Limits...
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.

Show MeSH

Related in: MedlinePlus

Bcl-2 overexpression increases λ/κ ratio of B cells in both 3–83  CDTg mice and non-Ig Tg mice. (A) Lymph node cells from CDTg and  CDTg/bcl-2 mice were double stained with anti-IgDa and anti-λ antibodies. Percentage of lymph node cells staining positive for IgDa and negative  for λ were scored as κ positive. (B) Increased percentage of λ-expressing  B cells in (non-Ig Tg) bcl-2 Tg mice. The percentage of IgM+ cells that  were also λ positive was determined. Data presented as mean ± SEM.  Numbers above bars reflect number of mice examined.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2199120&req=5

Figure 8: Bcl-2 overexpression increases λ/κ ratio of B cells in both 3–83 CDTg mice and non-Ig Tg mice. (A) Lymph node cells from CDTg and CDTg/bcl-2 mice were double stained with anti-IgDa and anti-λ antibodies. Percentage of lymph node cells staining positive for IgDa and negative for λ were scored as κ positive. (B) Increased percentage of λ-expressing B cells in (non-Ig Tg) bcl-2 Tg mice. The percentage of IgM+ cells that were also λ positive was determined. Data presented as mean ± SEM. Numbers above bars reflect number of mice examined.

Mentions: The elevated frequency of nonautoreactive B cells in the CDTg/bcl-2 mice could theoretically have been the result of expansion or prolonged survival of B cells in the peripheral lymphoid organs. This simple explanation would predict that the relative frequencies of B cells bearing endogenous Ig-λ and Ig-κ light chains would be the same in both CDTg and CDTg/bcl-2 mice. To test this notion, we measured the frequencies of Id− B cells that expressed κ or λ light chains. Fig. 8 A shows that most of the increase in peripheral B cells of the CDTg/bcl-2 mice could be accounted for by an increase in λ+ B cells, suggesting that the bcl-2 transgene influences B cells undergoing light chain gene rearrangement. Interestingly, this elevated λ expression was also observed in bcl-2 Tg mice lacking Ig transgenes (Fig. 8 B), which consistently had a significantly higher percentage (∼17%) of λ+ B cells compared to non-Tg mice (∼6% λ+).


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)

Bcl-2 overexpression increases λ/κ ratio of B cells in both 3–83  CDTg mice and non-Ig Tg mice. (A) Lymph node cells from CDTg and  CDTg/bcl-2 mice were double stained with anti-IgDa and anti-λ antibodies. Percentage of lymph node cells staining positive for IgDa and negative  for λ were scored as κ positive. (B) Increased percentage of λ-expressing  B cells in (non-Ig Tg) bcl-2 Tg mice. The percentage of IgM+ cells that  were also λ positive was determined. Data presented as mean ± SEM.  Numbers above bars reflect number of mice examined.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 8: Bcl-2 overexpression increases λ/κ ratio of B cells in both 3–83 CDTg mice and non-Ig Tg mice. (A) Lymph node cells from CDTg and CDTg/bcl-2 mice were double stained with anti-IgDa and anti-λ antibodies. Percentage of lymph node cells staining positive for IgDa and negative for λ were scored as κ positive. (B) Increased percentage of λ-expressing B cells in (non-Ig Tg) bcl-2 Tg mice. The percentage of IgM+ cells that were also λ positive was determined. Data presented as mean ± SEM. Numbers above bars reflect number of mice examined.
Mentions: The elevated frequency of nonautoreactive B cells in the CDTg/bcl-2 mice could theoretically have been the result of expansion or prolonged survival of B cells in the peripheral lymphoid organs. This simple explanation would predict that the relative frequencies of B cells bearing endogenous Ig-λ and Ig-κ light chains would be the same in both CDTg and CDTg/bcl-2 mice. To test this notion, we measured the frequencies of Id− B cells that expressed κ or λ light chains. Fig. 8 A shows that most of the increase in peripheral B cells of the CDTg/bcl-2 mice could be accounted for by an increase in λ+ B cells, suggesting that the bcl-2 transgene influences B cells undergoing light chain gene rearrangement. Interestingly, this elevated λ expression was also observed in bcl-2 Tg mice lacking Ig transgenes (Fig. 8 B), which consistently had a significantly higher percentage (∼17%) of λ+ B cells compared to non-Tg mice (∼6% λ+).

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