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PubMed2003

Gene expression profiling of plasma cells and plasmablasts: toward a better understanding of the late stages of B-cell differentiation.

Plasma cells (PCs), the end point of B-cell differentiation, are a heterogeneous cell compartment comprising several cell subsets from short-lived highly proliferative plasmablasts to long-lived nondividing fully mature PCs. Whereas the major transcription factors driving the differentiation of B cells to PCs were recently identified, the subtle genetic changes that underlie the transition from plasmablasts to mature PCs are poorly understood. We recently described an in vitro model making it possible to obtain a large number of cells with the morphologic, phenotypic, and functional characteristics of normal polyclonal plasmablastic cells (PPCs). Using Affymetrix microarrays we compared the gene expression profiles of these PPCs with those of mature PCs isolated from tonsils (TPCs) and bone marrow (BMPCs), and with those of B cells purified from peripheral blood (PBB cells) and tonsils (TBCs). Unsupervised principal component analysis clearly distinguished the 5 cell populations on the basis of their differentiation and proliferation status. Detailed statistical analysis allowed the identification of 85 PC genes and 40 B-cell genes, overexpressed, respectively, in the 3 PC subsets or in the 2 B-cell subsets. In addition, several signaling molecules and antiapoptotic proteins were found to be induced in BMPCs compared with PPCs and could be involved in the accumulation and prolonged survival of BMPCs in close contact with specialized stromal microenvironment. These data should help to better understand the molecular events that regulate commitment to a PC fate, mediate PC maintenance in survival niches, and could facilitate PC immortalization in plasma cell dyscrasias.

Autocrine Communication↗
PubMed2004

Neurologic complications of plasma cell disorders.

Plasma cell disorders are associated with a wide spectrum of neurologic complications that predominantly involve the peripheral nervous system. Distinct clinical syndromes have been recognized, and antibodies to several glycoproteins of the peripheral nervous system have been identified. The main clinical, laboratory, immunologic, and pathologic features of neurologic complications that occur in patients with monoclonal gammopathies of unknown significance, multiple myeloma, plasmacytoma, plasma cell leukemia, Waldenstrom's macroglobulinemia, and immunoglobulin-related amyloidosis are summarized in this review. Knowledge of the pathogenesis in this group of disorders has increased in recent years, allowing better diagnosis and treatment.

Cryoglobulinemia↗
PubMed2003

Enhanced differentiation of splenic plasma cells but diminished long-lived high-affinity bone marrow plasma cells in aged mice.

In the present work, we have dissected the mechanisms responsible for the impaired humoral responses in aging. We found that there was a substantially higher level of Ab-forming cells in the spleens of aged mice than that of young controls. However, the number of high-affinity, class-switched Ab-forming cells was severely decreased in the spleen of aged mice. The accumulation of low-affinity IgM Ab-forming cells in the spleens of aged animals was not due to a deficiency in isotype switching because the number of total IgG1 splenic plasma cells was not significantly reduced. Remarkably, plasma cells of both low and high affinity were significantly diminished in the bone marrow of aged mice compared with that of young mice. The results from reconstitution experiments showed that aged bone marrow was less supportive for plasma cells derived from young splenic B cells. These findings suggest that humoral immune deficiency in aging results from at least two mechanisms: the inability to generate sufficient numbers of high-affinity Ab-forming cells, which is a result of diminished germinal center reaction, and the defective bone marrow environment that has diminished ability to support the selection and survival of long-term Ab-forming cells.

Aging↗
PubMed1997

Human naive B cells cultured with EL-4 T cells mimic a germinal center-related B cell stage before generating plasma cells. Concordant changes in Bcl-2 protein and messenger RNA levels.

The T cell-dependent B cell response in vivo occurs in organized microenvironments. Alternative routes exist in that early plasma cells are generated in the T zone while others emerge later from the germinal center (GC) reaction. We investigated whether B cell stages resembling those defined in vivo/ex vivo might be induced in an in vitro system in which naive human B cells are activated by EL-4 T cells and cytokines. Adult peripheral blood- or cord blood-derived B cells were found to mimic an early activated stage (CD38(low), IgD+, increased CD5+) followed by a centroblastic GC-related stage (CD38(int), CD77+, CD95(Fas)+, Bcl-2 protein(low)) before differentiating into morphologically typical, CD38(high), Fas- plasma cells of an immature type (Bcl-2(low), VLA-5-). The GC-related cells and the plasma cells exhibited spontaneous apoptosis in medium, the former also undergoing anti-Fas antibody-induced apoptosis in medium as well as during CD40L exposure in the EL-4 cultures. These Bcl-2(low) cells maintained a high viability in contact with EL-4 cells. Thus, some, major B cell stages with typical functional features as described for cells in vivo/ex vivo are sequentially generated in this in vitro system and the kinetics of the changes can be analyzed in a synchronized cell population. With regard to previous apparently conflicting observations on the Bcl-2 mRNA level in GC B cells, we performed competitive reverse-transcription polymerase chain reaction. Concordant changes in Bcl-2 mRNA and protein levels were found, i.e. during Bcl-2 down-regulation in the GC-related B cells in ongoing EL-4 cultures or in medium, and during a more modest up-regulation upon contact with fresh EL-4 cells. Regulation of Bcl-2 protein, therefore, predominantly occurred at the mRNA steady-state level.

Adult↗
PubMed2003

Intraepithelial plasma cells in the avian copulatory organ of two tinamou species: quantitative variation during the breeding season.

A recent observation concerning the phallus of the tinamou Nothura maculosa was the presence of cells resembling plasma cells within the epithelium of the fixed tubular portion. Owing to this unusual location of plasma cells, we studied the phalli of the tinamous N. maculosa and Rhynchotus rufescens to confirm the occurrence of intraepithelial plasma cells and to evaluate the seasonal variation in these cells. Abundant plasma cells were found within the epithelium of the fixed tubular portion of the phallus but not in the evertible portion. Migration of plasma cells from the adjacent connective tissue through the basement membrane and between the epithelial cells was frequent. Some plasma cells exhibited a rough endoplasmic reticulum with variable cisternal distension, containing fine, slightly electron-dense, granular material suggestive of immunoglobulin accumulation. An expressive increase of more than 800% in the number of intraepithelial plasma cells was found during the breeding season compared to the non-breeding season. By establishing the occurrence of intraepithelial plasma cells in the phallus and their seasonal variation, the results contribute to a better understanding of the role of these cells in the mucosal immune system of the reproductive tract of male birds.

Animals↗
PubMed2000

Intracranial plasma cell granuloma.

Plasma cell granulomas (PCGs) are benign, inflammatory masses of unknown etiology composed of polyclonal mature plasma and lymphoid cells. The lung is their most common location, and occurrence within the cranial cavity is extremely rare. We report the case of an 11-year-old girl who presented with seizures and was diagnosed as having a dural-based right frontal tumor that extended toward the sagittal sinus and the falx. The lesion was totally excised, together with the abnormal dura. A limited cortical excision was also performed using electrocorticographic guidance. Histopathologic diagnosis of intracranial plasma cell granuloma was reached after extensive immunohistochemical tests and electron microscopy. This is the third case of PCG with description of changes in the neighboring cerebral tissue. Although PCGs are well-circumscribed lesions, lymphoplasmocytic inflammation, neuronal loss, and reactive gliosis occur within the adjacent cortex. Disturbed cortical lamination, as we have observed, appears to be a histological finding that has not been described previously.

Adolescent↗
PubMed2005

Clonal plasma cells from monoclonal gammopathy of undetermined significance, multiple myeloma and plasma cell leukemia show different expression profiles of molecules involved in the interaction with the immunological bone marrow microenvironment.

The immunological bone marrow (BM) microenvironment plays a major role in controlling growth and survival of clonal plasma cells (PC); this might translate into different patterns of expression of molecules involved in immune responses on PC from different types of monoclonal gammopathies (MG). We have studied the expression of a group of nine such molecules on both BMPC and the plasma of 61 newly diagnosed MG patients (30 MG of undetermined significance (MGUS), 27 multiple myeloma (MM) and four plasma cell leukemia (PCL)) and five normal individuals. Clonal PC from all MG displayed significantly increased levels of CD56, CD86 and CD126, and decreased amounts of CD38 (P<0.001). Additionally, HLA-I and beta2-microglobulin were abnormally highly expressed in MGUS, while CD40 expression was decreased in MM and PCL (P<0.05). Interestingly, a progressive increase in the soluble levels of beta2-microglobulin was found from MGUS to MM and PCL patients (P=0.03). In contrast, all groups showed similar surface and soluble amounts of CD126, CD130 and CD95, except for increased soluble levels of CD95 observed in PCL. Overall, those phenotypic differences are consistent with increased antigen presentation and costimulatory capacities in MGUS, which progressively deteriorate in malignant MG (MM and PCL).

Aged↗
PubMed1989

Endothelial cell receptors on leukemic plasma cells.

The binding of peripheral blood mononuclear cells of 7 patients with plasma cell leukemia to rat lymph node high endothelial venules has been studied in vitro. The mononuclear cells adhered selectively to the high endothelial venules. Their neoplastic origin was proved by in situ demonstration of their monoclonal cytoplasmic immunoglobulins. The in vitro binding of bone marrow mononuclear cells of 4 patients with multiple myeloma to high endothelial venules was also studied. In two patients there was no high endothelial cell binding. In the two others some adhering cells were observed. The plasmacytoid nature of these cells was, however, excluded for lack of cytoplasmic immunoglobulins. Since cells at the end stage of B-cell differentiation lose their surface receptors associated with lymphocyte recirculation, the presence of endothelium-recognizing structures on leukemic plasma cells seems to be remarkable.

Cell Adhesion↗
PubMed2002

The cholesterol lowering drug lovastatin induces cell death in myeloma plasma cells.

Lovastatin is an irreversible inhibitor of HMG-CoA reductase and blocks the production of mevalonate, a critical compound in the production of cholesterol and isoprenoids. Isoprenylation of target proteins, like the GTP-binding protein Ras, is essential for their membrane localization and subsequent participation in intracellular signaling cascades. Lovastatin effectively decreased the viability of plasma cells from cell lines (n = 10) and myeloma patients' samples (n = 8) in a dose- and time-dependent way. Importantly, co-incubation of lovastatin with dexamethasone had a synergistic effect in inducing plasma cell cytotoxity. This effect was not the consequence of a change in the protein expression levels of Bcl-2 or Bax induced by lovastatin. The decrease in plasma cell viability was the result of induction of apoptosis and inhibition of proliferation. Mevalonate effectively reversed the cytotoxic and cytostatic effects of lovastatin in plasma cells. The cytotoxic activity of lovastatin was higher in Pgp expressing cell lines, but did not correlate with the multidrug resistance (MDR)-related proteins LRP, Bcl-2 and Bax. Lovastatin treatment resulted in a shift of Ras localization from the membrane to the cytosol that was reversed by mevalonate. The data presented in this paper warrant study of lovastatin alone or in combination with therapeutic drugs, in the treatment of myeloma patients.

Anticholesteremic Agents↗
PubMed1999

Mature plasma cells as indicator of better prognosis in multiple myeloma. New methodology for the assessment of plasma cell morphology.

The relationship between plasmablastic cells and outcome in multiple myeloma (MM) has been established for nearly 15 years. But the assessment of these cells is not easy to perform and it allows the identification of only a small proportion of patients. We investigated the plasma cell morphology using a progressive evaluation of consecutive criteria: nucleolus, chromatin and nuclear-cellular ratio (N/C). The combination of these three items produces a subclassification where four cellular subtypes identify 93% of the plasma cells, and these subtypes are related to the outcome. The interest of this methodology is to be based on the mature plasma cells that are easier to identify than the plasmablastic cells. These new cell subtypes introduce a new classification for patients: Group 1 includes patients with at least 66% mature plasma cells (P000). Both Group 2 and 3 have less than 66% P000 and are separated by their degree of maturation (Proplasma I > or = Proplasma II + plasmablastic). The distinction of these three groups of patients is highly related to the prognosis (P < 10(-4)). These results have been confirmed on a second group of patients coming from a different institution. In conclusion, we propose a new methodology for the plasma cell evaluation in MM, that is based on the morphological criteria and that has the advantage of identifying an intermediate (30%) subgroup of patients with a prognostic significance.

Algorithms↗
PubMed1996

Clonal circulating cells are common in plasma cell proliferative disorders: a comparison of monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and active myeloma.

The blood of most patients with active multiple myeloma (MM) contains cells related to the bone marrow tumor. However, identifying clonal cells in the blood of patients with monoclonal gammopathy of undetermined significance (MGUS) has been difficult. In this study, we analyzed blood mononuclear cells (BMNCs) from 16 patients with MGUS, 2 with amyloidosis, 8 with smoldering MM (SMM), 2 with indolent MM (IMM), and 15 with active MM using three different methods to detect and quantitate clonal cells, ie, immunofluorescence microscopy (IM) for monoclonal plasma cells, three-color flow cytometry (FC) for CD38(+)CD45- CD45(dim) cells, and the allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). Using ASO-PCR, we were able to detect clonal cells in the blood in 13 of 16 patients with MGUS, 2 of 2 with amyloid, 6 of 8 with SMM, 2 of 2 with IMM, and 13 of 15 with MM. In 9 of the 13 patients with MGUS with blood involvement, the number of clonal cells was very small ( < 0.04% of the BMNCs). The median percentage of clonal cells as determined by ASO-PCR was 0.02 for MGUS, 0.02 for SMM, and 0.24 for MM. Clonal plasma cells or CD38+CD45-CD45(dim) cells were identified by IM or FC in 6 of 16 MGUS patients, 4 of 8 with SMM, and 11 of 15 with MM. In all cases in which IM or FC detected clonal cells, the ASO-PCR was positive. This study shows that, by using ASO-PCR, clonal cells can be found at very low levels in the blood in most patients with MGUS. However, the number of clonal cells in the blood of MGUS patients is less than those with overt MM (P = .006). In contrast to MGUS, patients with active MM are more likely to have identifiable clonal circulating plasma cells (P = .05).

Alleles↗
PubMed1982

Flow cytometric analysis of DNA content of bone marrow cells in patients with plasma cell myeloma: clinical implications.

DNA content analysis by flow cytometry was performed in 32 patients with plasma cell myeloma and 3 patients with Waldenstrom's macroglobulinemia to determine the biologic and potential clinical usefulness of this technique. Hyperdiploid tumor DNA content was found in 23 myeloma patients (72%) during the course of illness, including 16/28 at presentation, but in none of 3 patients with Waldenstrom's macroglobulinemia. There was no significant association of aneuploidy in myeloma patients with age, sex, race, or M-protein class. Myeloma patients with aneuploid tumor cells were more likely to have advanced stage (p = 0.032) than patients with diploid plasma cells, and all patients with renal failure had aneuploid tumors. Pretreatment factors significantly associated with survival included stage (p = 0.01), serum creatinine (p = 0.003), and tumor DNA content (p = 0.005). Multivariate analysis using the Cox life table regression procedure indicated that the significant relation of tumor DNA content with survival remained after adjusting for stage (p less than 0.005). Myeloma patients with diploid tumors at diagnosis frequently had aneuploid plasma cells at the time of relapse, indicating a possible relationship of chromosomal alterations in the tumor to clinical drug resistance. We conclude that aneuploid tumor cells at the time of diagnosis of myeloma are of independent prognostic significance, and the development of aneuploidy is a frequent occurrence at clinical relapse, suggesting the change in DNA content are of biologic and clinical significance.

Adult↗
PubMed1993

Quantitation of circulating peripheral blood plasma cells and their relationship to disease activity in patients with multiple myeloma.

BACKGROUND: The analysis of peripheral blood mononuclear cells for plasma cells and B-cell surface light chain ratios may provide additional insight on the pathogenesis of multiple myeloma and predict disease activity. The goals of this study were to correlate these parameters with clinically determined disease activity and establish a cutoff value of circulating plasma cells that could be used in future clinical trials. METHODS: Peripheral blood samples from 84 patients with monoclonal gammopathies were analyzed by an immunofluorescence, slide-based, labeling index (LI) technique for detection of plasma cells, the LI, and light chain ratios. These parameters were compared with disease activity. RESULTS: Of the 84 patients studied, 27% had inactive and 73% had active disease. The mean number of plasma cells for patients with inactive disease was 0.61 x 10(6)/l, compared with 139.6 x 10(6)/l for patients with active disease (P < 0.001). The mean ratios of involved to uninvolved light chain percentages for patients with inactive and active disease were 1.6 and 9.2, respectively (P = 0.002). The absolute number of plasma cells better predicted disease activity than the light chain ratio. By use of a cutoff value of 3 x 10(6)/l, 67% of patients with active disease were determined to have 3 x 10(6)/l or more plasma cells, and 96% of those with inactive disease had less than 3 x 10(6)/l plasma cells. CONCLUSIONS: These results suggest that detection of circulating plasma cells is a marker of disease activity in patients with plasma cell disorders and that an appropriate cutoff value is 3 x 10(6)/l or more circulating plasma cells.

Blood Cell Count↗
PubMed2005

IL-21 induces differentiation of human naive and memory B cells into antibody-secreting plasma cells.

IL-21 is a type I cytokine that influences the function of T cells, NK cells, and B cells. In this study, we report that IL-21 plays a major role in stimulating the differentiation of human B cells. When human B cells were stimulated through the BCR, IL-21 induced minimal proliferation, IgD down-modulation, and small numbers of plasma cells. In contrast, after CD40 engagement, IL-21 induced extensive proliferation, class switch recombination (CSR), and plasma cell differentiation. Upon cross-linking both BCR and CD40, IL-21 induced the largest numbers of plasma cells. IL-21 drove both postswitch memory cells as well as poorly responsive naive cord blood B cells to differentiate into plasma cells. The effect of IL-21 was more potent than the combination of IL-2 and IL-10, especially when responsiveness of cord blood B cells was examined. IL-21 costimulation potently induced the expression of both B lymphocyte-induced maturation protein-1 (BLIMP-1) and activation-induced cytidine deaminase as well as the production of large amounts of IgG from B cells. Despite the induction of activation-induced cytidine deaminase and CSR, IL-21 did not induce somatic hypermutation. Finally, IL-2 enhanced the effects of IL-21, whereas IL-4 inhibited IL-21-induced plasma cell differentiation. Taken together, our data show that IL-21 plays a central role in CSR and plasma cell differentiation during T cell-dependent B cell responses.

Antibody Formation↗
PubMed2001

Plasma cell leukemia.

Plasma cell leukemia (PCL) is a rare aggressive variant of multiple myeloma (MM) characterized by a fulminant course and poor prognosis. The median survival is measured in months. Therapy and prognosis partially depend on whether the disease presents de novo or as a secondary process involving the leukemic transformation of a previously diagnosed MM. Secondary PCL represents a terminal event for refractory/relapsed MM and is usually not responsive to any treatment modality. The optimal regimens for the treatment of primary PCL have not been firmly established. Induction with combination chemotherapy, followed by high-dose chemotherapy (preferably within the setting of a clinical trial), is the current recommended approach for eligible patients.

Antineoplastic Agents↗
PubMed1996

A combination of IL-10 and direct contact with plasma cell tumors decreases CD23 expression on splenic B cells.

We and others have previously found that splenic B cells from plasma cell tumor-bearing mice exhibit decreased CD23 expression. In the present study we further examined the mechanism of CD23 down-regulation by plasma cell tumors. We show here that although direct contact is required between the tumor cells and B cells, it is not sufficient, since fixed tumor cells do not induce the same reduction in CD23 expression. We have identified IL-10, a cytokine produce by the tumors, as the sole soluble factor that contributes to decreased CD23 expression on B cells induced by plasma cell tumors because 1) Abs to IL-10 prevent the loss of CD23 induced by plasma cell tumors both in vitro and in vivo; 2) engineered IL-10 negative variants of these tumors are reduced in their ability to down-regulate CD23 expression; 3) rIL-10 alone induces partial, but significant, decreases in CD23 expression on normal splenic B cells; and 4) the addition of IL-10 and fixed tumor cells to cultures of normal splenocytes decreases CD23 expression to levels similar to those in cocultures with live tumor cells. Collectively, these results demonstrate that plasma cell tumors down-regulate CD23 expression on B cells by a coordinate mechanism of IL-10 plus contact-mediated events and reveal a novel role for IL-10 in the regulation of CD23 expression on B cells that is suggestive of host B cell activation in the presence of the tumor.

Animals↗
PubMed1992

Expression of the bcl-2 gene in human multiple myeloma cell lines and normal plasma cells.

The bcl-2 gene, encoding a mitochondrial membrane protein suggested to play an important role in cell survival, is translocated into the Ig loci in about 80% of human follicular lymphomas, which results in a high level of expression. This report shows that bcl-2 was expressed in eight of eight human multiple myeloma cell lines and in normal lymph node and bone marrow plasma cells. In the majority of the myeloma lines, the level of expression was comparable with that observed in Karpas 422, a follicular lymphoma cell line carrying a 14;18 translocation of the bcl-2 gene. DNA rearrangements of the bcl-2 locus were evident in only one of the myeloma cell lines, U-266-1970. In this cell line, which exhibited the highest bcl-2 expression, a fourfold increased copy number of the bcl-2 gene was estimated by Southern analysis. This amplification was lost in cells of later passages (U-266-1984), suggesting that bcl-2 might possibly have played a role in the tumor development in vivo. Our results are in contrast to previous observations in murine plasmacytoma, in which bcl-2 was shown to be silent. The results also contradict the published observation that bcl-2 is not expressed at terminal stages of B-cell differentiation. It is at present unclear whether the high expression of bcl-2 in human myeloma is the result of a deregulated expression associated with the malignant phenotype or a mere reflection of the bcl-2 expression typical of normal plasma cells.

Blotting, Southern↗