scholarly journals Bcl-2+ tonsillar plasma cells are rescued from apoptosis by bone marrow fibroblasts.

1996 ◽  
Vol 183 (1) ◽  
pp. 227-236 ◽  
Author(s):  
P Merville ◽  
J Déchanet ◽  
A Desmoulière ◽  
I Durand ◽  
O de Bouteiller ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Survival ◽  
Plasma Cell ◽  
B Lymphocyte ◽  
Plasma Cells ◽  
Lymphoid Tissues ◽  
Hla Dq ◽  
Cd20 Expression ◽  
Bone Marrow Fibroblasts

Plasma cells represent the final stage of B lymphocyte differentiation. Most plasma cells in secondary lymphoid tissues live for a few days, whereas those in the lamina propria of mucosa and in bone marrow live for several weeks. To investigate the regulation of human plasma cell survival, plasma cells were isolated from tonsils according to high CD38 and low CD20 expression. Tonsillar plasma cells express CD9, CD19, CD24, CD37, CD40, CD74, and HLA-DR, but not CD10, HLA-DQ, CD28, CD56, and Fas/CD95. Although plasma cells express intracytoplasmic Bcl-2, they undergo swift apoptosis in vitro and do not respond to CD40 triggering. Bone marrow fibroblasts and rheumatoid synoviocytes, however, prevented plasma cells from undergoing apoptosis in a contact-dependent fashion. These data indicate that fibroblasts may form a microenvironment favorable for plasma cell survival under normal and pathological conditions.

The heterogeneity shown by human plasma cells from tonsil, blood, and bone marrow reveals graded stages of increasing maturity, but local profiles of adhesion molecule expression

Blood ◽  
2002 ◽  
Vol 99 (6) ◽  
pp. 2154-2161 ◽  
Author(s):  
Francisco Medina ◽  
Carmen Segundo ◽  
Antonio Campos-Caro ◽  
Inés González-Garcı́a ◽  
José A. Brieva
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
Adhesion Molecule ◽  
B Lymphocyte ◽  
Plasma Cells ◽  
Lymphoid Tissues ◽  
Adhesion Molecule Expression ◽  
B Cell Differentiation ◽  
Final Destination

Abstract Plasma cells (PCs) are the final B-cell differentiation stage. Recent evidence reveals relevant functional differences within the PC compartment. In rodents, early PCs formed in secondary lymphoid tissues show enhanced apoptosis and short life span, whereas PCs present in a final destination organ, such as the bone marrow (BM), have reached a stable prolonged survival state. BM PCs arrive at this organ as a circulating precursor whose cellular nature remains uncertain. An initial aim of this study was to characterize this circulating cell. We hypothesized that antibody-secreting cells detectable in the human blood after immunization might be a candidate precursor. These cells were obtained from the blood of volunteers immunized 6 days earlier with tetanus toxoid (tet), and they were unambiguously identified as PCs, as demonstrated by their expression of the CD38h phenotype, by morphology, by immunoglobulin (Ig) intracytoplasmic staining, and by IgG-tet–secreting capacity in vitro. In addition, by using the common CD38h feature, human PCs from tonsil (as a possible source of early PCs), from blood from tet-immunized donors (as the putative precursors of BM PCs), and from BM (as a deposit organ) have been purified and their phenotypes compared. The results show that a variety of differentiation molecules, proteins involved in the control of apoptosis, the B-cell transcription factors, positive regulatory domain I-binding factor 1/B lymphocyte-induced maturation protein 1 and B cell–specific activating protein and, at least partially, the chemokine receptor CXCR4 were expressed by human PCs following a gradient of increasing maturity in the direction: tonsil→blood→BM. However, PCs from these different organs showed a local pattern of adhesion molecule expression. These observations are discussed in light of the complex physiology of the human PC compartment.

APRIL Provides Springtime for Antibody-Producing Plasma-Cell Lifetime

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2568-2568
Author(s):  
Bertrand Huard ◽  
Elodie Belnoue ◽  
Thomas Mc Kee ◽  
Thomas Matthes ◽  
Claire-Anne Siegrist ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Constitutive Expression ◽  
Lymphoid Tissues ◽  
Tnf Superfamily ◽  
Unique Source

Abstract Antibody-producing plasma cells depend on their environment for survival, but the molecules involved in this process are still not well defined. Plasma cells are fully equipped to respond to a proliferation inducing ligand (APRIL) from the tumor necrosis factor (TNF) superfamily, by virtue of their constitutive expression of the B-cell maturation antigen (BCMA), as canonical receptor from the TNF receptor superfamily, and the heparan sulfate proteoglycan (HSPG), CD138, as co-receptor. Here, we report that APRIL promoted the in vitro survival of plasma cells by upregulating expression of several anti-apoptotic molecules, such as bcl-2, bcl-xL and mcl-1. We further observed an in situ localization for APRIL consistent with this pro-survival role, both in mucosa-associated lymphoid tissues (MALT) and the bone marrow. In upper MALT, the tonsillar epithelium produced APRIL. Upon infection, APRIL production increased considerably when APRIL-secreting neutrophils, recruited from the blood, infiltrated the crypt epithelium. HSPG retained secreted APRIL in the sub-epithelium of the infected zone to create APRIL-rich niches, wherein IgG-producing plasma cells accumulated. In lower MALT, neutrophils were the unique source of APRIL giving rise to similar niches for IgA-producing plasmocytes in villi of lamina propria. The requirement on an inflammatory reaction in niche establishment implies that plasma-cell survival in mucosa is associated to pathogen presence, and must be short as a consequence. We observed also APRIL in the bone marrow. In this latter organ, maturating granulocytes produced constitutively APRIL. Such constitutive expression of a plasma cell pro-survival explains, at least in part, why plasma-cell longevity in the bone marrow can be so long lasting. These in situ human observations were confirmed in vivo with APRIL-deficient mice.

CD28 Supports Normal Plasma Cell Survival and Interactions with Microenvironment

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2713-2713
Author(s):  
Cheryl H Rozanski ◽  
Jayakumar Nair ◽  
Louise Carlson ◽  
Kelvin P. Lee
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Dendritic Cells ◽  
Cell Survival ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Bone Marrow Biopsies ◽  
Myeloma Cells ◽  
Normal Plasma

Abstract The long term generation of protective antibodies (Abs) requires the continuous survival of long-lived plasma cells that are maintained within specialized bone marrow niches by complex interactions that remain largely uncharacterized. Previous studies have shown that the T cell costimulatory receptor CD28 is expressed on normal and transformed (murine plasmacytoma, human multiple myeloma) plasma cells – however, its role in the B cell lineage remained unclear. We have recently shown that CD28 expressed on transformed human plasma cells (multiple myeloma cells) directly delivers pro-survival signals to the myeloma cells and protects them against intrinsically and extrinsically induced death (Bahlis et al, 2007). Furthermore, myeloma cells directly interact with dendritic cells (DC, both in vitro and in patient bone marrow biopsies), and the DC provide the ligands (i.e. CD80 and CD86) for myeloma-CD28. Others studies utilizing competitive bone marrow reconstitution have indirectly suggest a role for CD28 in the function and/or survival of normal murine plasma cells (Delogu et al, 2006). These observations led us to directly investigate the role of CD28 in normal plasma cell survival as well as cell-cell interactions with CD80/CD86+ bone marrow derived dendritic cells (BMDC). In vitro serum starvation experiments, direct activation of CD28 by an agonistic anti-CD28 mAb increased survival of serum-starved PC by 63% (p<0.001). Addition of BMDC improved the survival of PC by 20% over that seen with media alone, and resulted in a significant increase in IgG production (p<0.01). We and others have shown that CD28 binding to CD80/CD86 on DC also “backsignals” to the DC to produce the PC survival factor IL-6. We found that co-culture with the murine plasmacytoma cell line S194 induced 155 pg/ml of IL-6 from BMDC (p<0.01 vs. BMDC alone and S194 alone), and primary plasma cells isolated from bone marrow induced 290 pg/ml of IL-6 from BMDC (p<0.001 vs. BMDC alone). Induction of BMDC production of IL-6 by both primary and transformed PC was significantly inhibited (p<0.05) by antibody blockade of CD80 and CD86. Our data demonstrates that signaling through CD28 directly supports the survival of normal bone marrow plasma cells, and that “backsignaling” through PC-CD28 engagement of DC-CD80/CD86 induces DC to secrete the pro-survival cytokine IL-6. These findings suggest that CD28 is a key molecular bridge that connect normal plasma cells to the supportive microenvironment.

scholarly journals Production of interleukin-1 by bone marrow myeloma cells

Blood ◽  
1989 ◽  
Vol 74 (1) ◽  
pp. 380-387 ◽  
Author(s):  
F Cozzolino ◽  
M Torcia ◽  
D Aldinucci ◽  
A Rubartelli ◽  
A Miliani ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Interleukin 1 ◽  
Long Bone ◽  
Bone Lesions ◽  
Normal Donor ◽  
Biologic Activity ◽  
Culture Supernatants

Plasma cells isolated from bone marrow (BM) aspirates of 12 patients with multiple myeloma (MM) and nine patients with monoclonal gammopathy of undetermined significance (MGUS) were analyzed for production of cytokines with bone-resorbing activity, such as interleukin-1 (IL-1), tumor necrosis factor (TNF), and lymphotoxin (LT). Culture supernatants of plasma cells from MM, but not from MGUS or normal donor, invariably contained high amounts of IL-1-beta and lower amounts of IL-1-alpha. With a single exception, TNF/LT biologic activity was not detected in the same supernatants. IL-6 was present in two of five supernatants tested. Normal B lymphocytes released both IL-1 and TNF/LT activities for four days after activation in vitro; however, production of these cytokines ceased at the final stage of plasma cell. Unexpectedly, the mRNA extracted from MM plasma cell hybridized with TNF- and LT- specific, as well as IL-1-specific probes, although the culture supernatants did not contain detectable TNF/LT biologic activity. When tested in the fetal rat long bone assay, MM plasma cell supernatants displayed a strong osteoclast-activating factor (OAF) activity, which was greatly reduced but not completely abolished by neutralizing anti- IL-1 antibodies. Anti-TNF or anti-LT antibodies were ineffective in the same test. We conclude that the IL-1 released in vivo by malignant plasma cells has a major role in pathogenesis of lytic bone lesions of human MM.

scholarly journals Production of interleukin-1 by bone marrow myeloma cells

Blood ◽  
1989 ◽  
Vol 74 (1) ◽  
pp. 380-387 ◽  
Author(s):  
F Cozzolino ◽  
M Torcia ◽  
D Aldinucci ◽  
A Rubartelli ◽  
A Miliani ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Interleukin 1 ◽  
Long Bone ◽  
Bone Lesions ◽  
Normal Donor ◽  
Biologic Activity ◽  
Culture Supernatants

Abstract Plasma cells isolated from bone marrow (BM) aspirates of 12 patients with multiple myeloma (MM) and nine patients with monoclonal gammopathy of undetermined significance (MGUS) were analyzed for production of cytokines with bone-resorbing activity, such as interleukin-1 (IL-1), tumor necrosis factor (TNF), and lymphotoxin (LT). Culture supernatants of plasma cells from MM, but not from MGUS or normal donor, invariably contained high amounts of IL-1-beta and lower amounts of IL-1-alpha. With a single exception, TNF/LT biologic activity was not detected in the same supernatants. IL-6 was present in two of five supernatants tested. Normal B lymphocytes released both IL-1 and TNF/LT activities for four days after activation in vitro; however, production of these cytokines ceased at the final stage of plasma cell. Unexpectedly, the mRNA extracted from MM plasma cell hybridized with TNF- and LT- specific, as well as IL-1-specific probes, although the culture supernatants did not contain detectable TNF/LT biologic activity. When tested in the fetal rat long bone assay, MM plasma cell supernatants displayed a strong osteoclast-activating factor (OAF) activity, which was greatly reduced but not completely abolished by neutralizing anti- IL-1 antibodies. Anti-TNF or anti-LT antibodies were ineffective in the same test. We conclude that the IL-1 released in vivo by malignant plasma cells has a major role in pathogenesis of lytic bone lesions of human MM.

scholarly journals Plasma Cell Ontogeny Defined by Quantitative Changes in Blimp-1 Expression

2004 ◽  
Vol 200 (8) ◽  
pp. 967-977 ◽  
Author(s):  
Axel Kallies ◽  
Jhagvaral Hasbold ◽  
David M. Tarlinton ◽  
Wendy Dietrich ◽  
Lynn M. Corcoran ◽  
...  
Keyword(s):  
Plasma Cell ◽  
B Lymphocyte ◽  
Plasma Cells ◽  
Fluorescent Protein ◽  
Developmental Stages ◽  
Maturation Protein ◽  
Quantitative Changes ◽  
Green Fluorescent

Plasma cells comprise a population of terminally differentiated B cells that are dependent on the transcriptional regulator B lymphocyte–induced maturation protein 1 (Blimp-1) for their development. We have introduced a gfp reporter into the Blimp-1 locus and shown that heterozygous mice express the green fluorescent protein in all antibody-secreting cells (ASCs) in vivo and in vitro. In vitro, these cells display considerable heterogeneity in surface phenotype, immunoglobulin secretion rate, and Blimp-1 expression levels. Importantly, analysis of in vivo ASCs induced by immunization reveals a developmental pathway in which increasing levels of Blimp-1 expression define developmental stages of plasma cell differentiation that have many phenotypic and molecular correlates. Thus, maturation from transient plasmablast to long-lived ASCs in bone marrow is predicated on quantitative increases in Blimp-1 expression.

An In Vivo Model To Investigate the Identity of the Cell-of-Origin of Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1534-1534
Author(s):  
Fotios A. Asimakopoulos ◽  
Harold E. Varmus
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Transcription Factor ◽  
Plasma Cell ◽  
Germinal Center ◽  
Plasma Cells ◽  
Lymphoid Tissues ◽  
Cell Of Origin ◽  
Dark Zone ◽  
Bone Marrow Plasma

Abstract Multiple myeloma (MM) is characterized by monoclonal expansion of bone marrow plasma cells. However, long-lived plasma cells resident in the marrow are terminally differentiated and possess a limited replicative lifespan; it is puzzling how they could be the source of aggressive and relapsing neoplasms. We postulate that the myeloma clonogenic progenitor may reside in a more immature compartment with greater self-renewal capacity, most probably a cell participating in, or having shortly exited the germinal center reaction. However, it is unclear whether critical mutations occur in the target cell prior to, or following commitment to the plasma cell fate. To investigate the nature of the MM cell-of-origin, we have created a novel flexible mouse model system that enables the delivery of stochastic, sequential, somatic mutations to precisely defined compartments of the germinal center in secondary lymphoid tissues. To this end, we have used BAC transgenic technology to express distinct types of avian leukosis virus (ALV) receptors, TVA and TVB, in the expanding centroblast of the dark zone and the committed plasmablast of the light zone, respectively. Mammalian tissues are refractory to transduction by retroviruses of the ALV family unless they ectopically express the cognate avian-derived receptors. Thus, the coding sequences for the TVA receptor, fused to a fluorescent protein tag were placed under the control of transcription factor A-myb, expressed in centroblasts of the dark zone. Similarly, sequences encoding a fluorescent-tagged TVB receptor were placed under the control of transcription factor Blimp1, expressed in the earliest committed plasmablasts as well as mature plasma cells. Analysis of the Blimp1: TVB mice showed that expression of the avian retroviral receptor in the hematopoietic system is limited to the light zone of germinal centers, extrafollicular collections of CD138+ cells in the spleen and lymph nodes as well as long-lived bone marrow plasma cells. Analysis of A-myb: TVA transgenic mice is currently underway. The system permits the introduction of a variety of molecular lesions to specific plasma cell precursors via retroviral transduction of oncogenes, shRNAs against tumor suppressor genes or inducible regulators of gene expression in an attempt to re-create the sequence of molecular lesions leading to MM in the relevant cellular context.

scholarly journals Human CD38hiCD138+Plasma Cells Can Be Generated In Vitro from CD40-Activated Switched-Memory B Lymphocytes

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Rayelle Itoua Maïga ◽  
Guillaume Bonnaure ◽  
Josiane Tremblay Rochette ◽  
Sonia Néron
Keyword(s):  
Bone Marrow ◽  
B Lymphocytes ◽  
B Lymphocyte ◽  
Plasma Cells ◽  
De Novo ◽  
Human Peripheral Blood ◽  
Lymphocyte Differentiation ◽  
Protective Antibodies

B lymphocyte differentiation into long-lived plasma cells is the keystone event for the production of long-term protective antibodies. CD40-CD154 and CD27-CD70 interactions are involved in human B lymphocyte differentiation into CD38hiCD138+cells in vivo as well as in vitro. In this study, we have compared these interactions in their capacity to drive switched-memory B lymphocytes differentiation into CD38hiCD138+plasma cells. The targeted B lymphocytes were isolated from human peripheral blood, expanded for 19 days, and then submitted to CD70 or CD154 interactions for 14 days. The expanded B lymphocytes were constitutively expressing CD39, whereas CD31’s expression was noticed only following the in vitro differentiation step (day 5) and was exclusively present on the CD38hicell population. Furthermore, the generated CD38hiCD138+cells showed a higher proportion of CD31+cells than the CD38hiCD138-cells. Besides, analyses done with human blood and bone marrow plasma cells showed that in vivo and de novo generated CD38hiCD138+cells have a similar CD31 expression profile but are distinct according to their reduced CD39 expression level. Overall, we have evidences that in vitro generated plasma cells are heterogeneous and appear as CD39+precursors to the ones present in bone marrow niches.

Bone-marrow plasma cell burden correlates with IgM paraprotein concentration in Waldenström macroglobulinaemia

2011 ◽  
Vol 64 (6) ◽  
pp. 520-523 ◽  
Author(s):  
Sant-Rayn Pasricha ◽  
Surender K Juneja ◽  
David A Westerman ◽  
Neil A Came
Keyword(s):  
Bone Marrow ◽  
Plasma Cell ◽  
B Lymphocyte ◽  
Plasma Cells ◽  
Clinical Laboratory ◽  
Clinical Findings ◽  
Lymphocytic Infiltrate ◽  
Cell Compartment ◽  
Bone Marrow Trephine ◽  
Bone Marrow Plasma

AimsCorrelations between the marrow histopathology and clinical findings in Waldenström macroglobulinaemia (WM) are not well defined, and the pathophysiology of the plasma cell involvement is poorly understood. The authors used a standardised immunohistological approach to the enumeration of B lymphocyte and plasma cell compartments in the bone-marrow trephine to investigate associations between bone-marrow morphology and clinical/laboratory indices.MethodsIn 80 newly diagnosed, untreated cases of WM, the authors determined the degree and pattern of B lymphocyte (CD20+) and plasma cell (CD138+) infiltration in the bone-marrow trephine, as defined by immunohistochemistry, and correlated the disease in the marrow with components of the international scoring system for WM (age, serum IgM paraprotein level, haemoglobin, platelet count and β2 microglobulin). Plasma cell clonality was assessed by κ and λ staining.ResultsSerum IgM paraprotein concentration was related to the plasma cell burden in the bone marrow (coefficient 0.231, p<0.005), but not the B lymphocytic infiltrate. Overall lymphoplasmacytic disease burden weakly correlated with severity of anaemia (coefficient 0.236, p=0.055). In 28/28 evaluated cases, plasma cells exhibited light chain restriction that was concordant with both that of the B lymphocytic infiltrate and paraprotein.ConclusionsBone-marrow features, in particular the degree of plasma cell infiltration, correlate with IgM paraprotein concentration at diagnosis in WM. The plasma cell compartment in this condition appears to be part of the neoplastic clone. In WM, specific evaluation of the plasma cell compartment in the bone marrow at baseline and following therapy may be valuable.

scholarly journals Interleukin 3 and interleukin 6 synergistically promote the proliferation and differentiation of malignant plasma cell precursors in multiple myeloma.

1989 ◽  
Vol 170 (2) ◽  
pp. 613-618 ◽  
Author(s):  
L Bergui ◽  
M Schena ◽  
G Gaidano ◽  
M Riva ◽  
F Caligaris-Cappio
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Heavy Chain ◽  
Plasma Cells ◽  
Terminal Differentiation ◽  
Individual Case ◽  
Malignant Plasma Cell ◽  
Proliferation And Differentiation

PBMC from 11 patients with multiple myeloma (MM) were cultured in vitro in presence of IL-3 and IL-6. After 3 d, actively proliferating immunoblast-like B cells (20-62%) were apparent. After 6 d, a population of morphologically evident plasma cells was observed (30-50%) that expressed, in each individual case, the same light and heavy chain produced by bone marrow malignant plasma cells. We conclude that in MM the malignant plasma cell precursors are circulating and their growth and terminal differentiation are under the synergistic control of IL-3 and IL-6.

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