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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 fails to block central deletion induced by the ultralow affinity 3–83 ligand Dk. Lymph node and spleen  cells from mice of the indicated genotypes were double stained for the  presence of B cells bearing the 3–83 Tg BCR with 54.1 anti-Id and anti-IgM antibodies. The substantial population of IgM+ B cells present in the  CDTg mice were clonotype− and are presumably the result of receptor  editing. The large percentage of B cells in the ND control in this experiment reflects the RAG deficiency of this particular mouse.
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Figure 5: Enforced Bcl-2 expression fails to block central deletion induced by the ultralow affinity 3–83 ligand Dk. Lymph node and spleen cells from mice of the indicated genotypes were double stained for the presence of B cells bearing the 3–83 Tg BCR with 54.1 anti-Id and anti-IgM antibodies. The substantial population of IgM+ B cells present in the CDTg mice were clonotype− and are presumably the result of receptor editing. The large percentage of B cells in the ND control in this experiment reflects the RAG deficiency of this particular mouse.

Mentions: The Eμ–bcl-2-22 transgene drives expression of functionally active Bcl-2 in immature bone marrow B cells that normally lack Bcl-2 expression (46). To test the effect of this transgene on central B cell tolerance, we bred H-2b mice to 3–83μδ and bcl-2/3–83μδ mice, generating central deleting (CD)Tg and CDTg/bcl-2 mice, respectively. Like CDTg mice, CDTg/bcl-2 mice lacked Id+ B cells in the peripheral lymphoid organs (Fig. 2, H-2b; Table 1) and Id+ antibodies in the sera (Fig. 4 C). In addition, no Id+ antibodies were found in the supernatants of LPS-stimulated spleen cells from CDTg or CDTg/bcl-2 mice, whereas NDTg and NDTg/bcl-2 controls had significant levels of Id+ antibodies in both the sera and LPS culture supernatants (Fig. 4 A; data not shown). Since previous central tolerance studies investigating Bcl-2 overexpression used high-affinity antigens (KA ∼109 M−1), we tested whether or not Bcl-2 overexpression had perhaps a subtle, antigen affinity-dependent effect on tolerance induction by generating CDTg/bcl-2 mice expressing the Dk class I molecule to which 3–83 has very low affinity (KA ∼104 M−1; reference 58). Again the CDTg/ bcl-2 mice had no detectable increase of Id+ B cells in the peripheral lymphoid organs (Fig. 5) nor IgM idiotype in the serum (data not shown).


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 fails to block central deletion induced by the ultralow affinity 3–83 ligand Dk. Lymph node and spleen  cells from mice of the indicated genotypes were double stained for the  presence of B cells bearing the 3–83 Tg BCR with 54.1 anti-Id and anti-IgM antibodies. The substantial population of IgM+ B cells present in the  CDTg mice were clonotype− and are presumably the result of receptor  editing. The large percentage of B cells in the ND control in this experiment reflects the RAG deficiency of this particular mouse.
© Copyright Policy
Related In: Results  -  Collection

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Figure 5: Enforced Bcl-2 expression fails to block central deletion induced by the ultralow affinity 3–83 ligand Dk. Lymph node and spleen cells from mice of the indicated genotypes were double stained for the presence of B cells bearing the 3–83 Tg BCR with 54.1 anti-Id and anti-IgM antibodies. The substantial population of IgM+ B cells present in the CDTg mice were clonotype− and are presumably the result of receptor editing. The large percentage of B cells in the ND control in this experiment reflects the RAG deficiency of this particular mouse.
Mentions: The Eμ–bcl-2-22 transgene drives expression of functionally active Bcl-2 in immature bone marrow B cells that normally lack Bcl-2 expression (46). To test the effect of this transgene on central B cell tolerance, we bred H-2b mice to 3–83μδ and bcl-2/3–83μδ mice, generating central deleting (CD)Tg and CDTg/bcl-2 mice, respectively. Like CDTg mice, CDTg/bcl-2 mice lacked Id+ B cells in the peripheral lymphoid organs (Fig. 2, H-2b; Table 1) and Id+ antibodies in the sera (Fig. 4 C). In addition, no Id+ antibodies were found in the supernatants of LPS-stimulated spleen cells from CDTg or CDTg/bcl-2 mice, whereas NDTg and NDTg/bcl-2 controls had significant levels of Id+ antibodies in both the sera and LPS culture supernatants (Fig. 4 A; data not shown). Since previous central tolerance studies investigating Bcl-2 overexpression used high-affinity antigens (KA ∼109 M−1), we tested whether or not Bcl-2 overexpression had perhaps a subtle, antigen affinity-dependent effect on tolerance induction by generating CDTg/bcl-2 mice expressing the Dk class I molecule to which 3–83 has very low affinity (KA ∼104 M−1; reference 58). Again the CDTg/ bcl-2 mice had no detectable increase of Id+ B cells in the peripheral lymphoid organs (Fig. 5) nor IgM idiotype in the serum (data not shown).

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