Tumor Protein D52 (TPD52): A Novel B Cell/Plasma Cell Molecule Identified through a Proteomic Approach and Characterized by Unique Expression Pattern and Ca2+-Dependent Association with Annexin VI.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3652-3652
Author(s):  
Enrico Tiacci ◽  
Pier-Luigi Orvietani ◽  
Barbara Bigerna ◽  
Alessandra Pucciarini ◽  
Roberta Pacini ◽  
...  
Keyword(s):  
B Cells ◽  
Epithelial Cells ◽  
B Cell ◽  
Expression Pattern ◽  
Plasma Cell ◽  
Cell Protein ◽  
Cell Plasma ◽  
Annexin Vi ◽  
Hodgkin's Lymphomas ◽  
Unique Expression Pattern

Abstract Background. Proteomics can integrate hybridoma technology in discovering new antigens through the characterization of monoclonal antibodies (mAbs) of unknown specificity, that are generated when using whole cells and even purified known proteins as immunogens. Aim. To characterize, by means of a new mAb (B28p), a protein sharing an antigenic determinant with IRTA1, i.e. the unrelated immunogen used in the unforeseen generation of B28p. Methods/Results. Among ~1000 hybridomas from mice immunized with IRTA1, one producing an IgG1 mAb (B28p), cross-reactive with IRTA1, recognized also a 28 kDa cytoplasmic protein expressed strongly by all mature B cell subsets, with the highest levels in plasma cells (PC), and weakly by epithelial cells. This pattern clearly differs from that expected for IRTA1, a 70 kDa cell membrane receptor selectively expressed in MALT marginal zone B cells (Falini et al, Blood2003;102:3684). To identify the 28 kDa antigen, the proteome of a B28p+ B-NHL was resolved by 2D-PAGE, and tandem mass spectrometry analysis revealed the B28p-immunoreactive spot as human tumor protein D52 (TPD52), previously described to be expressed only in epithelial tissues. The specificity of B28p mAb for TPD52 was confirmed by immunostaining/immunoblotting TPD52-transfected cells and by observing an identical labeling pattern (mature B cells/PC and, less strongly, epithelial cells) upon immunohistology with a specfic anti-TPD52 polyclonal antibody. In routine tumor biopsies, TPD52 was expressed in all peripheral B-NHL subtypes (except some DLCLs) and most abundantly in multiple myeloma (MM). TPD52-staining proved to be a useful diagnostic tool in the quantification of bone marrow PC infiltration (thus helping in discriminating between MGUS and MM and in assessing minimal residual disease after therapy for MM), as well as in the evaluation of lymphomas associated with PC differentiation (including transplant-associated lymphomas, plasmablastic lymphomas of the oral cavity and primary effusion lymphomas). Notably, TPD52 was also expressed by a proportion of tumor cells in about 40% classical Hodgkin’s lymphomas, including cases misdiagnosed as ALK− ALCL with null phenotype. Unlike other B cell markers (PAX5,CD19,C79a,CD22,CD20), TPD52 represents the first example of a B cell protein whose expression increases during PC differentiation Intriguingly, in the Thiel myeloma cell line (similarly to what previously observed during zymogen secretion in pancreatic acinar cells), we found a strong and Ca+2-dependent co-immunoprecipitation of TPD52 with annexin VI, suggesting TPD52 up-regulation in PC may play a role in immunoglobulin-related secretory processes through interaction with annexin VI (which we also showed to be strongly expressed in PC). Conclusions. By combining proteomic and hybridoma technologies, we first identified the epithelium-associated TPD52 protein as a new B cell/plasma cell protein showing unique expression pattern, diagnostic value and, likely, biological importance.

scholarly journals Down-regulation of BLIMP1α by the EBV oncogene, LMP-1, disrupts the plasma cell differentiation program and prevents viral replication in B cells: implications for the pathogenesis of EBV-associated B-cell lymphomas

Blood ◽  
2011 ◽  
Vol 117 (22) ◽  
pp. 5907-5917 ◽  
Author(s):  
Katerina Vrzalikova ◽  
Martina Vockerodt ◽  
Sarah Leonard ◽  
Andrew Bell ◽  
Wenbin Wei ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Virus Replication ◽  
Plasma Cell ◽  
Germinal Center ◽  
Lytic Cycle ◽  
Transformed Cells ◽  
Down Regulation ◽  
Plasma Cell Differentiation

AbstractAn important pathogenic event in Epstein-Barr virus (EBV)-associated lymphomas is the suppression of virus replication, which would otherwise lead to cell death. Because virus replication in B cells is intimately linked to their differentiation toward plasma cells, we asked whether the physiologic signals that drive normal B-cell differentiation are absent in EBV-transformed cells. We focused on BLIMP1α, a transcription factor that is required for plasma cell differentiation and that is inactivated in diffuse large B-cell lymphomas. We show that BLIMP1α expression is down-regulated after EBV infection of primary germinal center B cells and that the EBV oncogene, latent membrane protein-1 (LMP-1), is alone capable of inducing this down-regulation in these cells. Furthermore, the down-regulation of BLIMP1α by LMP-1 was accompanied by a partial disruption of the BLIMP1α transcriptional program, including the aberrant induction of MYC, the repression of which is required for terminal differentiation. Finally, we show that the ectopic expression of BLIMP1α in EBV-transformed cells can induce the viral lytic cycle. Our results suggest that LMP-1 expression in progenitor germinal center B cells could contribute to the pathogenesis of EBV-associated lymphomas by down-regulating BLIMP1α, in turn preventing plasma cell differentiation and induction of the viral lytic cycle.

scholarly journals Immunolocalization of the ICE/Ced-3–Family Protease, CPP32 (Caspase-3), in Non-Hodgkin's Lymphomas, Chronic Lymphocytic Leukemias, and Reactive Lymph Nodes

Blood ◽  
1997 ◽  
Vol 89 (10) ◽  
pp. 3817-3825 ◽  
Author(s):  
Stanislaw Krajewski ◽  
Randy D. Gascoyne ◽  
Juan M. Zapata ◽  
Maryla Krajewska ◽  
Shinichi Kitada ◽  
...  
Keyword(s):  
B Cells ◽  
Lymph Nodes ◽  
B Cell ◽  
Germinal Center ◽  
Caspase 3 ◽  
Large Cell ◽  
B Cell Lymphomas ◽  
Mantle Zone ◽  
Dynamic Regulation ◽  
Hodgkin's Lymphomas

Immunohistochemical analysis of the apoptosis-effector protease CPP32 (Caspase-3) in normal lymph nodes, tonsils, and nodes affected with reactive hyperplasia (n = 22) showed strong immunoreactivity in the apoptosis-prone germinal center B-lymphocytes of secondary follicles, but little or no reactivity in the surrounding long-lived mantle zone lymphocytes. Immunoblot analysis of fluorescence-activated cell sorted germinal center and mantle zone B cells supported the immunohistochemical results. In 22 of 27 (81%) follicular small cleaved cell non-Hodgkin's B-cell lymphomas, the CPP32-immunopositive germinal center lymphocytes were replaced by CPP32-negative tumor cells. In contrast, the large cell component of follicular mixed cells (FMs) and follicular large cell lymphomas (FLCLs) was strongly CPP32 immunopositive in 12 of 17 (71%) and in 8 of 14 (57%) cases, respectively, whereas the residual small-cleaved cells were poorly stained for CPP32 in all FLCLs and in 12 of 17 (71%) FMs, suggesting that an upregulation of CPP32 immunoreactivity occurred during progression. Similarly, cytosolic immunostaining for CPP32 was present in 10 of 12 (83%) diffuse large cell lymphomas (DLCLs) and 2 of 3 diffuse mixed B-cell lymphomas (DMs). Immunopositivity for CPP32 was also found in the majority of other types of non-Hodgkin's lymphomas studied. Plasmacytomas were CPP32 immunonegative in 4 of 12 (33%) cases, in contrast to normal plasma cells, which uniformly contained intense CPP32 immunoreactivity, implying downregulation of CPP32 in a subset of these malignancies. All 12 peripheral blood B-cell chronic lymphocyte leukemia specimens examined were CPP32 immunopositive, whereas 3 of 3 small lymphocytic lymphomas were CPP32 negative, suggesting that CPP32 expression may vary depending on the tissue compartment in which these neoplastic B cells reside. The results show dynamic regulation of CPP32 expression in normal and malignant lymphocytes.

scholarly journals Potential anti-EBV effects associated with elevated interleukin-21 levels: a case report

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Kristian Assing ◽  
Christian Nielsen ◽  
Marianne Jakobsen ◽  
Charlotte B. Andersen ◽  
Kristin Skogstrand ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
Germinal Center ◽  
Plasma Cells ◽  
Cell Formation ◽  
Memory B Cells ◽  
Memory B Cell

Abstract Background Germinal center derived memory B cells and plasma cells constitute, in health and during EBV reactivation, the largest functional EBV reservoir. Hence, by reducing germinal center derived formation of memory B cells and plasma cells, EBV loads may be reduced. Animal and in-vitro models have shown that IL-21 can support memory B and plasma cell formation and thereby potentially contribute to EBV persistence. However, IL-21 also displays anti-viral effects, as mice models have shown that CD4+ T cell produced IL-21 is critical for the differentiation, function and survival of anti-viral CD8+ T cells able to contain chronic virus infections. Case presentation We present immunological work-up (flow-cytometry, ELISA and genetics) related to a patient suffering from a condition resembling B cell chronic active EBV infection, albeit with moderately elevated EBV copy numbers. No mutations in genes associated with EBV disease, common variable immunodeficiency or pertaining to the IL-21 signaling pathway (including hypermorphic IL-21 mutations) were found. Increased (> 5-fold increase 7 days post-vaccination) CD4+ T cell produced (p < 0.01) and extracellular IL-21 levels characterized our patient and coexisted with: CD8+ lymphopenia, B lymphopenia, hypogammaglobulinemia, compromised memory B cell differentiation, absent induction of B-cell lymphoma 6 protein (Bcl-6) dependent peripheral follicular helper T cells (pTFH, p = 0.01), reduced frequencies of peripheral CD4+ Bcl-6+ T cells (p = 0.05), compromised plasmablast differentiation (reduced protein vaccine responses (p < 0.001) as well as reduced Treg frequencies. Supporting IL-21 mediated suppression of pTFH formation, pTFH and CD4+ IL-21+ frequencies were strongly inversely correlated, prior to and after vaccination, in the patient and in controls, Spearman’s rho: − 0.86, p < 0.001. Conclusions To the best of our knowledge, this is the first report of elevated CD4+ IL-21+ T cell frequencies in human EBV disease. IL-21 overproduction may, apart from driving T cell mediated anti-EBV responses, disrupt germinal center derived memory B cell and plasma cell formation, and thereby contribute to EBV disease control.

scholarly journals HOXC4, HOXC5, and HOXC6 Expression in Non-Hodgkin's Lymphoma: Preferential Expression of the HOXC5 Gene in Primary Cutaneous Anaplastic T-Cell and Oro-Gastrointestinal Tract Mucosa-Associated B-Cell Lymphomas

Blood ◽  
1997 ◽  
Vol 90 (10) ◽  
pp. 4116-4125 ◽  
Author(s):  
Janet J. Bijl ◽  
Johan W. van Oostveen ◽  
Jan M.M. Walboomers ◽  
Anja Horstman ◽  
Adriaan J.C. van den Brule ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
B Cell ◽  
Expression Pattern ◽  
Gene Expression Pattern ◽  
Lymphoid Cells ◽  
B Cell Lymphomas ◽  
Preferential Expression ◽  
T Cell Lymphomas ◽  
Hodgkin's Lymphomas

Abstract Most of the 39 members of the homeobox (HOX) gene family are believed to control blood cell development. HOXC4 and HOXC6 gene expression levels increase with differentiation of lymphoid cells. In contrast, HOXC5 is not expressed in the lymphoid lineage, but was found in lymphoid cell lines, representing the neoplastic equivalents of various differentiation stages of T and B lymphocytes. In the present study, we investigated the HOXC4, HOXC5, and HOXC6 gene expression pattern in 89 non-Hodgkin's lymphomas (NHLs) of different histologic subtypes and originating from different sites. Using RNA in situ hybridization and semiquantitative reverse transcription-polymerase chain reaction, we found expression of HOXC4 in 83 of 88 and HOXC6 in 77 of 88 NHLs and leukemias investigated. In contrast, HOXC5 expression was found in only 26 of 87 NHLs and appeared to be preferentially expressed by two specific subsets of lymphomas, ie, primary cutaneous anaplastic T-cell lymphomas (9 of 9) and extranodal marginal zone B-cell lymphomas (maltomas; 7 of 9). These results indicate that, in contrast to HOXC4 and HOXC6, HOXC5 shows a type- and site-restricted expression pattern in both T- and B-cell NHLs.

Lack of Hcv Infection in Malignant, Cells Refutes the Hypothesis of a Direct Transforming Action of the Virus in the Pathogenesis of Hcv-Associated B-Cell Nhls

2002 ◽  
Vol 88 (5) ◽  
pp. 400-406 ◽  
Author(s):  
Salvatore De Vita ◽  
Valli De Re ◽  
Domenico Sansonno ◽  
Annunziata Gloghini ◽  
Daniela Gasparotto ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Hcv Infection ◽  
Low Grade ◽  
Immunoglobulin Gene ◽  
Pathogenetic Role ◽  
Exogenous Trigger ◽  
Grade One ◽  
Hodgkin's Lymphomas

Aims and background Preliminary evidence suggests that hepatitis C virus (HCV) might play a pathogenetic role in autoimmune-related, non-malignant B-cell lymphoproliferation, as well as in a subset of B-cell non-Hodgkin's lymphomas (NHLs). With regard to the mechanism(s) by which HCV might favor B-cell expansion and malignant transformation, most data support an indirect pathogenetic role of the virus as an exogenous trigger. A direct oncogenetic role of HCV by direct cell infection and deregulation has only been hypothesized on the basis of the lymphotropism of the virus. Methods In this study we investigated the possible HCV infection of NHL B cells by means of sensitive and quantitative polymerase chain reaction (PCR) on affinity-purified neoplastic cells, and by HCV-specific immunohistochemistry and in situ hybridization. Results HCV infection of neoplastic B cells was documented in only three cases, namely the low-grade B-cell NHLs that arose in the course of mixed cryoglobulinemia syndrome (MC). HCV infection, below one viral genome per cell, was detectable only by PCR. All the remaining low-grade (one case) and high-grade B-cell NHLs (two cases) were HCV uninfected. Previous immunoglobulin gene analyses were consistent with an antigen-driven B-cell lymphoproliferation in the studied cases. Conclusions Overall, our data are consistent with an indirect oncogenetic role of HCV in B-cell lymphomagenesis as an exogenous trigger. Infection of B cells by HCV appears possible in some NHL subsets, but the implications remain unknown.

scholarly journals Intrinsic Plasma Cell Differentiation Defects in B Cell Expansion with NF-κB and T Cell Anergy Patient B Cells

2017 ◽  
Vol 8 ◽  
Author(s):  
Swadhinya Arjunaraja ◽  
Brent D. Nosé ◽  
Gauthaman Sukumar ◽  
Nathaniel M. Lott ◽  
Clifton L. Dalgard ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
Cell Expansion ◽  
Plasma Cell Differentiation ◽  
T Cell Anergy ◽  
Cell Anergy

FRI0010 Disruption of dominant B-cell/plasma cell clones in rheumatoid arthritis synovium by rituximab correlates with treatment response

2013 ◽  
Vol 71 (Suppl 3) ◽  
pp. 313.3-313
Author(s):  
M.E. Doorenspleet ◽  
P.L. Klarenbeek ◽  
M.J. Boumans ◽  
R.M. Thurlings ◽  
R.E. Esveldt ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cell ◽  
Treatment Response ◽  
Plasma Cell ◽  
Rheumatoid Arthritis Synovium ◽  
Cell Clones ◽  
Cell Plasma

scholarly journals CD1c but neither CD1a nor CD1b molecules are expressed on normal, activated, and malignant human B cells: identification of a new B-cell subset

Blood ◽  
1988 ◽  
Vol 72 (1) ◽  
pp. 241-247 ◽  
Author(s):  
D Delia ◽  
G Cattoretti ◽  
N Polli ◽  
E Fontanella ◽  
A Aiello ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
De Novo ◽  
Cell Subset ◽  
Ultrastructural Level ◽  
Cytoplasmic Staining ◽  
Clear Cut ◽  
Hodgkin's Lymphomas

Abstract The CD1 cluster of monoclonal antibodies (MoAbs) CD1a, CD1b, and CD1c, identifies molecules that are differentially expressed on hematopoietic and nonhematopoietic tissues. Our earlier finding that the mantle zone (MZ) but not the germinal center (GC) of normal lymph nodes (LN) is CD1c+, CD1a-, and CD1b- prompted us to further investigate the expression of these molecules on normal, activated, and malignant B cells. We report that blood and spleen contain CD1c+ B cells that account for 49% +/- 20.4% (mean +/- SD) and 50.9% +/- 4.4% of the total B cell population, respectively. CD1a- and CD1b-specific MoAbs are unreactive with both B and T cells; these latter are CD1c- as well. When CD1c+ and CD1c- B cells are activated in vitro, the CD1c molecule is upregulated in the former subset and induced de novo in the latter. Conversely, activated blood T cells remain CD1c-. Neither CD1a nor CD1b molecules are detected on activated T and B lymphocytes. At ultrastructural level, the CD1c+ B cells exhibit distinctive features, namely, condensed chromatin with or without a nucleolus and a unique cluster of cytoplasmic vesicles and organelles; the number of nucleolated cells is higher in the spleen (95%) than in the tonsil (40%) or blood (5%). These findings further confirm the similarity between blood and MZ B cells. The CD1c expression assessed on 27 B-cell chronic lymphocytic leukemias (B-CLL) and 46 B non-Hodgkin's lymphomas (B-NHL) was detected on 41% and 32% of cases, respectively; the latter comprised four follicular and 11 diffuse histotypes. The Burkitt's lymphomas were CD1c-negative. The B-cell neoplasms were all CD1a- and, except for four with a weak cytoplasmic staining, all CD1b- as well. The clear-cut CD1c distribution in normal LN (MZ+, GC-) contrasted with the evidence that some B-NHL cells of GC origin (eg, follicular with predominantly small cleaved cells) were CD1c+. Overall, the finding that CD1c expression is restricted to a fraction of B cells present in lymphoid organs and in peripheral blood indicates that CD1c is a powerful marker for the identification and dissection of B-cell subsets whose functional properties can now be evaluated.

scholarly journals Complement receptors regulate differentiation of bone marrow plasma cell precursors expressing transcription factors Blimp-1 and XBP-1

2005 ◽  
Vol 201 (6) ◽  
pp. 993-1005 ◽  
Author(s):  
Dominique Gatto ◽  
Thomas Pfister ◽  
Andrea Jegerlehner ◽  
Stephen W. Martin ◽  
Manfred Kopf ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
Cell Activation ◽  
Plasma Cells ◽  
Antibody Responses ◽  
Complement Receptors ◽  
Essentially Normal ◽  
Bone Marrow Plasma

Humoral immune responses are thought to be enhanced by complement-mediated recruitment of the CD21–CD19–CD81 coreceptor complex into the B cell antigen receptor (BCR) complex, which lowers the threshold of B cell activation and increases the survival and proliferative capacity of responding B cells. To investigate the role of the CD21–CD35 complement receptors in the generation of B cell memory, we analyzed the response against viral particles derived from the bacteriophage Qβ in mice deficient in CD21–CD35 (Cr2−/−). Despite highly efficient induction of early antibody responses and germinal center (GC) reactions to immunization with Qβ, Cr2−/− mice exhibited impaired antibody persistence paralleled by a strongly reduced development of bone marrow plasma cells. Surprisingly, antigen-specific memory B cells were essentially normal in these mice. In the absence of CD21-mediated costimulation, Qβ-specific post-GC B cells failed to induce the transcriptional regulators Blimp-1 and XBP-1 driving plasma cell differentiation, and the antiapoptotic protein Bcl-2, which resulted in failure to generate the precursor population of long-lived plasma cells residing in the bone marrow. These results suggest that complement receptors maintain antibody responses by delivery of differentiation and survival signals to precursors of bone marrow plasma cells.

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