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 Increase in the Number of Bone Marrow Osteoclast Precursors at Different Skeletal Sites, Particularly in Long Bone and Jaw Marrow in Mice Lacking IL-1RA

2020 ◽  
Vol 21 (11) ◽  
pp. 3774
Author(s):  
Giuliana Ascone ◽  
Yixuan Cao ◽  
Ineke D.C. Jansen ◽  
Irene Di Ceglie ◽  
Martijn H.J. van den Bosch ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Interleukin 1 ◽  
Bone Destruction ◽  
Mineral Dissolution ◽  
Long Bone ◽  
Osteoclast Precursors ◽  
Marrow Cells

Recently, it was shown that interleukin-1β (IL-1β) has diverse stimulatory effects on different murine long bone marrow osteoclast precursors (OCPs) in vitro. In this study, interleukin-1 receptor antagonist deficient (Il1rn−/−) and wild-type (WT) mice were compared to investigate the effects of enhanced IL-1 signaling on the composition of OCPs in long bone, calvaria, vertebra, and jaw. Bone marrow cells were isolated from these sites and the percentage of early blast (CD31hi Ly-6C−), myeloid blast (CD31+ Ly-6C+), and monocyte (CD31− Ly-6Chi) OCPs was assessed by flow cytometry. At the time-point of cell isolation, Il1rn−/− mice showed no inflammation or bone destruction yet as determined by histology and microcomputed tomography. However, Il1rn−/− mice had an approximately two-fold higher percentage of OCPs in long bone and jaw marrow compared to WT. Conversely, vertebrae and calvaria marrow contained a similar composition of OCPs in both strains. Bone marrow cells were cultured with macrophage colony stimulating factor (M-CSF) and receptor of NfκB ligand (RANKL) on bone slices to assess osteoclastogenesis and on calcium phosphate-coated plates to analyze mineral dissolution. Deletion of Il1rn increased osteoclastogenesis from long bone, calvaria, and jaw marrows, and all Il1rn−/− cultures showed increased mineral dissolution compared to WT. However, osteoclast markers increased exclusively in Il1rn−/− osteoclasts from long bone and jaw. Collectively, these findings indicate that a lack of IL-1RA increases the numbers of OCPs in vivo, particularly in long bone and jaw, where rheumatoid arthritis and periodontitis develop. Thus, increased bone loss at these sites may be triggered by a larger pool of OCPs due to the disruption of IL-1 inhibitors.

scholarly journals Response patterns of purified myeloma cells to hematopoietic growth factors

Blood ◽  
1989 ◽  
Vol 73 (7) ◽  
pp. 1915-1924 ◽  
Author(s):  
KC Anderson ◽  
RM Jones ◽  
C Morimoto ◽  
P Leavitt ◽  
BA Barut
Keyword(s):  
Growth Factors ◽  
Cell Lines ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Interleukin 1 ◽  
Interleukin 2 ◽  
Interleukin 4 ◽  
Hematopoietic Growth Factors ◽  
Myeloma Cells

Abstract Tumor cells were isolated from the bone marrow of seven patients with multiple myeloma and from the peripheral blood of three patients with plasma cell leukemia using Ficoll-Hypaque (FH) density sedimentation followed by immune rosette depletion of T, myeloid, monocytoid, and natural killer (NK) cells. Enrichment to greater than or equal to 93% plasma cells was confirmed with Wright's-Giemsa staining, with intracytoplasmic immunoglobulin staining, and with staining using monoclonal antibodies (MoAbs) directed at B, T, myeloid, monocytoid, and myeloma antigens in indirect immunofluorescence assays. Myeloma cells neither proliferated nor secreted Ig in response to G/M-CSF, G- CSF, M-CSF, interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta), interleukin-2 (IL-2), or interleukin-4 (IL-4). Significant proliferation (SI greater than or equal to 3.0) was induced by interleukin-6 (IL-6) in six of ten patients (SI of 31 and 43 in two cases); and to interleukin-3 (IL-3) and interleukin-5 (IL-5), independently, in two patients each. Peak proliferation to IL-5 or IL-6 and to IL-3 occurred in cells pulsed with 3[H] thymidine at 24 and 48 hours, respectively; and proliferation to combinations of factors did not exceed that noted to IL-6 alone; Ig secretion was not documented under any culture conditions. Three myeloma-derived cell lines similarly studied demonstrated variable responses. The heterogeneity in the in vitro responses of myeloma cells and derived cell lines to exogenous growth factors enhances our understanding of abnormal plasma cell growth and may yield insight into the pathophysiology of plasma cell dyscrasias.

scholarly journals Response patterns of purified myeloma cells to hematopoietic growth factors

Blood ◽  
1989 ◽  
Vol 73 (7) ◽  
pp. 1915-1924 ◽  
Author(s):  
KC Anderson ◽  
RM Jones ◽  
C Morimoto ◽  
P Leavitt ◽  
BA Barut
Keyword(s):  
Growth Factors ◽  
Cell Lines ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Interleukin 1 ◽  
Interleukin 2 ◽  
Interleukin 4 ◽  
Hematopoietic Growth Factors ◽  
Myeloma Cells

Tumor cells were isolated from the bone marrow of seven patients with multiple myeloma and from the peripheral blood of three patients with plasma cell leukemia using Ficoll-Hypaque (FH) density sedimentation followed by immune rosette depletion of T, myeloid, monocytoid, and natural killer (NK) cells. Enrichment to greater than or equal to 93% plasma cells was confirmed with Wright's-Giemsa staining, with intracytoplasmic immunoglobulin staining, and with staining using monoclonal antibodies (MoAbs) directed at B, T, myeloid, monocytoid, and myeloma antigens in indirect immunofluorescence assays. Myeloma cells neither proliferated nor secreted Ig in response to G/M-CSF, G- CSF, M-CSF, interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta), interleukin-2 (IL-2), or interleukin-4 (IL-4). Significant proliferation (SI greater than or equal to 3.0) was induced by interleukin-6 (IL-6) in six of ten patients (SI of 31 and 43 in two cases); and to interleukin-3 (IL-3) and interleukin-5 (IL-5), independently, in two patients each. Peak proliferation to IL-5 or IL-6 and to IL-3 occurred in cells pulsed with 3[H] thymidine at 24 and 48 hours, respectively; and proliferation to combinations of factors did not exceed that noted to IL-6 alone; Ig secretion was not documented under any culture conditions. Three myeloma-derived cell lines similarly studied demonstrated variable responses. The heterogeneity in the in vitro responses of myeloma cells and derived cell lines to exogenous growth factors enhances our understanding of abnormal plasma cell growth and may yield insight into the pathophysiology of plasma cell dyscrasias.

scholarly journals Differentiation of early plasma cells on bone marrow stromal cells requires interleukin-6 for escaping from apoptosis

Blood ◽  
1995 ◽  
Vol 85 (2) ◽  
pp. 487-494 ◽  
Author(s):  
MM Kawano ◽  
K Mihara ◽  
N Huang ◽  
T Tsujimoto ◽  
A Kuramoto
Keyword(s):  
Bone Marrow ◽  
Stromal Cells ◽  
Interleukin 6 ◽  
Bone Marrow Stromal Cells ◽  
Stromal Cell ◽  
Direct Evidence ◽  
Plasma Cells ◽  
Stromal Cell Line ◽  
Culture Supernatants

The bone marrow (BM) is well known to be the major site of Ig production in secondary immune responses; thus, the microenvironment of BM is considered to be essential for final differentiation of plasma cells. We identified in the peripheral blood (PB) early plasma cells (CD38++CD19+VLA-5-) committed to entering the BM. The sorted early plasma cells rapidly entered apoptosis in vitro, but these cells could survive and further differentiate into mature plasma cells (CD38 CD19+) just as BM plasma cells in the presence of a BM-derived stromal cell line (KM-102). Culture supernatants of KM-102 cell lines could also support survival of these cells, and antibody to interleukin-6 (IL-6) completely blocked the effect of these supernatants. Furthermore, recombinant IL-6, but not IL-1 or IL-3, could support their survival and their differentiation into mature plasma cells (CD38 CD19+VLA-5+) with expression of VLA-5 mRNA. Therefore, here is direct evidence that early plasma cells found in the PB differentiated into mature plasma cells with stromal cell-derived IL-6 in vitro; thus, BM stromal cells control the final checkpoint of plasma cell differentiation with secretion of IL-6 in the BM.

AL Amyloidosis and Concomitant Myeloma: Time to Reconsider Assumptions

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4044-4044
Author(s):  
Wesley Witteles ◽  
Ronald Witteles ◽  
Michaela Liedtke ◽  
Sally Arai ◽  
Richard Lafayette ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Plasma Cell ◽  
Research Funding ◽  
Plasma Cells ◽  
Renal Involvement ◽  
World Health ◽  
Bone Lesions ◽  
Al Amyloidosis ◽  
Bone Marrow Biopsies

Abstract Abstract 4044 Background: Conventionally, multiple myeloma is believed to coexist in approximately 10% of AL amyloidosis patients. However, it is unclear whether this figure is too low based on current World Health Organization criteria. These criteria, mainly created to differentiate myeloma from monoclonal gammopathy of undetermined significance, include the presence of ≥ 10% plasma cells on a bone marrow biopsy or aspirate as being diagnostic of myeloma. Aims: To define the frequency and relevance of a concomitant diagnosis of myeloma in patients with AL amyloidosis. Methods: Records from consecutive patients with biopsy-proven AL amyloidosis treated at the Stanford University Amyloid Center were reviewed. Plasma cell percentages were determined by manual counts from bone marrow aspirate smears and by CD138 immunohistochemistry (IHC) performed on bone marrow core biopsies. Results: A total of 41 patients (median age 61 years, 32% female) were evaluated. The median number of organs involved with amyloidosis was 2 (range 1–4), with 28 patients (68%) having cardiac involvement, 22 patients (54%) having renal involvement, 15 patients (37%) having gastrointestinal involvement, 12 patients (29%) having soft tissue involvement, and 10 patients (24%) having nervous system involvement. All patients had bone marrow biopsies and aspirates performed at the time of amyloid diagnosis, with most undergoing both manual counts of plasma cells from aspirates and IHC from core biopsies. Based on conventional criteria, manual aspirate counts defined 15/28 (54%) patients as having myeloma, and IHC defined 26/31 (84%) patients as having myeloma (p=0.01). Only nine patients had a detectable serum paraprotein on immunofixation (median 1.1 g/dl, range 0.4–2.6). 81% of patients had an elevated serum free light chain (85% lambda), with a median level of 37.3 mg/dl (range 8.6–256 mg/dl). Compared to the frequency of elevated plasma cells, the prevalence of anemia (29%), hypercalcemia (14%), impaired kidney function (21%), and lytic lesions (7%) was low. After a median follow-up of 13 months (range 1–127 months), the one-year overall survival (74% vs. 58%) and three-year overall survival (50% vs. 50%) was not significantly different between patients with ≥10% plasma cells and patients with <10% plasma cells (p=NS). Discussion: As defined by bone marrow plasma cell involvement, a strikingly high percentage (84%) of AL amyloidosis patients would be considered to have concurrent myeloma. This figure is much higher than has been traditionally quoted in the literature, likely due to the utilization of newer methods of counting plasma cells. There was a low prevalence of myeloma-associated end-organ effects (hypercalcemia, anemia, renal insufficiency, lytic bone lesions), and a myeloma diagnosis had no impact on survival. Conclusion: In this cohort of AL amyloid patients, concomitant myeloma was present in the vast majority of patients using modern diagnostic techniques. The significance of this diagnosis appears to be minimal – calling into question whether the diagnostic criteria for myeloma should be redefined in this population. Disclosures: Witteles: Celgene: Research Funding. Liedtke:Celgene: Lecture fee, Research Funding. Schrier:Celgene: Research Funding.

Myeloma and paraproteinaemias

2010 ◽  
pp. 4342-4355
Author(s):  
Robert A. Kyle ◽  
S. Vincent Rajkumar
Keyword(s):  
Bone Marrow ◽  
Renal Insufficiency ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Organ Damage ◽  
Bone Lesions ◽  
Neoplastic Diseases ◽  
End Organ Damage ◽  
Single Clone

The paraproteinaemias are a group of neoplastic (or potentially neoplastic) diseases associated with the proliferation of a single clone of immunoglobulin-secreting plasma cells. This asymptomatic condition of unknown cause is characterized by a serum paraprotein concentration under 30 g/l, less than 10% monoclonal plasma cells in the bone marrow, and no evidence of end-organ damage (CRAB) hypercalcaemia, renal insufficiency, anemia, and bone lesions related to the plasma cell proliferative process....

Pure Red Cell Aplasia Associated with Plasma Cell Myeloma: Does Monoclonal Protein Inhibit Erythropoiesis?

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 642-642
Author(s):  
Neha Korde ◽  
Kelsey Loeliger ◽  
Olga Simakova ◽  
Adriana Zingone ◽  
Richard Childs ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Plasma Cell ◽  
Light Chain ◽  
Plasma Cells ◽  
Pure Red Cell Aplasia ◽  
M Protein ◽  
Normal Donor ◽  
Red Cell ◽  
Plasma Cell Myeloma ◽  
M Proteins

Abstract Abstract 642 Pure red cell aplasia (PRCA) is a rare hematologic disorder characterized by selective inhibition of red cell precursors in the bone marrow. The pathogenesis of PRCA is unclear. Reported secondary causes of PRCA include thymoma, lymphoproliferative disorders (large granular lymphocyte leukemia, chronic lymphocytic leukemia), and viral infection such as human B19 parvovirus; however, in a large portion of patients the cause of PRCA is not able to be elucidated. In this study, we report a series of PRCA patients with unusual histopathological features and associated increase in clonal plasma cells that appear to represent a previously unrecognized PRCA variant associated with MGUS/plasma cell myeloma. We performed a retrospective analysis of bone marrow biopsies and aspirates from 50 patients diagnosed with idiopathic PRCA at the National Institutes of Health between 2001 and 2009. All samples underwent morphological, immunohistochemical and molecular analysis. Serum protein assays were performed on a cohort of patients that demonstrated increased plasma cells and/or light chain restricted plasma cells. In addition to the classical PRCA finding of marked erythroid hypoplasia with maturation arrest, we found 11/50 (22%) PRCA patients with the following atypical bone marrow features: hypercellularity with increased fibrosis and variable degree of plasmacytosis with light chain restriction and frequent aberrant CD56 or cyclin D1 expression, indicating clonality. Based on CD138 staining, 10 of the 11 (91%) patients had 10–20% plasma cells on marrow biopsies, while 1 patient demonstrated 5% plasma cells. Light chain restriction of plasma cells was morphologically demonstrated in 7/11 (64%) patients. 8/11 (72%) patients demonstrated M-proteins on serum protein electrophoresis (SPEP) and/or immunofixation; 6 of the 7 evaluable patients with M-proteins had a skewed serum free light chain (FLC) kappa/lambda (K/L) ratio. There were 7 IgG M-proteins, and the isotype of the M-protein was not defined for one patient. Mean M-protein concentration was 1.18 g/dL (0.6-2.5 gm/dL). Among the 3/11 (27%) patients without M-protein, 2 patients had a skewed FLC K/L-ratio (normal range 0.26–1.65), and 1 patient had a K/L ratio of 1.57. Based on these findings, 9/11 (82%) patients were diagnosed with plasma cell myeloma, 1 patient with MGUS, and clonality of plasma cells could not be demonstrated in 1 patient. In order to better understand underlying mechanisms, we performed an erythroid colony forming assay by co-culturing normal donor hematopoietic stem cells (HSCs) with serum from a PRCA patient containing M-protein versus serum from a normal donor. Compared to normal serum, colony cultures containing M-protein had a 43% reduction in CFU-E and BFU-E suggesting inhibition of erythroid colonies by the monoclonal protein. Clinically, response rates to daclizumab are increased in idiopathic PRCA compared to PRCA variant associated with MGUS/plasma cell myeloma, 10/23 (43%) vs. 0/6 (0%), respectively, (p=0.04). Among 3/11 patients receiving anti-myeloma therapy, 1 patient had resolution of PRCA and later became transfusion independent after bortezomib and 2 patients were lost to follow-up. Over 20% of patients originally diagnosed with idiopathic PRCA were shown to harbor clonal plasma cells and exhibit atypical histopathological marrow features. CFU-E and BFU-E colony growth from normal donor HSCs was inhibited by patient serum containin M-protein. Resolution of PRCA with transfusion independence was achieved in a patient treated with bortezomib based therapy. These findings point to a novel, previously not recognized pathogenetic mechanism of PRCA associated with relatively low plasma cell burden and demonstrate that these patients may benefit from myeloma based treatment strategies rather than standard immunosuppression. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Differentiation of early plasma cells on bone marrow stromal cells requires interleukin-6 for escaping from apoptosis

Blood ◽  
1995 ◽  
Vol 85 (2) ◽  
pp. 487-494 ◽  
Author(s):  
MM Kawano ◽  
K Mihara ◽  
N Huang ◽  
T Tsujimoto ◽  
A Kuramoto
Keyword(s):  
Bone Marrow ◽  
Stromal Cells ◽  
Interleukin 6 ◽  
Bone Marrow Stromal Cells ◽  
Stromal Cell ◽  
Direct Evidence ◽  
Plasma Cells ◽  
Stromal Cell Line ◽  
Culture Supernatants

Abstract The bone marrow (BM) is well known to be the major site of Ig production in secondary immune responses; thus, the microenvironment of BM is considered to be essential for final differentiation of plasma cells. We identified in the peripheral blood (PB) early plasma cells (CD38++CD19+VLA-5-) committed to entering the BM. The sorted early plasma cells rapidly entered apoptosis in vitro, but these cells could survive and further differentiate into mature plasma cells (CD38 CD19+) just as BM plasma cells in the presence of a BM-derived stromal cell line (KM-102). Culture supernatants of KM-102 cell lines could also support survival of these cells, and antibody to interleukin-6 (IL-6) completely blocked the effect of these supernatants. Furthermore, recombinant IL-6, but not IL-1 or IL-3, could support their survival and their differentiation into mature plasma cells (CD38 CD19+VLA-5+) with expression of VLA-5 mRNA. Therefore, here is direct evidence that early plasma cells found in the PB differentiated into mature plasma cells with stromal cell-derived IL-6 in vitro; thus, BM stromal cells control the final checkpoint of plasma cell differentiation with secretion of IL-6 in the BM.

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.

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