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PubMed2002

Nodal marginal zone B-cell lymphoma resembling plasmacytoma arising from a plasma cell variant of localized Castleman's disease: a case report.

Nodal marginal zone B-cell lymphoma (NMZBL) occasionally represents prominent plasma cell differentiation. Recently, primary lymph node plasmacytoma has been suggested to represent an extremely plasmacytic differentiation of NMZBL. We here report a case of NMZBL showing histological features resembling plasmacytoma arising from a plasma cell variant of localized Castleman's disease (PCLCD). The patient was a 69-year-old Japanese female with a 20-year history of a right inguinal mass. Histologically, a prominent proliferation of plasma cells occupied the interfollicular area of the central portion of the lymph node, whereas centrocyte-like (CCL) cells were the main cellular component in the peripheral portion of the lymph node. Although most of the plasma cells were mature 'Marshalko-type', occasional atypical forms with enlarged nuclei were also present. The majority of the lymphoid follicles had atrophic or regressive germinal centers. A few lymphoid follicles were colonized by CCL cells. Immunohistochemistry study revealed that both plasma cells and some CCL cells had a monotypic intracytoplasmic lambda light chain. When monoclonal plasma cell infiltration is observed in PCLCD, the light chains are mostly restricted to the lambda chain. This case suggests that some plasma cell-containing tumors arising from PCLCD may represent a variant of NMZBL.

Aged↗
PubMed1992

Expression of adhesion molecules LFA-3 and N-CAM on normal and malignant human plasma cells.

Normal and malignant plasma cells were investigated for the expression of seven cellular adhesion molecules by immunofluorescence microscopy. The antigens investigated were CD2 and its ligand, LFA-3 (CD58). LFA-1 alpha (CD11a) and LFA-1 beta (CD18) and their ligand ICAM-1 (CD54), H-CAM (lymphocyte homing receptor; CD44) and N-CAM (CD56). Marrow from 18 patients with myeloma, two with plasma cell leukaemia (PCL), four with monoclonal gammopathy of uncertain significance (MGUS) and 10 normal allogeneic bone marrow donors was studied. All plasma cells from normals and multiple myeloma patients were negative for CD2, CD11a and CD18. All normal and myeloma marrow plasma cells were positive for ICAM-1. 16/18 myeloma cases tested, and all other samples (normal, MGUS and PCL), contained plasma cells positive for H-CAM. Only one normal, but 12/16 myelomas tested were positive for N-CAM (P less than 0.02). One of four MGUS cases was moderately positive and one other weakly positive for N-CAM. Both PCLs were N-CAM negative. 12/18 myelomas were positive for LFA-3, but only two normals (P less than 0.05). All MGUS cases were negative for LFA-3, as was one PCL, the other being weakly positive. Three cases were negative for both adhesion molecules, three cases expressed only N-CAM or LFA-3 and 10 cases expressed both. LFA-3 and N-CAM are expressed significantly in myeloma rather than normal plasma cells. Cases of MGUS may express N-CAM but not, in this small series, LFA-3. Plasma cells in the peripheral blood (PCL) and plasma cell lines express little or no LFA-3 or N-CAM.

Antigens, CD↗
PubMed2002

Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program.

Blimp-1, a transcriptional repressor, drives the terminal differentiation of B cells to plasma cells. Using DNA microarrays, we found that introduction of Blimp-1 into B cells blocked expression of a remarkably large set of genes, while a much smaller number was induced. Blimp-1 initiated this cascade of gene expression changes by directly repressing genes encoding several transcription factors, including Spi-B and Id3, that regulate signaling by the B cell receptor. Blimp-1 also inhibited immunoglobulin class switching by blocking expression of AID, Ku70, Ku86, DNA-PKcs, and STAT6. These findings suggest that Blimp-1 promotes plasmacytic differentiation by extinguishing gene expression important for B cell receptor signaling, germinal center B cell function, and proliferation while allowing expression of important plasma cell genes such as XBP-1.

Animals↗
PubMed2001

A coordinated change in chemokine responsiveness guides plasma cell movements.

Antibody-secreting plasma cells are nonrecirculatory and lodge in splenic red pulp, lymph node medullary cords, and bone marrow. The factors that regulate plasma cell localization are poorly defined. Here we demonstrate that, compared with their B cell precursors, plasma cells exhibit increased chemotactic sensitivity to the CXCR4 ligand CXCL12. At the same time, they downregulate CXCR5 and CCR7 and have reduced responsiveness to the B and T zone chemokines CXCL13, CCL19, and CCL21. We demonstrate that CXCL12 is expressed within splenic red pulp and lymph node medullary cords as well as in bone marrow. In chimeric mice reconstituted with CXCR4-deficient fetal liver cells, plasma cells are mislocalized in the spleen, found in elevated numbers in blood, and fail to accumulate normally in the bone marrow. Our findings indicate that as B cells differentiate into plasma cells they undergo a coordinated change in chemokine responsiveness that regulates their movements in secondary lymphoid organs and promotes lodgment within the bone marrow.

Animals↗
PubMed2006

The sensitivity of CD138 immunostaining of bone marrow trephine specimens for quantifying marrow involvement in MGUS and myeloma, including samples with a low percentage of plasma cells.

Accurate quantification of plasma cells in bone marrow samples is essential for the diagnosis, classification and prognosis of plasma-cell dyscrasias. Published comparisons between aspirate/trephine morphology, flow cytometry and immunohistochemistry are lacking. Bone marrow plasma cells from 100 patients with plasma cell myeloma or monoclonal gammopathy of undetermined significance were quantified by a 500-cell differential count on Romanowsky-stained aspirate slides, flow-cytometry gating of CD38bright+/CD138+ cells, hematoxylin and eosin trephine section examination and CD138 trephine immunohistology. The results of quantification by the different methods were compared. Compared to other methods, CD138 trephine immunohistology consistently demonstrated greater plasma-cell infiltration. Immunohistology is the most sensitive method for assessment of plasma-cell infiltration at diagnosis or post-therapy, especially in patients with minimal bone marrow involvement.

ADP-ribosyl Cyclase 1↗
PubMed1993

Human pre-B cells differentiate into Ig-secreting plasma cells in the presence of interleukin-4 and activated CD4+ T cells or their membranes.

Studies on human B-cell development have been hampered by the lack of reproducible culture techniques to induce pre-B cells to differentiate into Ig-secreting plasma cells. Here, we describe that highly purified surface (s) mu-, cytoplasmic (c) mu+, CD10+, CD19+ human pre-B cells derived from fetal bone marrow (BM) differentiate with high frequencies into Ig-secreting plasma cells, when cocultured with activated, cloned CD4+ T cells and with interleukin-4 (IL-4). Production of IgM, total IgG, IgG4, and IgE in pre-B-cell cultures was detected, indicating that the cells also underwent Ig isotype switching. Pre-B-cell differentiation occurred in the absence of BM stromal cells, IL-7, and stem cell factor (SCF). However, IL-7 significantly enhanced the levels of Ig produced, whereas SCF was ineffective. Neutralizing anti-IL-4 monoclonal antibodies (MoAbs) completely inhibited pre-B-cell differentiation showing the specificity of the reaction. Intact CD4+ T-cell clones could be replaced by membrane preparations of these cells, indicating that the costimulatory signals provided by the activated CD4+ T cells are contact-mediated. In contrast, anti-CD40 MoAbs failed to provide the costimulatory signal required for pre-B-cell differentiation, which may be related to the very low expression of CD40 on fetal BM B cells. Activated CD4+ T cells and IL-4 also induced s mu expression and Ig synthesis in cultures initiated with pre-B cells that had been preincubated in medium for 2 days, and from which spontaneously emerging s mu+ B cells were removed by using a fluorescence-activated cell sorter. These results support the notion that the Ig synthesis observed in pre-B-cell cultures was not caused by outgrowth and differentiation of cells that spontaneously matured into s mu+ B cells. In addition, IL-4 and CD4+ T cells strongly enhanced CD40 and HLA-DR expression on the majority of cultured pre-B cells, further indicating that CD4+ T cells and IL-4 activate bona fide pre-B cells. Taken together, these data indicate that activated CD4+ T cells and IL-4 can provide all the necessary signals required for human pre-B cells to differentiate into Ig-secreting plasma cells.

Antigens, CD↗
PubMed2002

IL-10 enhances B-cell IgE synthesis by promoting differentiation into plasma cells, a process that is inhibited by CD27/CD70 interaction.

Interleukin-10 (IL-10) is a major regulatory cytokine of inflammatory responses that is considered to play an important role in specific immunotherapy. However, whether IL-10 enhances or inhibits B-cell IgE production has remained a matter of contention. To clarify the effect of IL-10 on IgE synthesis in the presence of IL-4 and CD40 signalling, we examined B-cell proliferation, germline epsilon transcripts and plasma cell differentiation. In addition, the effect of CD27 signalling on IgE synthesis in the presence of IL-10, IL-4 and CD40 signalling was investigated. IL-10 facilitated the production of IgE in mononuclear cells and highly purified B-cells, enhanced B-cell proliferation and, most importantly, promoted the generation of plasma cells. However, IL-10 did not enhance expression of germline epsilon transcripts. The addition of CD27 signalling through the use of CD32-CD27 ligand (CD70) double transfectants significantly diminished the B-cell proliferation, IgE synthesis and plasma cell differentiation enhanced by IL-10. IL-10 enhances B-cell IgE production by promoting differentiation into plasma cells. CD27/CD70 interactions under IL-10 and sufficient CD40 cosignalling exert the opposite effect on IgE synthesis. The results of this study indicate that precautions are critical when planning immunotherapy using IL-10 in IgE-related allergic diseases.

Adult↗
PubMed2003

Plasma cell leukemia--a case report.

Plasma cell leukemia, occurring either de novo or in patients with long standing multiple myeloma, is the least common type of plasma cell dyscrasia. Histogenetically plasma cell leukemia is derived from terminally differentiated B cells. It is diagnosed by presence of absolute plasma cell count >2000/cm or >20% circulating plasma cells. Two cases of plasma-cell leukemia are reported here. Clinical spectrum and course of the disease, are discussed. Both cases (of primary plasma cell leukemia) had abrupt onset of disease, poor response to therapy and short survival time. Both presented with fatiguability and weakness. Evidence of organomegaly and radiological and hematological evidence of plasma cell leukemia, with thrombocytopenia and evidence of visceral involvement with leukemic cells, was seen in one case.

Bone Marrow↗
PubMed1988

Heterogeneity of the plasma cell response to bovine staphylococcal mastitis: an ultrastructural study.

Mammary tissue samples from glands of dairy cows with chronic Staphylococcus aureus mastitis were examined by light and transmission electron microscopy. Cytological observations were limited to the mucosal tissues of the gland and teat cisternal areas where accumulations of lymphoid cells predominated. Plasma cells were the most numerous leucocyte type present in these areas and exhibited varied ultrastructural characteristics. Although the majority of plasma cells were normal in appearance, cells with abnormal ultrastructure were frequently observed, including cells with distended rough endoplasmic reticulum, cells with cytoplasm entirely engorged with immunoglobulin, and necrobiotic cells. Results demonstrated copious production of local immunoglobulins, predominantly IgG, in response to staphylococcal infection. Atypical cell types observed may have indicated a functional disturbance of immunoglobulin secretion associated with chronic mastitis.

Animals↗
PubMed1980

The separation of human palatine tonsillar cells in the reorienting gradient zonal rotor: a large-capacity enrichment of plasma cells.

Velocity sedimentation by centrifugation in a previously described isokinetic gradient, at unit gravity, or with an elutriator has proved to be highly effective as a method for the enrichment of many kinds of cells. For many biochemical and immunological purposes, the available techniques for the separation of cells have been incapable of separating a sufficient number of cells. With a newly designed rotor, we have separated more than twenty-fold more human tonsillar cells that can be separated in the previously described isokinetic gradient. Without exceeding the band capacity, we separated 692 million tonsillar cells. Plasma cells were more than seven-fold enriched from human tonsillar cells. When 692 million tonsillar cells were separated in the rotor, the five most enriched, contiguous fractions of plasma cells contained 44 million cells. The most enriched fraction contained 27% plasma cells. We are not aware of any method for velocity sedimentation which will separate such large numbers of tonsillar cells.

Cell Count↗
PubMed2006

Immunization-induced perturbation of human blood plasma cell pool: progressive maturation, IL-6 responsiveness, and high PRDI-BF1/BLIMP1 expression are critical distinctions between antigen-specific and nonspecific plasma cells.

The present study shows that reimmunization with tetanus toxoid (tet) caused a transient increase of the human blood plasma cell (PC) pool, detectable from 6th to 15th day postboost, as well as the temporal alteration of several PC features. Labeling of specific PC with FITC-tet C fragment (tetC) allowed kinetics analysis of the tetC(+) and tetC(-) PC, and revealed remarkable differences between them: 1) the kinetics of tetC(+) PC occurrence was exponential, and most of them appeared in a narrow time frame (5th to 8th day postboost), whereas the tetC(-) PC increase was lower (three to five times) and more prolonged (4th to 15th day postboost). 2) The tetC(+) PC subset contained a fraction of cycling cells, expressed high levels of DR, CD138, and CD126, and responded to IL-6 by improving their survival and Ig secretion; in contrast, the tetC(-) PC showed higher CXCR4 and lower DR and CD138, did not respond to IL-6, and contained a fraction of apoptotic cells. 3) Sequential phenotypic analysis revealed maturational changes within the tetC(+), but not tetC(-), PC subset; sequencing of tetC(+) PC IgVH genes showed clear features of Ag selection. 4) The tetC(+) PC expressed several times more positive regulatory domain I- binding factor 1/B lymphocyte-induced maturation protein 1 transcription factor than the tetC(-) PC. 5) The tetC(-) PC and bone marrow resident PC similarly expressed low DR and high CXCR4, but differed in that the latter exhibited higher levels of CD31, CD138, and positive regulatory domain I- binding factor 1/B lymphocyte-induced maturation protein 1. These findings support the view that tetC(+) PC contain bone marrow PC precursors, and tetC(-) PC probably belong to a removable compartment of aged PC.

Antigens↗
PubMed2002

Expression of transcription factors Pu.1, Spi-B, Blimp-1, BSAP and oct-2 in normal human plasma cells and in multiple myeloma cells.

Differentiation of B lymphocytes into plasma cells is regulated by the interaction of distinct transcription factors (TFs) which activate gene expression in a lineage- and stage-specific pattern. Using reverse transcription polymerase chain reaction, we studied the expression of five TFs (octamer binding factor oct-2, ets family members PU.1 and Spi-B, pax gene family member BSAP, and Blimp-1) in (1) human cell lines with a plasma cell phenotype, (2) primary malignant plasma cells [obtained from patients with plasma cell leukaemia (PCL) and multiple myeloma], and (3) normal human plasma cells generated in vitro or isolated from normal bone marrows. The expression pattern was compared with TFs expressed by normal CD19+ B lymphocytes and by B cells from chronic lymphocytic leukaemia patients. Our results showed that plasma cells expressed a restricted set of TFs compared with CD19+ B lymphocytes, with continued expression of Spi-B and oct-2, increased Blimp-1 expression, and downregulation of BSAP and PU.1. Cells from PCL lost Spi-B and PU.1 expression completely and expressed only oct-2 and Blimp-1, and thus resembled plasma cell lines. Human plasma cell differentiation therefore seems to be positively regulated by Blimp-1; whether this TF has any oncogenic potential will have to be analysed in future studies.

Antigens, CD19↗
PubMed1991

Interleukin 6 (IL-6) and its receptor: their role in plasma cell neoplasias.

Interleukin 6 (IL-6) is a multifunctional cytokine regulating immune response acute phase reaction and hematopoiesis. IL-6 plays a critical role in B cell differentiation to plasma cells and is a potent growth factor for plasmacytoma and myeloma. Abnormal production of IL-6 has been suggested to be involved in polyclonal plasma cell abnormalities and plasma cell neoplasias. The deregulated expression of the IL-6 gene in transgenic mice resulted in the generation of malignant plasmacytoma. Based on these findings, it could be considered that continuous IL-6 gene expression plays an essential role in a multistep oncogenesis of plasma cell neoplasias. The role of IL-6 and its receptor in the generation of plasma cell neoplasias and the mechanisms of the IL-6 gene expression and IL-6 receptor-mediated signal transduction are described.

Animals↗
PubMed2003

Gene expression profiling reveals a highly specialized genetic program of plasma cells.

The formation of terminally differentiated plasma cells represents the critical final step in B-cell differentiation. In this study, utilizing oligonucleotide microarray analysis, we describe the highly specialized genetic profile exhibited by terminally differentiated plasma cells. A total of 1476 known genes were differentially expressed by plasma cells compared with B cells. Plasma cells displayed an up-regulation, induction, or a selective retention of a unique constellation of transcription factors, including members of the AP-1, nuclear factor-kappaB (NF-kappaB), nuclear factor of activated T cells (NFAT), and octamer binding factor families. Interestingly, plasma cells also displayed a down-regulation of several RNA polymerase I- related factors, consistent with terminal differentiation, and exhibited a down-regulation of the TATA box binding protein. Furthermore, plasma cells displayed alterations in multiple components of the Wnt and Notch signaling pathways and showed a unique pattern of apoptosis and proliferation-associated genes. Unexpectedly, plasma cells displayed an up-regulation of 2 factors normally associated with microenvironmental positioning of neuronal cells, reelin and neuropilin-1. These results supply insight into the developmental genetics of plasma cell differentiation and provide a foundation for further analysis of plasma cell biology.

Animals↗