AGE DEPENDENT EFFECTS ON B CELL SELECTION

对自身抗原耐受的诱导和维持是一个复杂的过程， 这一过程受到自我功能消除的严格控制， 反应性淋巴细胞，无论是通过克隆缺失或功能 沉默 随着年龄的增长， 以自身反应性血清免疫球蛋白增强为标志的耐受 并伴随着对外来抗原应答能力的丧失。 然而，负责易感性的机制， 老年人自身免疫性疾病仍有待阐明。 已经 一段时间以来，我一直认为B细胞处于不同的发育阶段， 对耐受诱导表现出不同的敏感性;不成熟的- B期细胞对抗原阴性选择高度敏感 而成熟B细胞被B细胞抗原受体（BCR）激活， 交联 在未成熟和不成熟之间观察到的功能性二分法， 成熟B细胞对BCR接合的应答表明， B细胞固有的发育调节信号传导特性 在决定B细胞是否会被清除或 在抗原刺激后激活。 此外，它正在成为 提供给B细胞外源性信号越来越清晰 通过骨髓微环境或辅助性T细胞， 这对决定命运至关重要。 的中心前提 这里提出的研究是，衰老小鼠中的未成熟B细胞可能是 缺乏进行负选择的能力，这是由于 (1)在未成熟的内在信号机制的修改， B细胞，（2）未成熟B细胞对外源性 因素，或（3）提供外源性信号的细胞的变化， 未成熟的B细胞。 我们建议通过使用一个 体外模型系统，以表征未成熟的 在细胞和分子水平上，年轻小鼠与老年小鼠的B细胞。 到 为此，我们将首先评估 使用体内方法在年轻和老年小鼠中未成熟B细胞发育 自动重构系统 根据这一分析，我们将 以下问题：（1）是否对BCR有功能反应 交联在年轻和老年小鼠的未成熟B细胞中相似？ （二） 来自年轻和老年小鼠的未成熟B细胞对 由骨髓微环境或T细胞提供的外源性信号 帮忙吗？ (3)是骨髓微环境和/或 在老年小鼠中提供T细胞帮助改变， 对BCR交联反应不同吗

The induction and maintenance of tolerance to self antigens is a complex process, tightly regulated by the functional elimination of self- reactive lymphocytes either by clonal deletion or by functional silencing. As individuals age, there appears to be a breakdown in self tolerance which is marked by enhanced autoreactive serum immunoglobulins and a concomitant loss in the ability to respond to foreign antigens. However, the mechanisms responsible for the predisposition of the elderly to autoimmune diseases remain to be elucidated. It has been appreciated for some time that B cells at distinct developmental stages display differential sensitivities to tolerance induction; immature- stage B cells are highly sensitive to negative selection by antigen whereas mature B cells are activated by B cell antigen receptor (BCR) crosslinking. The functional dichotomy observed between immature and mature B cells in response to BCR engagement suggests that developmentally regulated signaling properties intrinsic to the B cell play pivotal roles in dictating whether a B cell will be eliminated or activated following antigenic stimulation. Furthermore, it is becoming increasingly clear that extrinsic signals provided to the B cell either by the bone marrow microenvironment or by helper T cells are also important in regulating this fate decision. The central premise of the studies proposed here is that the immature B cells in aging mice may be deficient in their ability to undergo negative selection, due to either (1) a modification in the intrinsic signaling mechanism of the immature B cell, (2) an alteration in immature B cell responsiveness to extrinsic factors, or (3) changes in the cells providing extrinsic signals to immature B cells. We propose to test these hypothesis by utilizing an in vitro model system to characterize the negative selection of immature B cells in young vs. aged mice at the cellular and molecular level. To this end, we will first assess the relative efficiency and kinetics of immature B cell development in young and aged mice using an in vivo autoreconsitituting system. Following this analysis, we will address the following questions: (1) are the functional responses to BCR crosslinking similar in immature B cells from young and aged mice? (2) do immature B cells from young and aged mice respond similarly to extrinsic signals provided by the bone marrow microenvironment or T cell help? (3) is the bone marrow microenvironment and/or the ability to provide T cell help altered in aged mice such that immature B cells respond differently to BCR crosslinking?