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BCMA is essential for the survival of long-lived bone marrow plasma cells.

O'Connor BP, Raman VS, Erickson LD, Cook WJ, Weaver LK, Ahonen C, Lin LL, Mantchev GT, Bram RJ, Noelle RJ - J. Exp. Med. (2004)

Bottom Line: Blockade of BLyS, via transmembrane activator and cyclophilin ligand interactor-immunoglobulin treatment, inhibited PC survival in vitro and in vivo.Heightened expression of B cell maturation antigen (BCMA), and lowered expression of transmembrane activator and cyclophilin ligand interactor and BAFF receptor in PCs relative to resting B cells suggests a vital role of BCMA in PC survival.These findings offer new insights into the molecular basis for the long-term survival of PCs.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Dartmouth Medical School, 1 Medical Center Drive, Lebanon, NH 03756, USA.

ABSTRACT
Long-lived humoral immunity is manifested by the ability of bone marrow plasma cells (PCs) to survive for extended periods of time. Recent studies have underscored the importance of BLyS and APRIL as factors that can support the survival of B lineage lymphocytes. We show that BLyS can sustain PC survival in vitro, and this survival can be further enhanced by interleukin 6. Selective up-regulation of Mcl-1 in PCs by BLyS suggests that this alpha-apoptotic gene product may play an important role in PC survival. Blockade of BLyS, via transmembrane activator and cyclophilin ligand interactor-immunoglobulin treatment, inhibited PC survival in vitro and in vivo. Heightened expression of B cell maturation antigen (BCMA), and lowered expression of transmembrane activator and cyclophilin ligand interactor and BAFF receptor in PCs relative to resting B cells suggests a vital role of BCMA in PC survival. Affirmation of the importance of BCMA in PC survival was provided by studies in BCMA-/- mice in which the survival of long-lived bone marrow PCs was impaired compared with wild-type controls. These findings offer new insights into the molecular basis for the long-term survival of PCs.

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BLyS and IL-6 enhances BM PC survival in vitro. After a 6–8-wk immunization with 10 μg PE, whole BM samples were isolated from BALB/c and cultured in vitro with the indicated stimuli for a period of 10 d. (A) After isolation of whole BM samples, 8 × 106 BM cells were cultured in medium alone (♦), 200 ng/ml BLyS (▵), 500 pg/ml IL-6 (▪), IL-6 and BLyS (X), or 10 μg/ml TACI-Ig (•). At days 2, 4, 7, and 10 of in vitro culture, samples were isolated, and the number of PE-specific IgG BM ASCs was enumerated by ELISPOT. These data are representative of four experiments. (B) Immune BM was cultured as in A, and on day 7, samples were stained with αB220, αCD138, and αLy6C antibodies to estimate the number of total PCs (B220−CD138+Ly6C+) in culture. Two representative experiments out of four are shown.
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fig1: BLyS and IL-6 enhances BM PC survival in vitro. After a 6–8-wk immunization with 10 μg PE, whole BM samples were isolated from BALB/c and cultured in vitro with the indicated stimuli for a period of 10 d. (A) After isolation of whole BM samples, 8 × 106 BM cells were cultured in medium alone (♦), 200 ng/ml BLyS (▵), 500 pg/ml IL-6 (▪), IL-6 and BLyS (X), or 10 μg/ml TACI-Ig (•). At days 2, 4, 7, and 10 of in vitro culture, samples were isolated, and the number of PE-specific IgG BM ASCs was enumerated by ELISPOT. These data are representative of four experiments. (B) Immune BM was cultured as in A, and on day 7, samples were stained with αB220, αCD138, and αLy6C antibodies to estimate the number of total PCs (B220−CD138+Ly6C+) in culture. Two representative experiments out of four are shown.

Mentions: It has been shown that during the later stages of an immune response, the majority of PCs within the BM are long lived (21–23). Because BLyS has been shown to be a key survival factor for B cells in general, and recent transcriptional profiling has shown increased expression of BCMA on PCs, we asked whether BLyS could contribute to the survival of BM PCs (24). To this end, BM from mice 30 d after immunization with PE was isolated and cultured with IL-6 and/or BLyS for 10 d. As reported previously (2), and shown here, the addition of IL-6 can enhance Ag-specific PC survival over short time intervals (2–4 d); however, over extended time periods (10 d), IL-6 was not effective (Fig. 1 A). The addition of BLyS alone exerted a modest twofold effect on αPE ASC survival over 10 d, but in combination with IL-6, it enhanced the number of ASCs on day 10 over fourfold (from <200 to 800 ASCs).


BCMA is essential for the survival of long-lived bone marrow plasma cells.

O'Connor BP, Raman VS, Erickson LD, Cook WJ, Weaver LK, Ahonen C, Lin LL, Mantchev GT, Bram RJ, Noelle RJ - J. Exp. Med. (2004)

BLyS and IL-6 enhances BM PC survival in vitro. After a 6–8-wk immunization with 10 μg PE, whole BM samples were isolated from BALB/c and cultured in vitro with the indicated stimuli for a period of 10 d. (A) After isolation of whole BM samples, 8 × 106 BM cells were cultured in medium alone (♦), 200 ng/ml BLyS (▵), 500 pg/ml IL-6 (▪), IL-6 and BLyS (X), or 10 μg/ml TACI-Ig (•). At days 2, 4, 7, and 10 of in vitro culture, samples were isolated, and the number of PE-specific IgG BM ASCs was enumerated by ELISPOT. These data are representative of four experiments. (B) Immune BM was cultured as in A, and on day 7, samples were stained with αB220, αCD138, and αLy6C antibodies to estimate the number of total PCs (B220−CD138+Ly6C+) in culture. Two representative experiments out of four are shown.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1887725&req=5

fig1: BLyS and IL-6 enhances BM PC survival in vitro. After a 6–8-wk immunization with 10 μg PE, whole BM samples were isolated from BALB/c and cultured in vitro with the indicated stimuli for a period of 10 d. (A) After isolation of whole BM samples, 8 × 106 BM cells were cultured in medium alone (♦), 200 ng/ml BLyS (▵), 500 pg/ml IL-6 (▪), IL-6 and BLyS (X), or 10 μg/ml TACI-Ig (•). At days 2, 4, 7, and 10 of in vitro culture, samples were isolated, and the number of PE-specific IgG BM ASCs was enumerated by ELISPOT. These data are representative of four experiments. (B) Immune BM was cultured as in A, and on day 7, samples were stained with αB220, αCD138, and αLy6C antibodies to estimate the number of total PCs (B220−CD138+Ly6C+) in culture. Two representative experiments out of four are shown.
Mentions: It has been shown that during the later stages of an immune response, the majority of PCs within the BM are long lived (21–23). Because BLyS has been shown to be a key survival factor for B cells in general, and recent transcriptional profiling has shown increased expression of BCMA on PCs, we asked whether BLyS could contribute to the survival of BM PCs (24). To this end, BM from mice 30 d after immunization with PE was isolated and cultured with IL-6 and/or BLyS for 10 d. As reported previously (2), and shown here, the addition of IL-6 can enhance Ag-specific PC survival over short time intervals (2–4 d); however, over extended time periods (10 d), IL-6 was not effective (Fig. 1 A). The addition of BLyS alone exerted a modest twofold effect on αPE ASC survival over 10 d, but in combination with IL-6, it enhanced the number of ASCs on day 10 over fourfold (from <200 to 800 ASCs).

Bottom Line: Blockade of BLyS, via transmembrane activator and cyclophilin ligand interactor-immunoglobulin treatment, inhibited PC survival in vitro and in vivo.Heightened expression of B cell maturation antigen (BCMA), and lowered expression of transmembrane activator and cyclophilin ligand interactor and BAFF receptor in PCs relative to resting B cells suggests a vital role of BCMA in PC survival.These findings offer new insights into the molecular basis for the long-term survival of PCs.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Dartmouth Medical School, 1 Medical Center Drive, Lebanon, NH 03756, USA.

ABSTRACT
Long-lived humoral immunity is manifested by the ability of bone marrow plasma cells (PCs) to survive for extended periods of time. Recent studies have underscored the importance of BLyS and APRIL as factors that can support the survival of B lineage lymphocytes. We show that BLyS can sustain PC survival in vitro, and this survival can be further enhanced by interleukin 6. Selective up-regulation of Mcl-1 in PCs by BLyS suggests that this alpha-apoptotic gene product may play an important role in PC survival. Blockade of BLyS, via transmembrane activator and cyclophilin ligand interactor-immunoglobulin treatment, inhibited PC survival in vitro and in vivo. Heightened expression of B cell maturation antigen (BCMA), and lowered expression of transmembrane activator and cyclophilin ligand interactor and BAFF receptor in PCs relative to resting B cells suggests a vital role of BCMA in PC survival. Affirmation of the importance of BCMA in PC survival was provided by studies in BCMA-/- mice in which the survival of long-lived bone marrow PCs was impaired compared with wild-type controls. These findings offer new insights into the molecular basis for the long-term survival of PCs.

Show MeSH