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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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Increased percentage of  IgDa, λ+ cells in CDTg mice with  enforced Bcl-2 expression. 3–83μδ  Tg mice were bred with bcl-2 Tg  mice in the presence (CDTg) or absence (NDTg) of bone marrow antigen expression. To determine the  extent of receptor editing, lymph  node cells were double stained for  Tg heavy chain (anti-IgDa) and endogenous light chain (anti-λ). (A)  Each row illustrates FACS® analysis  from independent experiments. (B)  Summary data showing percentage  of IgDa-positive, Id− cells in both  CDTg and CDTg mice with Bcl-2  overexpression. Data are presented  as mean ± SEM.
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Figure 7: Increased percentage of IgDa, λ+ cells in CDTg mice with enforced Bcl-2 expression. 3–83μδ Tg mice were bred with bcl-2 Tg mice in the presence (CDTg) or absence (NDTg) of bone marrow antigen expression. To determine the extent of receptor editing, lymph node cells were double stained for Tg heavy chain (anti-IgDa) and endogenous light chain (anti-λ). (A) Each row illustrates FACS® analysis from independent experiments. (B) Summary data showing percentage of IgDa-positive, Id− cells in both CDTg and CDTg mice with Bcl-2 overexpression. Data are presented as mean ± SEM.

Mentions: Bcl-2 overexpression increased the numbers of nonautoreactive, Id− B cells that developed in CD H-2b/ 3–83μδ Tg mice by two- to fivefold (Fig. 7 B; Table 1). In contrast to the results with the mice bearing antigen targeted to peripheral tissues in which autoreactive B cells with enforced Bcl-2 expression were spared, the B cells appearing in the spleen and lymph nodes of CDTg/bcl-2 mice were nonautoreactive and had undergone receptor editing (Figs. 2 and 5). One clear indication of receptor editing was the appearance of B cells bearing both the Tg heavy chain, as detected with anti-IgDa, and endogenously encoded light chains, detected with λ chain–specific antibody (Fig. 7 A, and reference 49). The increase in the percentages of “edited” cells was the result of an increase in the total number of these cells in the lymphoid organs (Table 1). Thus, Bcl-2 overexpression apparently enhanced receptor editing or allowed survival of cells that had undergone receptor editing, or both.


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)

Increased percentage of  IgDa, λ+ cells in CDTg mice with  enforced Bcl-2 expression. 3–83μδ  Tg mice were bred with bcl-2 Tg  mice in the presence (CDTg) or absence (NDTg) of bone marrow antigen expression. To determine the  extent of receptor editing, lymph  node cells were double stained for  Tg heavy chain (anti-IgDa) and endogenous light chain (anti-λ). (A)  Each row illustrates FACS® analysis  from independent experiments. (B)  Summary data showing percentage  of IgDa-positive, Id− cells in both  CDTg and CDTg mice with Bcl-2  overexpression. Data are presented  as mean ± SEM.
© Copyright Policy
Related In: Results  -  Collection

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Figure 7: Increased percentage of IgDa, λ+ cells in CDTg mice with enforced Bcl-2 expression. 3–83μδ Tg mice were bred with bcl-2 Tg mice in the presence (CDTg) or absence (NDTg) of bone marrow antigen expression. To determine the extent of receptor editing, lymph node cells were double stained for Tg heavy chain (anti-IgDa) and endogenous light chain (anti-λ). (A) Each row illustrates FACS® analysis from independent experiments. (B) Summary data showing percentage of IgDa-positive, Id− cells in both CDTg and CDTg mice with Bcl-2 overexpression. Data are presented as mean ± SEM.
Mentions: Bcl-2 overexpression increased the numbers of nonautoreactive, Id− B cells that developed in CD H-2b/ 3–83μδ Tg mice by two- to fivefold (Fig. 7 B; Table 1). In contrast to the results with the mice bearing antigen targeted to peripheral tissues in which autoreactive B cells with enforced Bcl-2 expression were spared, the B cells appearing in the spleen and lymph nodes of CDTg/bcl-2 mice were nonautoreactive and had undergone receptor editing (Figs. 2 and 5). One clear indication of receptor editing was the appearance of B cells bearing both the Tg heavy chain, as detected with anti-IgDa, and endogenously encoded light chains, detected with λ chain–specific antibody (Fig. 7 A, and reference 49). The increase in the percentages of “edited” cells was the result of an increase in the total number of these cells in the lymphoid organs (Table 1). Thus, Bcl-2 overexpression apparently enhanced receptor editing or allowed survival of cells that had undergone receptor editing, or both.

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