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Enforced Bcl-2 expression inhibits antigen-mediated clonal elimination of peripheral B cells in an antigen dose-dependent manner and promotes receptor editing in autoreactive, immature B cells.

Lang J, Arnold B, Hammerling G, Harris AW, Korsmeyer S, Russell D, Strasser A, Nemazee D - J. Exp. Med. (1997)

Bottom Line: Furthermore, Bcl-2 protected peritoneal B-2 B cells from deletion mediated by acute antigen exposure, but this protection could be overcome by higher antigen dose.In contrast to its ability to block peripheral self-tolerance, Bcl-2 overexpression failed to inhibit central tolerance induced by bone marrow antigen expression, but instead, enhanced the receptor editing process.These studies indicate that apoptosis plays distinct roles in central and peripheral B cell tolerance.

View Article: PubMed Central - PubMed

Affiliation: Division of Basic Sciences, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206, USA.

ABSTRACT
The mechanisms that establish immune tolerance in immature and mature B cells appear to be distinct. Membrane-bound autoantigen is thought to induce developmental arrest and receptor editing in immature B cells, whereas mature B cells have shortened lifespans when exposed to the same stimulus. In this study, we used Emu-bcl-2-22 transgenic (Tg) mice to test the prediction that enforced expression of the Bcl-2 apoptotic inhibitor in B cells would rescue mature, but not immature, B cells from tolerance induction. To monitor tolerance to the natural membrane autoantigen H-2Kb, we bred 3-83mudelta (anti-Kk,b) Ig Tg mice to H-2(b) mice or to mice expressing transgene-driven Kb in the periphery. In 3-83mudelta/bcl-2 Tg mice, deletion of autoreactive B cells induced by peripheral Kb antigen expression in the liver (MT-Kb Tg) or epithelia (KerIV-Kb Tg), was partly or completely inhibited, respectively. Furthermore, Bcl-2 protected peritoneal B-2 B cells from deletion mediated by acute antigen exposure, but this protection could be overcome by higher antigen dose. In contrast to its ability to block peripheral self-tolerance, Bcl-2 overexpression failed to inhibit central tolerance induced by bone marrow antigen expression, but instead, enhanced the receptor editing process. These studies indicate that apoptosis plays distinct roles in central and peripheral B cell tolerance.

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Enforced Bcl-2 expression inhibits B cell deletion induced by  acute challenge with membrane antigen in an antigen dose–dependent  manner. NDTg and NDTg/bcl-2 mice were injected intraperitoneally  with either PBS control, Kk-expressing tumor cells, or Kd tumor cells, and  the peritoneal cells were analyzed 16 h later for the loss of 3–83 B cells using 54.1 anticlonotype and anti-IgM antibodies. The data from three experiments are presented as mean ± SEM. In some data points, error bars  are not apparent because of their small range.
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Figure 1: Enforced Bcl-2 expression inhibits B cell deletion induced by acute challenge with membrane antigen in an antigen dose–dependent manner. NDTg and NDTg/bcl-2 mice were injected intraperitoneally with either PBS control, Kk-expressing tumor cells, or Kd tumor cells, and the peritoneal cells were analyzed 16 h later for the loss of 3–83 B cells using 54.1 anticlonotype and anti-IgM antibodies. The data from three experiments are presented as mean ± SEM. In some data points, error bars are not apparent because of their small range.

Mentions: The 3–83μδ Ig transgene encodes a BCR that is reactive to a number of MHC class I alloforms including Kk, Dk, and Kb, but fails to bind to H-2d; thus, 3–83μδ/H-2d mice contain a virtually monoclonal B cell population bearing the 3–83 BCR and are called nondeleting (ND)Tg mice (14). To probe the ability of enforced Bcl-2 expression to block tolerance to acute intraperitoneal antigen challenge, we injected NDTg and NDTg/bcl-2 mice with antigen-bearing cells, a protocol that stimulates rapid apoptosis of fully mature antigen-specific peritoneal B cells (15, 16). Injection of hybridoma cells bearing the high-affinity Kk antigen consistently led to massive loss (∼80%) of the 3–83μδ peritoneal B cells over a 16-h period, whereas injection of control H-2d cells did not (Fig. 1). At low antigen dose (5 × 106 cells), NDTg/bcl-2 B cells resisted deletion induced by the Kk antigen (Fig. 1); however, this protection from death afforded by Bcl-2 overexpression was overcome with a 10-fold increased antigen dose (Fig. 1).


Enforced Bcl-2 expression inhibits antigen-mediated clonal elimination of peripheral B cells in an antigen dose-dependent manner and promotes receptor editing in autoreactive, immature B cells.

Lang J, Arnold B, Hammerling G, Harris AW, Korsmeyer S, Russell D, Strasser A, Nemazee D - J. Exp. Med. (1997)

Enforced Bcl-2 expression inhibits B cell deletion induced by  acute challenge with membrane antigen in an antigen dose–dependent  manner. NDTg and NDTg/bcl-2 mice were injected intraperitoneally  with either PBS control, Kk-expressing tumor cells, or Kd tumor cells, and  the peritoneal cells were analyzed 16 h later for the loss of 3–83 B cells using 54.1 anticlonotype and anti-IgM antibodies. The data from three experiments are presented as mean ± SEM. In some data points, error bars  are not apparent because of their small range.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199120&req=5

Figure 1: Enforced Bcl-2 expression inhibits B cell deletion induced by acute challenge with membrane antigen in an antigen dose–dependent manner. NDTg and NDTg/bcl-2 mice were injected intraperitoneally with either PBS control, Kk-expressing tumor cells, or Kd tumor cells, and the peritoneal cells were analyzed 16 h later for the loss of 3–83 B cells using 54.1 anticlonotype and anti-IgM antibodies. The data from three experiments are presented as mean ± SEM. In some data points, error bars are not apparent because of their small range.
Mentions: The 3–83μδ Ig transgene encodes a BCR that is reactive to a number of MHC class I alloforms including Kk, Dk, and Kb, but fails to bind to H-2d; thus, 3–83μδ/H-2d mice contain a virtually monoclonal B cell population bearing the 3–83 BCR and are called nondeleting (ND)Tg mice (14). To probe the ability of enforced Bcl-2 expression to block tolerance to acute intraperitoneal antigen challenge, we injected NDTg and NDTg/bcl-2 mice with antigen-bearing cells, a protocol that stimulates rapid apoptosis of fully mature antigen-specific peritoneal B cells (15, 16). Injection of hybridoma cells bearing the high-affinity Kk antigen consistently led to massive loss (∼80%) of the 3–83μδ peritoneal B cells over a 16-h period, whereas injection of control H-2d cells did not (Fig. 1). At low antigen dose (5 × 106 cells), NDTg/bcl-2 B cells resisted deletion induced by the Kk antigen (Fig. 1); however, this protection from death afforded by Bcl-2 overexpression was overcome with a 10-fold increased antigen dose (Fig. 1).

Bottom Line: Furthermore, Bcl-2 protected peritoneal B-2 B cells from deletion mediated by acute antigen exposure, but this protection could be overcome by higher antigen dose.In contrast to its ability to block peripheral self-tolerance, Bcl-2 overexpression failed to inhibit central tolerance induced by bone marrow antigen expression, but instead, enhanced the receptor editing process.These studies indicate that apoptosis plays distinct roles in central and peripheral B cell tolerance.

View Article: PubMed Central - PubMed

Affiliation: Division of Basic Sciences, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206, USA.

ABSTRACT
The mechanisms that establish immune tolerance in immature and mature B cells appear to be distinct. Membrane-bound autoantigen is thought to induce developmental arrest and receptor editing in immature B cells, whereas mature B cells have shortened lifespans when exposed to the same stimulus. In this study, we used Emu-bcl-2-22 transgenic (Tg) mice to test the prediction that enforced expression of the Bcl-2 apoptotic inhibitor in B cells would rescue mature, but not immature, B cells from tolerance induction. To monitor tolerance to the natural membrane autoantigen H-2Kb, we bred 3-83mudelta (anti-Kk,b) Ig Tg mice to H-2(b) mice or to mice expressing transgene-driven Kb in the periphery. In 3-83mudelta/bcl-2 Tg mice, deletion of autoreactive B cells induced by peripheral Kb antigen expression in the liver (MT-Kb Tg) or epithelia (KerIV-Kb Tg), was partly or completely inhibited, respectively. Furthermore, Bcl-2 protected peritoneal B-2 B cells from deletion mediated by acute antigen exposure, but this protection could be overcome by higher antigen dose. In contrast to its ability to block peripheral self-tolerance, Bcl-2 overexpression failed to inhibit central tolerance induced by bone marrow antigen expression, but instead, enhanced the receptor editing process. These studies indicate that apoptosis plays distinct roles in central and peripheral B cell tolerance.

Show MeSH
Related in: MedlinePlus