Transmembrane Signals and Intracellular “Second Messengers” in the Regulation of Quiescent B‐Lymphocyte Activation

Cambier, John C.; Justement, Louis B.; KarenNewell, M.; Chen, Zheng Z.; Harris, Lesley K.; Sandoval, Victoria M.; Klemsz, Michael J.; Ransom, John

doi:10.1111/j.1600-065x.1987.tb00499.x

Cited by 130 publications

(55 citation statements)

References 63 publications

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“…Stimulation of cells in the presence of CsA appears to allow the initial events of activation, i.e., elevations in [Ca2+]i and changes in cell volume, but inhibits or delays subsequent essential steps, e.g., synthesis and secretion of lymphokines and expression of cell surface receptors. It has recently been proposed in studies of B lymphocyte activation that such abortive signalling may lead to "tolerance," or even to the elimination of these cells (5). If true of T cells, then many of the clinical findings from studies of CsA immunosuppression following transplantation would be explained as a continual blockade and/or removal of cells activated by the allograft but blocked by CsA.…”

Section: Discussionmentioning

confidence: 99%

Cyclosporin a does not inhibit the PHA‐stimulated increase in intracellular Ca²⁺ concentration but inhibits the increase in e‐rosette receptor (CD2) expression and appearance of interleukin‐2 receptors (CD25)

Redelman

1988

Cytometry

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The immunosuppressive drug cyclosporin A (CsA) inhibits mixed lymphocyte responses, blocks the generation of cytotoxic T lymphocytes, and inhibits the T lymphocyte proliferative response stimulated by polyclonal activators such as phytohemagglutinin (PHA). Nevertheless, there have been contradictory reports attempting to explain the mechanism(s1 for this immunosuppressive activity. In the current studies, human peripheral blood mononuclear cells (PBM) were stimulated with PHA in the presence or absence of CsA. Flow cytometric examination of PBM loaded with the Ca2+-sensitive dye Indo-1 showed that concentrations of CsA sufficient to inhibit 90-100% of tritiated thymidine incorporation had no effect on the PHA-stimulated increase in the intracellular Ca2+ concentration ([Ca2+]i). Likewise, inhibitory amounts of CsA had virtually no effect on the increase in cell volume that occurs during T lymphocyte activation. These results were not altered by pretreating the PBM with CsA for 30 min at 37°C prior to adding the PHA. On the other hand, inhibitory concentrations of CsA prevented the expression of receptors for T cell growth factor (interleukin-2, IL-21, as measured by monoclonal antibodies to CD25 after 16-24-hr incubation. In like manner, CsA also prevented the increase in the expression of the E-rosette receptor (CD2) on these same cells. If cultures containing PHA and inhibitory amounts of CsA were incubated for 40-72 h, there was partial recovery both of proliferative activity and of the expression of CD25 and CD2. Thus, CsA does not appear to affect the initial activation signal(s), but does interfere with one or more subsequent events necessary to initiate the appearance of "activation antigens."

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Section: Discussionmentioning

confidence: 99%

Cyclosporin a does not inhibit the PHA‐stimulated increase in intracellular Ca²⁺ concentration but inhibits the increase in e‐rosette receptor (CD2) expression and appearance of interleukin‐2 receptors (CD25)

Redelman

1988

Cytometry

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“…IgD can have a regulatory role, e.g., to enhance a protective antibody response of the IgM, IgG, or IgA isotype, or to interfere with viral replication (110). IgD can also participate in the generation and maintenance of B-cell memory and might have an important role in the transition from a stage of susceptibility to induction of B-cell tolerance to one of responsiveness (22,142). Finally, IgD is a potent inducer of tumor necrosis factor alpha (TNF-␣), IL-1␤, and IL-1 receptor antagonist (38).…”

Section: Properties Of Igd and Its Role In The Immune Responsementioning

confidence: 99%

Immunoglobulin D: Properties, Measurement, and Clinical Relevance

Vladutiu

2000

Clin Diagn Lab Immunol

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“…In B lymphocytes, [Ca 2ϩ ] i controls cell proliferation, differentiation and apoptotic processes (2,3). Cross-linking of B cell receptors (BCR) with specific antigens activates phospholipase C␥ (PLC␥) through a series of tyrosine phosphorylations, resulting in hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP 2 ).…”

Section: Intracellular Calcium Concentration ([Camentioning

confidence: 99%

Inhibitory Modulation of B Cell Receptor-mediated Ca2+ Mobilization by Src Homology 2 Domain-containing Inositol 5′-Phosphatase (SHIP)

Hashimoto

Hirose

Okada

et al. 1999

Journal of Biological Chemistry

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2؉ influx (SOC) elicited by thapsigargin-induced store depletion was not affected by SHIP. These results indicate that the primary target pathway of SHIP is the Ca 2؉release from the stores, and that Ca 2؉ influx by the SOC mechanism is secondarily controlled by the level of Ca (4,5). BCR activation also results in the activation of phosphoinositide 3-kinase, which converts PIP 2 to phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ).In addition to BCR, B lymphocytes express another class of immunoreceptors, Fc␥RIIB. Co-cross-linking of BCR and Fc␥RIIB attenuates the BCR-induced Ca 2ϩ response (6-10). The attenuation of the Ca 2ϩ response requires the activation of the SH2 domain-containing inositol polyphosphate 5Ј-phosphatase (SHIP) (11-14), which catalyzes dephosphorylation of PIP 3 and inositol 1,3,4,5-tetrakisphosphate at their 5-position of the inositol ring in vitro (15,16).One of the possible target mechanisms of SHIP in the attenuation of the Ca 2ϩ response is the SOC activity. Since the Fc␥RIIB-mediated inhibition of Ca 2ϩ signaling was more prominent in the presence of extracellular Ca 2ϩ than in its absence (8 -10), SHIP was postulated to attenuate Ca 2ϩ influx via the SOC channel (11)(12)(13)17). Another potential target of SHIP is the PLC␥ activity. Since PIP 3 was reported to stimulate Bruton's tyrosine kinase (Btk), which in turn tyrosine-phosphorylates PLC␥ (18 -20), degradation of PIP 3 upon activation of SHIP by the co-cross-linking of Fc␥RIIB would decrease PLC␥ activity and hence inhibit Ca 2ϩ release from the stores. However, direct demonstration that SHIP affects SOC or Ca 2ϩ release in Fc␥RIIB-mediated signaling remains to be reported.It has been shown that cross-linking of BCR alone leads to tyrosine phosphorylation of SHIP (21, 22). Furthermore, SHIP seems to inhibit the BCR-mediated Ca 2ϩ response even without co-cross-linking of Fc␥RIIB, because SHIP-deficient cells exhibit prolongation of the [Ca 2ϩ ] i transient upon BCR activation (23). While SHIP is recruited to the immunoreceptor tyrosine-based inhibitory motif on the intracellular region of Fc␥RIIB upon activation of this receptor (11), there is no immunoreceptor tyrosine-based inhibitory motif on the BCR complex. Therefore, SHIP is not a unique molecule for Fc␥RIIB-mediated inhibitory signaling, but plays an important role in BCR-mediated signaling; the mechanisms of the recruitment of SHIP seem different in the absence or presence of Fc␥RIIB-mediated signaling. It remains to be clarified how Ca 2ϩ mobilization is attenuated by SHIP in BCR-mediated signaling.In an effort to understand the role of SHIP in BCR-mediated signaling, we addressed the following questions in this work: 1) how are the patterns of Ca 2ϩ mobilization elicited by BCR stimulation modulated by SHIP, and 2) which Ca 2ϩ mobilization pathway is affected by SHIP: Ca 2ϩ release or SOC. To clarify these points, we compared the patterns of [Ca 2ϩ ] i mobilization in control and SHIP-deficient DT40 cells at the single * This work was supported in part by grants ...

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Transmembrane Signals and Intracellular “Second Messengers” in the Regulation of Quiescent B‐Lymphocyte Activation

Cited by 130 publications

References 63 publications

Cyclosporin a does not inhibit the PHA‐stimulated increase in intracellular Ca²⁺ concentration but inhibits the increase in e‐rosette receptor (CD2) expression and appearance of interleukin‐2 receptors (CD25)

Cyclosporin a does not inhibit the PHA‐stimulated increase in intracellular Ca²⁺ concentration but inhibits the increase in e‐rosette receptor (CD2) expression and appearance of interleukin‐2 receptors (CD25)

Immunoglobulin D: Properties, Measurement, and Clinical Relevance

Inhibitory Modulation of B Cell Receptor-mediated Ca2+ Mobilization by Src Homology 2 Domain-containing Inositol 5′-Phosphatase (SHIP)

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Transmembrane Signals and Intracellular “Second Messengers” in the Regulation of Quiescent B‐Lymphocyte Activation

Cited by 130 publications

References 63 publications

Cyclosporin a does not inhibit the PHA‐stimulated increase in intracellular Ca2+ concentration but inhibits the increase in e‐rosette receptor (CD2) expression and appearance of interleukin‐2 receptors (CD25)

Cyclosporin a does not inhibit the PHA‐stimulated increase in intracellular Ca2+ concentration but inhibits the increase in e‐rosette receptor (CD2) expression and appearance of interleukin‐2 receptors (CD25)

Immunoglobulin D: Properties, Measurement, and Clinical Relevance

Inhibitory Modulation of B Cell Receptor-mediated Ca2+ Mobilization by Src Homology 2 Domain-containing Inositol 5′-Phosphatase (SHIP)

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Cyclosporin a does not inhibit the PHA‐stimulated increase in intracellular Ca²⁺ concentration but inhibits the increase in e‐rosette receptor (CD2) expression and appearance of interleukin‐2 receptors (CD25)

Cyclosporin a does not inhibit the PHA‐stimulated increase in intracellular Ca²⁺ concentration but inhibits the increase in e‐rosette receptor (CD2) expression and appearance of interleukin‐2 receptors (CD25)