Transitional B cells are the target of negative selection in the B cell compartment.

Persistent cross-linking of hen egg lysozyme (HEL)-specific B cell membrane Ig (mIg) in double transgenic mice that express soluble HEL as a self Ag (HEL-Ig mice) decreases B cell mIgM expression, responsiveness, and life span. Because in vitro treatment with IL-4 inhibits T cell apoptosis through a Stat6-independent mechanism, increases mIg expression, and suppresses activation-induced B cell death, we studied IL-4 effects on B cell mIg expression, survival, and Ab secretion in Stat6-sufficient and deficient HEL-Ig mice. IL-4 treatment nearly normalized B cell number and greatly increased the percentage of mature B cells in HEL-Ig mice, but failed to normalize mIgM expression or spontaneous LPS-induced IgM secretion. IL-4 effects on B cell survival and maturation were CD4+ T cell independent, but Stat6 dependent, and did not involve receptor editing. IL-4 had to be present while B cells were generated to have a detectable effect on autoreactive B cell survival; however, the survival of B cells generated in the presence of IL-4 was substantially increased even after IL-4 was withdrawn. These observations suggest that: 1) activation-induced B cell death and anergy are independent processes; 2) B cells that survive to maturity develop increased resistance to Ag-induced deletion; and 3) IL-4 promotes B and T cell survival through different mechanisms.

Section: Relationship Between B Cell Survival and Maturitymentioning

confidence: 50%

IL-4 Promotes Stat6-Dependent Survival of Autoreactive B Cells In Vivo Without Inducing Autoantibody Production

Morris

Dragula

Finkelman

2002

“…The comparatively modest increase in Ccnd2 and Plk expression could reflect heterogeneity in the splenic B cell population; although most splenic B cells are mature follicular cells, they also include transitional immature cells and mature marginal zone cells (39,40). It is known that immature B cells undergo apoptosis and down-regulate Ccnd2 in response to anti-Ig (39,41,42), but do proliferate to the other mitogen, LPS (39). It is possible that different gene response patterns to anti-Ig in the B cell subsets could dilute or cancel each other out at the population level, contributing to less up-regulation of Ccnd2 and Plk.…”

Section: Gene Expression Change Patterns Distinguishing Anti-igmentioning

confidence: 99%

Analysis of the Major Patterns of B Cell Gene Expression Changes in Response to Short-Term Stimulation with 33 Single Ligands

Zhu

Hart

Chang

et al. 2004

We examined the major patterns of changes in gene expression in mouse splenic B cells in response to stimulation with 33 single ligands for 0.5, 1, 2, and 4 h. We found that ligands known to directly induce or costimulate proliferation, namely, anti-IgM (anti-Ig), anti-CD40 (CD40L), LPS, and, to a lesser extent, IL-4 and CpG-oligodeoxynucleotide (CpG), induced significant expression changes in a large number of genes. The remaining 28 single ligands produced changes in relatively few genes, even though they elicited measurable elevations in intracellular Ca2+ and cAMP concentration and/or protein phosphorylation, including cytokines, chemokines, and other ligands that interact with G protein-coupled receptors. A detailed comparison of gene expression responses to anti-Ig, CD40L, LPS, IL-4, and CpG indicates that while many genes had similar temporal patterns of change in expression in response to these ligands, subsets of genes showed unique expression patterns in response to IL-4, anti-Ig, and CD40L.

“…Here we show that ⌬V cells have a phenotype consistent with the idea that the mutant BCR has enhanced constitutive activity. ⌬V cells are functionally similar to tolerized B cells and are eliminated at the transitional B cell stage (18), cells with lower levels of receptors being spared. We also show that the truncated BCR allows the exit in periphery of cells with a very immature phenotype.…”

mentioning

confidence: 99%

Expression of a V Region-Less B Cell Receptor Confers a Tolerance-Like Phenotype on Transgenic B Cells

Corcos

Grandien

Vázquez

et al. 2001

Neoplastic B cells from H chain disease patients express a truncated B cell receptor (BCR), comprising a membrane Ig that lacks part of its extracellular domain. It has been speculated that deletion of the Ag binding domain would confer a constitutive activity on the BCR, as it has been shown for oncogenic growth factor receptors. A V region-less BCR has constitutive activity, because in transgenic mice it causes inhibition of endogenous H chain gene rearrangements and relieves the requirement for surrogate L chain in pre-B cell development. However, it has been speculated that normal Ag receptors also display constitutive activity. Here we show that transgenic B cells expressing a membrane H chain disease protein on their surface are phenotypically and functionally similar to B cells developing in the presence of their cognate Ag and that cells with normal levels of mutant BCR are eliminated in spleen via a bcl-2 sensitive pathway while progressing toward the mature stage. In contrast, cells with lower levels of mutant receptors develop as mature B cells. These findings support the view that the truncated BCR has a constitutive activity that mimics ligand binding, in analogy to what has been shown for oncogenic growth factor receptors.