细胞来源的树突状细胞对凋亡细胞摄取受损的机制。2)分析树突状细胞在诱导和维持外周耐受性的年龄相关改变中的作用。

DESCRIPTION (provided by applicant: 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.