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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 blocks peripheral clonal  deletion in 3–83μδ mice. (A  and C) 3–83μδ Tg mice (top) or  3–83μδ/ bcl-2 Tg mice (bottom)  bearing the indicated self-antigens were analyzed for Id+ B  cells in lymph node (A) and  spleen (C). (B and D) The compiled FACS® data as percentage  of IgM+/Id+ cells in the lymphoid analysis gate is shown.  Data are presented as mean ±  SEM. The numbers below each  bar represent the number of  mice analyzed per group.
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Figure 2: Enforced Bcl-2 expression blocks peripheral clonal deletion in 3–83μδ mice. (A and C) 3–83μδ Tg mice (top) or 3–83μδ/ bcl-2 Tg mice (bottom) bearing the indicated self-antigens were analyzed for Id+ B cells in lymph node (A) and spleen (C). (B and D) The compiled FACS® data as percentage of IgM+/Id+ cells in the lymphoid analysis gate is shown. Data are presented as mean ± SEM. The numbers below each bar represent the number of mice analyzed per group.

Mentions: To study peripheral B cell tolerance to natural chronic autoantigen exposure, we generated 3–83μδ mice bearing MT-Kb or KerIV-Kb transgenes, which target cell surface expression of the Kb protein to hepatocytes or epithelia, respectively (55, 56). Relative to antigen-free mice, antigen-bearing 3–83μδ mice had profoundly reduced B cell numbers in the lymph nodes (Fig. 2 A, top; Fig. 2 B, compare H-2d to MT-Kb and KerIV-Kb), and substantial, but on average, incomplete deletion of the B cells in the spleen (Fig. 2 C, top; Fig. 2 D and reference 14). Control mice bearing antigen on all tissues (Fig. 2, H-2b) exhibited the phenotype of central B cell tolerance in which antigen-reactive cells were absent from the spleen. In the mice that demonstrated peripheral B cell deletion (3–83μδ/MT-Kb or 3–83μδ/KerIV-Kb), the remaining splenic cells manifested rapid turnover as assessed by their BrdU uptake over a 1-wk labeling period (Fig. 3). It is important to note that the MT-Kb/3–83μδ mice showed a more profound tolerance than KerIV-Kb/3– 83μδ mice, and had more complete elimination of Id+ B cells in the lymph nodes (Fig. 2) and of Id+ antibodies in the serum (Fig. 4 C).


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 blocks peripheral clonal  deletion in 3–83μδ mice. (A  and C) 3–83μδ Tg mice (top) or  3–83μδ/ bcl-2 Tg mice (bottom)  bearing the indicated self-antigens were analyzed for Id+ B  cells in lymph node (A) and  spleen (C). (B and D) The compiled FACS® data as percentage  of IgM+/Id+ cells in the lymphoid analysis gate is shown.  Data are presented as mean ±  SEM. The numbers below each  bar represent the number of  mice analyzed per group.
© Copyright Policy
Related In: Results  -  Collection

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Figure 2: Enforced Bcl-2 expression blocks peripheral clonal deletion in 3–83μδ mice. (A and C) 3–83μδ Tg mice (top) or 3–83μδ/ bcl-2 Tg mice (bottom) bearing the indicated self-antigens were analyzed for Id+ B cells in lymph node (A) and spleen (C). (B and D) The compiled FACS® data as percentage of IgM+/Id+ cells in the lymphoid analysis gate is shown. Data are presented as mean ± SEM. The numbers below each bar represent the number of mice analyzed per group.
Mentions: To study peripheral B cell tolerance to natural chronic autoantigen exposure, we generated 3–83μδ mice bearing MT-Kb or KerIV-Kb transgenes, which target cell surface expression of the Kb protein to hepatocytes or epithelia, respectively (55, 56). Relative to antigen-free mice, antigen-bearing 3–83μδ mice had profoundly reduced B cell numbers in the lymph nodes (Fig. 2 A, top; Fig. 2 B, compare H-2d to MT-Kb and KerIV-Kb), and substantial, but on average, incomplete deletion of the B cells in the spleen (Fig. 2 C, top; Fig. 2 D and reference 14). Control mice bearing antigen on all tissues (Fig. 2, H-2b) exhibited the phenotype of central B cell tolerance in which antigen-reactive cells were absent from the spleen. In the mice that demonstrated peripheral B cell deletion (3–83μδ/MT-Kb or 3–83μδ/KerIV-Kb), the remaining splenic cells manifested rapid turnover as assessed by their BrdU uptake over a 1-wk labeling period (Fig. 3). It is important to note that the MT-Kb/3–83μδ mice showed a more profound tolerance than KerIV-Kb/3– 83μδ mice, and had more complete elimination of Id+ B cells in the lymph nodes (Fig. 2) and of Id+ antibodies in the serum (Fig. 4 C).

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