AGE DEPENDENT EFFECTS ON B CELL SELECTION

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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?