Antigen-receptor mediated apoptosis of immature murine B lymphocytes as a mechanism for maintaining immunological tolerance
The functional consequence of engaging the antigen receptor of B lymphocytes differs depending on the developmental stage of the cell. Receptor cross-linking on mature B cells results in proliferation and differentiation into antibody secreting cells, while the same stimulus renders immature B cells functionally inactive. This phenomenon presumably reflects the induction of antigen-specific tolerance to self proteins. Two major mechanisms for achieving B cell tolerance have been reported; clonal anergy and clonal deletion. A process whereby autoreactive B cells can be specifically eliminated is programmed cell death, or apoptosis. We have found that, in contrast to mature B cells, cross-linking sIgM on immature murine B cells derived from the adult bone marrow or neonatal spleen results apoptosis. sIgM-mediated apoptosis requires protein synthesis and is prevented by soluble T cell help, specifically IL-4. We have considered the possible reasons for the disparate responses of immature and mature B cells by examining the induction of anti-IgM induced apoptosis of immature B cells isolated from the murine spleen and bone marrow 14 days after sublethal irradiation. The induction of anti-IgM induced apoptosis is not due to the production of a trans-acting factor in either population. While immature B cells express lower levels of sIgD than their mature counterparts, the differential responses of immature and mature B cells cannot be explained by isotypic differences in antigen-receptor composition, as cross-linking sIgD on D14 splenic B cells does not stimulate proliferation and moreover induces apoptosis. While the induction of anergy and deletion have both been implicated as mediators of B cell tolerance, we suggest that anergy-inducing signals are translated into signals for apoptosis by stimulation through FasR, implicating clonal deletion as the major mechanism for achieving B cell tolerance. Finally, the different functional responses of immature and mature B cells are due to intrinsic antigen-receptor signaling differences; namely that immature B cells fail to activate protein kinase C upon sIgM ligation.
Norvell, Amanda, "Antigen-receptor mediated apoptosis of immature murine B lymphocytes as a mechanism for maintaining immunological tolerance" (1996). Dissertations available from ProQuest. AAI9627975.