title: Loss of the proapoptotic protein, Bim, breaks B cell anergy.
abstract: Although B cells that respond with high avidity to self-antigen are eliminated early in their development, many autoreactive B cells escape elimination and are tolerized later in their lives via anergy. Anergic B cells are unresponsive to antigen and die prematurely. It has been suggested that the proapoptotic protein, Bim, controls the fate of anergic B cells. To test this idea, mice lacking Bim were crossed with mice that express soluble hen egg lysozyme and whose B cells bear receptors specific for the protein. In Bim+/+ mice these B cells are anergic and die rapidly. If the mice lack Bim, however, the B cells live longer, are more mature, respond to antigen, and secrete anti-hen egg lysozyme antibodies. This break of tolerance is not due to expression of endogenous B cell receptors, nor is it dependent on T cells. Rather, it appears to be due to a reduced requirement for the cytokine BAFF. Normal B cells require BAFF both for differentiation and survival. Bim-/- B cells, on the other hand, require BAFF only for differentiation. Therefore, autoreactive B cells are allowed to survive if they lack Bim and thus accumulate sufficient signals from differentiating factors to drive their maturation and production of autoantibodies.
authors.affiliation: Howard Hughes Medical Institute and Integrated Department of Immunology, National Jewish Medical and Research Center, University of Colorado Health Sciences Center, Denver, CO 80206, USA.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Oliver
authors.forename: Tibor
authors.initials: T
authors.lastname: Vass
authors.forename: John
authors.initials: J
authors.lastname: Kappler
authors.forename: Philippa
authors.initials: P
authors.lastname: Marrack
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000235:genetics / Q000276:immunology; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D053264:B-Cell Activating Factor; D001402:B-Lymphocytes / Q000276:immunology*; D000072224:Bcl-2-Like Protein 11; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D017635:Clonal Anergy / Q000235:genetics / Q000276:immunology*; D003433:Crosses, Genetic; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000172:deficiency / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D051017:Apoptosis Regulatory Proteins; D001323:Autoantibodies; D053264:B-Cell Activating Factor; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C505720:Tnfsf13b protein, mouse; D014409:Tumor Necrosis Factor-alpha