Biomedical subjects

C Hivroz

Publications and source records attributed to C Hivroz.

45 records · Page 3Linked to original sources

PubMed1990

Altered signal transduction secondary to surface IgM cross-linking on B-chronic lymphocytic leukemia cells. Differential activation of the phosphatidylinositol-specific phospholipase C.

To further study the mechanisms by which surface Ig triggering activates the inositol phospholipid signaling pathway, we have used B cells from chronic lymphocytic leukemia patients which, as previously described, display two patterns of response upon sIg cross-linking: in one group this cross-linking induces an inositol phosphate release, an intracellular free Ca2+ concentration elevation and a subsequent cell proliferation; in a second group none of these events occur although there is an increased class II Ag expression following anti-mu stimulation as in the first group. We have been able to demonstrate that the phosphatidyl inositol specific phospholipase C (PI-PLC) can be activated in permeabilized B cells from the first group by direct stimulation, with GPT gamma S, of a guanine nucleotide binding (G) protein. In addition, since anti-mu + GTP gamma S stimulate an increased inositol phosphate production in these cells, this suggests that surface Ig cross-linking activates PI-PLC via a G protein. However, in cells from the second group no inositol phosphate is released after GTP gamma S stimulation although PI-PLC can be directly activated by high Ca2+ concentrations. This reflects in these cells, an interruption of the signaling cascade sIg/G protein/PI-PLC at the level of the G protein or at the G protein/PI-PLC coupling. In cells from both groups PMA treatment, which is known to alter phosphatidyl inositol metabolism in B cells, completely inhibits PI-PLC activation even by high Ca2+ concentrations. These studies show that the phosphatidyl inositol-dependent signaling cascade after surface Ig triggering can be altered at different levels in B cells.

B-Lymphocytes↗

PubMed1990

Lymphocyte activation via MHC class II antigens.

Class II antigens of the major histocompatibility complex (MHC) have a clear role in restricting cellular interactions and presenting processed antigen to T cells. In addition, a fundamental role for class II antigens in cellular activation has been suggested, following studies which demonstrated that class II antigen binding altered signal transduction in various cell types. We have investigated the role of HLA class II antigens in signal transduction of human B lymphocytes. Resting B lymphocytes proliferate in response to immobilized anti-class II antibodies and intracellular free calcium is increased following cross-linking of anti-class II antibodies. The two dimensional PAGE pattern of resting B lymphocytes was examined and differences were noted after stimulation with either anti-class II antibodies, anti-IgM or PMA. The 2D PAGE pattern following stimulation with anti-class II antibodies was not identical to that observed following stimulation with either anti-IgM or PMA. These data suggest that the activation of B-Go via the class II antigens shares part of the pathway of anti-IgM induced activation but does not follow an identical pathway.

B-Lymphocytes↗

PubMed1989

Regulation by interleukin 2 of CD23 expression of leukemic and normal B cells: comparison with interleukin 4.

Recombinant interleukin (IL) 4 has been shown to be able to up-regulate low-affinity Fc receptor for IgE (Fc epsilon RII)-CD23 expression on B cells as well as on other human mononuclear cells. We demonstrate here that, in opposition with previous reports, recombinant IL2 also can up-regulate CD23 expression on B cells. This was first observed on CLL cells which represent a monoclonal proliferation of B cells arrested at an intermediate stage of activation. Cells of 5 out of 12 B-CLL studied display such an increase and all 5 proliferated, in vitro, directly in response to IL2. Similarly, upon triggering with anti-mu and IL2, normal tonsillar B lymphocytes also demonstrate an increase of CD23 expression but this was observed only on day 3. Interferon-gamma was able to inhibit this IL2-mediated up-regulation of CD23 on normal B cells but not on CLL-B cells; on those cells interferon-gamma was similarly unable to inhibit the IL4-mediated CD23 up-regulation. These results suggest that CD23 regulation is complex and related to the stage of activation and the cell type.

Antibodies, Monoclonal↗

PubMed1989

A role for MHC class II antigens in B-cell activation.

Class II antigens of the major histocompatibility complex (MHC) have a well-defined role in restricting cellular interactions and presenting processed antigen to T cells. In addition, a fundamental role for Class II antigens in cellular activation has been suggested, following studies demonstrating that Class II antigen binding alters the proliferation of various cell types. This is further supported by biochemical evidence of signal transduction by second messengers after ligation of the Class II antigens. We have investigated the role of HLA Class II antigens in the activation of B cells. Both activated and resting B cells proliferate in the presence of Sepharose--conjugated anti-Class II antibodies. This proliferation was not epitope-restricted and was unaffected by low m.w. BCGF. Intracellular free calcium elevation was also examined as a marker of cellular activation. (Ca2+)i was increased after the binding and cross-linking of an anti-DR antibody. The above results further support the role of Class II antigens as signal-transducing molecules.

Antibodies↗

PubMed1988

Cross-linking of membrane IgM on B CLL cells: dissociation between intracellular free Ca2+ mobilization and cell proliferation.

It has been shown previously that chronic lymphocytic leukemia (CLL) B cells are frozen at different stages of activation with unique requirements for proliferation. Although most B CLL cells express surface IgM, anti-mu antibodies are able to trigger only some of them to proliferate and/or respond to B cell growth factor (BCGF) or interleukin 2 (IL2), as normal B cells. In this report we extend these observations using three different monoclonal antibodies (mAb) to human mu chain (one mitogenic in soluble form for normal B cells, the two others mitogenic only when coupled on Sepharose 4B beads). Cells from only 3 out of 11 B CLL patients proliferated in the presence of either mitogenic anti-mu. When the early events following surface Ig cross-linking, such as calcium mobilization (by flow cytometry on indo-1-labeled cells), were studied all three mAb in soluble form were able to induce a similar increase in the intracellular free calcium concentration ([Ca2+]i); analogous to [Ca2+]i rise after the mitogenic F(ab')2 anti-mu stimulation. This response was seen only in 8 out of the 12 CLL B cells studied. All B CLL cells, however, proliferate in response to a combination of phorbol ester 12,13-dibutyrate (PBt2) and ionomycin. Therefore, three patterns of response to sIg cross-linking by anti-mu could be distinguished: cells from 4 out of 12 cases proliferate and mobilize Ca2+ upon anti-mu triggering (behaving like resting B lymphocytes); in 4 other cases anti-mu lead to Ca2+ mobilization without cell proliferation; in the last 4 cases neither Ca2+ mobilization, IP3 generation (in the one case studied) nor cell proliferation are observed although these cells do proliferate directly in response to growth factors. Moreover, anti-mu stimulation in this group leads to increased proliferation in response to BCGF and IL2 suggesting an anti-Ig signaling independent of inositol phosphate metabolism. These results are interpreted in terms of differential anti-mu signaling on B cells at different stages of activation.

Antibodies, Anti-Idiotypic↗

PubMed1988

Cross-linking of membrane IgM on B CLL cells.

We report here the study of early events following surface Ig cross-linking such as Ca2+ mobilization and IP3 generation, in chronic lymphocytic leukemia (CLL) B cells. Those leukemic populations were previously shown to be frozen at different stages of activation with unique requirements for proliferation. The study reported here disclosed 3 patterns of response in terms of Ca2+ mobilization and proliferation. These results are interpreted in terms of differential anti-mu signalling on B cells at different stages of activation.

Antibodies, Anti-Idiotypic↗

PubMed1986

Heterogeneity of responsiveness of chronic lymphocytic leukemic B cells to B cell growth factor or interleukin 2.

We compared the proliferative responses of purified human leukemic B cells from 12 cases of chronic lymphocytic leukemia to highly purified B cell growth factor (BCGF) and recombinant interleukin 2 (rIL 2) spontaneously, and in a coactivation assay using anti-mu monoclonal antibodies. Heterogeneity of response to one or the other lymphokine was observed from case to case. Spontaneous responses were observed to BCGF in one case, to rIL 2 in 3 cases and to both lymphokines in one other case. Costimulation with anti-mu monoclonal antibody induced a proliferative response to BCGF in 3 additional cases and to rIL 2 in 4 cases. Interestingly, cells from BCGF-responsive cases also proliferated in response to rIL 2. The leukemic B cells from 4 chronic lymphocytic leukemia patients were unresponsive. Cells from 5 cases expressed IL 2 receptors, although rIL 2 induced a direct proliferative response in only 3 of these cases. Expression of the B cell activation antigen B5 was associated to BCGF responsiveness.

Antigens, Neoplasm↗

PubMedDate not supplied

Signal transduction via MHC class II antigens on B lymphocytes.

The role of the MHC class II antigens in the activation of resting human B lymphocytes (B-Go) was examined with respect to both early and late events in the activation process. The (Ca2+)i induced by anti-IgM was enhanced in the presence of, or following pre-incubation with, an anti-MHC class II DR antibody (D1.12). Pre-incubation with a sepharose conjugated antibody (Seph.-D1.12) augmented the proliferation of B-Go in response to a sub-optimal concentration of anti-IgM. The 2D PAGE profile of B-Go differed from that of in vivo activated B lymphocytes. The 2D PAGE profile of B-Go activated by Seph.-D1.12 was not identical to the profile of B-Go activated by either anti-IgM or PMA. These data suggest that the activation of B-Go via the class II antigens shares part of the pathway of anti-IgM induced activation but does not follow an identical pathway.

Antibodies, Monoclonal↗

PubMedDate not supplied

[Primary immunodeficiency secondary to ZAP-70 deficiency].

The authors present the case of a child with recurrent infections since the age of 4 months, including bilateral pneumonia by Pneumocystis carinii and protracted varicella. Serum immunoglobulin values (when 10 months old), and B cell values were normal. There was persistent lymphocytic leucocytosis, near absence of CD8+ cells, and an increased CD4/CD8 ratio. The percentage of activated T cells and the expression of HLA class I were normal. Proliferation, activation and IL-2 synthesis studies in T cells showed a TCR/CD3-associated signal transduction deficit. ZAP-70 cDNA sequencing showed a mutation, and no ZAP-70 protein was detected in T cells. ZAP-70 deficiency is associated with a rare immune deficiency with absence of CD8+ T cells as well as a functional deficiency in T cells. Seven months after bone marrow transplantation the child is clinically well and immunologically recovered.

Cytoplasmic Granules↗