Studies on the clonal origin of multiple myeloma. Use of individually specific (idiotype) antibodies to trace the oncogenic event to its earliest point of expression in B-cell differentiation.

IgA myeloma proteins of kappa- and lambda-types were isolated from two patients. These were used to produce and purify anti-idiotype antibodies of both broad (myeloma-related) and narrow (individual myeloma) specificities. The anti-idiotype antibodies were conjugated with fluorochromes and used as immunofluorescent probes to trace in the patients clonal expansion at different levels of B-cell differentiation. Our results (a) confirm that B lymphocyte precursors in IgA plasma-cell myelomas are involved in the malignant process, (b) show that B lymphocytes of the malignant clone include those expressing each of the major heavy-chain isotypes, mu, delta, gamma, and alpha, and (c) provide strong circumstantial evidence that pre-B-cell members of the malignant clone are also increased in frequency. T cells expressing idiotypic determinants were not detected. These findings argue that the initial oncogenic event may occur in a B-stem cell and is not influenced through stimulation by antigen. An interesting association was the increased frequency of related clones of B lymphocytes as detected by their reactivity with anti-idiotype antibodies of broad specificity. Neither plasma cell nor pre-B-cell members of these related clones were increased in frequency. Anti-idiotype antibodies or helper T cells reactive with myeloma-related idiotypes could be responsible for this phenomenon. We discuss other implications of these findings and speculate that all of the various phenotypes of B-lineage malignancies may result from oncogenic processes affecting stem cell targets.

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Negative selection of human germinal center B cells by prolonged BCR cross-linking.

Journal of Experimental Medicine ◽

10.1084/jem.183.5.2075 ◽

1996 ◽

Vol 183 (5) ◽

pp. 2075-2085 ◽

Cited By ~ 51

Author(s):

L Galibert ◽

N Burdin ◽

C Barthélémy ◽

G Meffre ◽

I Durand ◽

...

Keyword(s):

Cell Differentiation ◽

B Cells ◽

B Cell ◽

B Lymphocytes ◽

Germinal Center ◽

B Lymphocyte ◽

Calcium Flux ◽

Cross Linking ◽

B Cell Differentiation ◽

Selection Of

The antigen receptors on T and B lymphocytes can transduce both agonist and antagonist signals leading either to activation/survival or anergy/death. The outcome of B lymphocyte antigen receptor (BCR) triggering depends upon multiple parameters which include (a) antigen concentration and valency, (b) duration of BCR occupancy, (c) receptor affinity, and (d) B cell differentiation stages. Herein, using anti-immunoglobulin kappa and lambda light chain antibodies, we analyzed the response of human naive, germinal center (GC) or memory B cells to BCR cross-linking regardless of heavy chain Ig isotype or intrinsic BCR specificity. We show that after CD40-activation, anti-BCR (kappa + gamma) can elicit an intracellular calcium flux on both GC and non-GC cells. However, prolonged BCR cross-linking induces death of CD40-activated GC B cells but enhances proliferation of naive or memory cells. Anti-kappa antibody only kills kappa + GC B cells without affecting surrounding gamma + GC B cells, thus demonstrating that BCR-mediated killing of GC B lymphocytes is a direct effect that does not involve a paracrine mechanism. BCR-mediated killing of CD40-activated GC B cells could be partially antagonized by the addition of IL-4. Moreover, in the presence of IL-4, prestimulation through CD40 could prevent subsequent anti-Ig-mediated cell death, suggesting a specific role of this combination in selection of GC B cells. This report provides evidence that in human, susceptibility to BCR killing is regulated along peripheral B cell differentiation pathway.

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Switch in the protein tyrosine phosphatase associated with human CD100 semaphorin at terminal B-cell differentiation stage

Blood ◽

10.1182/blood.v95.3.965.003k39_965_972 ◽

2000 ◽

Vol 95 (3) ◽

pp. 965-972 ◽

Cited By ~ 24

Author(s):

Christian Billard ◽

Stéphanie Delaire ◽

Emmanuel Raffoux ◽

Armand Bensussan ◽

Laurence Boumsell

Keyword(s):

Cell Differentiation ◽

B Cell ◽

B Lymphocytes ◽

Cell Lines ◽

Plasma Cell ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Cell Populations ◽

B Cell Differentiation ◽

Differentiation Stage

Human CD100, the first semaphorin identified in the immune system, is a transmembrane protein involved in T-cell activation. In the present study, we showed that activation of peripheral blood or tonsillar B lymphocytes induced the expression of CD100 in CD38+CD138− cell populations, including in CD148+ subpopulations, thus expressing a memory B-cell–like phenotype. Using an in vitro enzymatic assay, we found that protein tyrosine phosphatase (PTP) activities were immunoprecipitated with CD100 in these cell populations, which were isolated by cell sorting, as well as in most B-cell lines representing various stages of B-cell differentiation. Immunodepletion and Western blotting experiments demonstrated that CD45 was the PTP associated with CD100 in cell lines displaying pre-B, activated B, and pre-plasma cell phenotypes. CD45 also accounted for PTP activity immunoprecipitated with CD100 in CD38+CD138− cells sorted after activation of peripheral blood or tonsillar B lymphocytes. In contrast, no CD100-CD45 association was observed in plasma cell lines corresponding to the terminal B-cell differentiation stage. CD148, the other transmembrane PTP known to be implicated in lymphocyte signaling pathways, was either only partly involved in the CD100-associated PTP activity or not expressed in plasma cell lines, indicating the association of CD100 with another main PTP. Our data show that CD100 is differentially expressed and can functionally associate with distinct PTPs in B cells depending on their activation and maturation state. They also provide evidence for a switch in the CD100-associated PTP at terminal stage of B-cell differentiation.

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Mesenchymal Stem Cell-Derived Interleukin 1 Receptor Antagonist Promotes Macrophage Polarization and Inhibits B Cell Differentiation

Stem Cells ◽

10.1002/stem.2254 ◽

2015 ◽

Vol 34 (2) ◽

pp. 483-492 ◽

Cited By ~ 80

Author(s):

Patricia Luz-Crawford ◽

Farida Djouad ◽

Karine Toupet ◽

Claire Bony ◽

Marcella Franquesa ◽

...

Keyword(s):

Stem Cell ◽

Cell Differentiation ◽

Mesenchymal Stem Cell ◽

B Cell ◽

Receptor Antagonist ◽

Macrophage Polarization ◽

Interleukin 1 ◽

B Cell Differentiation ◽

Interleukin 1 Receptor Antagonist

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Advances and Perspectives in the Treatment of B-Cell Malignancies

Cancers ◽

10.3390/cancers13092266 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2266

Author(s):

Marta Cuenca ◽

Victor Peperzak

Keyword(s):

Cell Differentiation ◽

B Cell ◽

Plasma Cell ◽

Heterogeneous Group ◽

B Cell Differentiation ◽

B Cell Lymphomas ◽

B Cell Malignancies ◽

Plasma Cell Dyscrasias

B-cell malignancies arise from different stages of B-cell differentiation and constitute a heterogeneous group of cancers including B-cell lymphomas, B-cell leukemias, and plasma cell dyscrasias [...]

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Partial characterization of the shift from IgG to IgA synthesis in the clonal differentiation of human leukemic bone marrow-derived lymphocytes.

Journal of Experimental Medicine ◽

10.1084/jem.142.3.549 ◽

1975 ◽

Vol 142 (3) ◽

pp. 549-559 ◽

Cited By ~ 21

Author(s):

R A Rudders ◽

R Ross

Keyword(s):

B Cell ◽

B Lymphocyte ◽

Plasma Cells ◽

Lymphocytic Leukemia ◽

B Cell Differentiation ◽

Cell Staining ◽

Clonal Origin ◽

Switch Mechanism ◽

Sequential Labeling ◽

Chain Synthesis

An unusual B-cell proliferation was noted in an individual (Tun) which was characterized by the presence of two separate populations of chronic lymphocytic leukemia (CLL) cell staining on the surface and in the cytoplasm for either IgG(k) or IgA(k). Utilizing an idiotypic antiserum prepared from the associated serum monoclonal IgG(k) protein the idiotype was detected on the surface and in the cytoplasm of both the IgG- and IgA-bearing cell populations. These observations are consistent with a common clonal origin and a switch mechanism involving IgG and IgA synthesis. Sequential-labeling of Surface Ig and intracellular Ig with antisera conjugated to opposite fluorochromes documented the progressive maturation of the terminal differentiation of the IgA-bearing cell population at a level before morphologically distinct plasma cells. The distribution and pattern of surface and cytoplasmic IgG and IgA staining in individual cells suggest that the direction of switching is from IgG to IgA synthesis. The demonstration of shared idiotypic specificity between the IgG- and IgA-bearing populations is consistent with a transition in Ig heavy chain synthesis resulting from an alternation in the CH gene. It is concluded that certain CLL clones may manifest a switch from IgG to IgA synthesis at a level of B-cell differentiation which encompasses both the B lymphocyte and the Ig-synthesizing plasma cell.

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