cells (induced by a low antigen concentration) result in clonal elimination, presumably by receptor editing. Simi- larly, the higher signal threshold for activation of mature B cells in the periphery protects against autoimmunity by preventing activation of mature B cells with low affinity for self. The question remains whether BCR-proximal signal transduction events differ between immature and mature B cells. It will be especially important to assess differences pertaining to the generation of Ca21 mobilization, as this leads to the activation of specific genes. The increased sen- sitivity to antigen imposed by these mechanisms in imma- ture B cells is likely to play a very important role in reper- toire development, purging the repertoire of cells with even low affinities for self-antigens. We thank William Townend and Shirley Sobus for technical assistance. These studies were supported by grants from the National Institutes of Health awarded to J.C. Cambier. J.C. Cambier is an Ida and Cecil Green Professor of Cell Biology, and R.J. Benschop is the recipient of a Leukemia Society of America Special Fellow Award. Address correspondence to John C. Cambier, Dept. of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson St., Denver, CO 80206. Phone: 303-398-1325; Fax: 303-398-1225; E-mail: cambierj @njc.org D. Melamed’s current address is Technion, Haifa 31096, Israel. D. Nemazee’s current address is The Scripps Research Institute, La Jolla, CA 92057. Submitted: 24 July 1998 Revised: 6 July 1999 Accepted: 20 July 1999 References 1. Russell, D.M., Z. Dembic, G. Morahan, J.F. Miller, K. Burki, and D. Nemazee. 1991. Peripheral deletion of self- reactive B cells. Nature. 354:308–311. 2. Goodnow, C.C., J. Crosbie, S. Adelstein, T.B. Lavoie, S.J. Smith-Gill, R.A. Brink, H. Pritchard-Briscoe, J.S. Wother- spoon, R.H. Loblay, K. Raphael, et al. 1988. Altered immu- noglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature. 334:676–682. 3. Tiegs, S.L., D.M. Russell, and D. Nemazee. 1993. Receptor editing in self-reactive bone marrow B cells. J. Exp. Med. 177:1009–1020. 4. Erikson, J., M.Z. Radic, S.A. Camper, R.R. Hardy, C. Car- mack, and M. Weigert. 1991. Expression of anti-DNA im- munoglobulin transgenes in non-autoimmune mice. Nature. 349:331–334. 5. Cambier, J.C., J.R. Kettman, E.S. Vitetta, and J.W. Uhr. 1976. Differential susceptibility of neonatal and adult murine spleen cells to in vitro induction of B cell tolerance. J. Exp. Med. 144:293–297. 6. Metcalf, E.S., and N.R. Klinman. 1976. In vitro tolerance induction of neonatal murine B cells. J. Exp. Med. 143:1327– 1340. 7. Nossal, G.J. 1983. Cellular mechanisms of immunologic tol- erance. Annu. Rev. Immunol. 1:33–62. 8. Kelley, D.E., B.A. Pollok, M.L. Atchison, and R.P. Perry. 1988. The coupling between enhancer activity and hypome- thylation of kappa immunoglobulin genes is developmentally regulated. Mol. Cell. Biol. 8:930–937. 9. Seyfert, V.L., S.B. McMahon, W.D. Glenn, A.J. Yellen, V.P. Sukhatme, X.M. Cao, and J.G. Monroe. 1990. Methylation of an immediate-early inducible gene as a mechanism for B cell tolerance induction. Science. 250:797–800. 10. Mostoslavsky, R., N. Singh, A. Kirillov, R. Pelanda, H. Ce- dar, A. Chess, and Y. Bergman. 1998. Kappa chain monoal- lelic demethylation and the establishment of allelic exclusion. Genes Dev. 12:1801–1811. 11. Weiner, H.L., J.W. Moorhead, and H.N. Claman. 1976. Anti-immunoglobulin stimulation of murine lymphocytes. I. Age dependency of the proliferative response. J. Immunol. 116:1656–1661. 12. Yellen, A.J., W. Glenn, V.P. Sukhatme, X.M. Cao, and J.G. Monroe. 1991. Signaling through surface IgM in tolerance- susceptible immature murine B lymphocytes. Developmen- tally regulated differences in transmembrane signaling in splenic B cells from adult and neonatal mice. J. Immunol. 146: 1446–1454. 13. Carman, J.A., R.J. Wechsler-Reya, and J.G. Monroe. 1996. Immature stage B cells enter but do not progress beyond the early G1 phase of the cell cycle in response to antigen recep- tor signaling. J. Immunol. 156:4562–4569. 14. Norvell, A., L. Mandik, and J.G. Monroe. 1995. Engage- ment of the antigen-receptor on immature murine B lym- phocytes results in death by apoptosis. J. Immunol. 154:4404– 4413. 15. Li, Y.S., K. Hayakawa, and R.R. Hardy. 1993. The regu- lated expression of B lineage–associated genes during B cell differentiation in bone marrow and fetal liver. J. Exp. Med. 178:951–960. 16. Melamed, D., and D. Nemazee. 1997. Self-antigen does not accelerate immature B cell apoptosis, but stimulates receptor editing as a consequence of developmental arrest. Proc. Natl. Acad. Sci. USA. 94:9267–9272. 17. Hertz, M., and D. Nemazee. 1997. BCR ligation induces re- ceptor editing in IgM1IgD2 bone marrow B cells in vitro. Immunity. 6:429–436. 18. Cambier, J.C., C.M. Pleiman, and M.R. Clark. 1994. Signal 754 BCR Signaling in Immature B Cells