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PubMed1992

Soluble forms of CD40 inhibit biologic responses of human B cells.

We have expressed the CD40 surface Ag as both a soluble 28-kDa molecule and a 57-kDa Fc fusion protein containing the human IgG1 Fc region. Soluble CD40 and the Fc fusion protein inhibited the proliferative response of anti-IgM-activated human B cells to the CD40 mAb G28-5. Similarly, G28-5- and IL-4-induced IgE secretion from PBMC depleted of T cells was effectively blocked by both forms of soluble CD40. Although the soluble constructs of CD40 had only a minimal inhibitory effect on IL-4-mediated proliferation of anti-IgM-activated B cells, IL-4-induced soluble CD23 shedding from both PBMC and T cells depleted of PBMC, and IgE secretion from PBMC, were significantly reduced in a concentration-dependent manner when soluble CD40 was present in the culture. The data presented demonstrate that both soluble forms of the CD40 molecule are biologically active, and suggest that the ligand for CD40 is inducible in IL-4-stimulated cultures and that it mediates both shedding of sCD23 and IgE secretion.

Antibodies, Monoclonal↗
PubMed1994

CD40 expression in malignant plasma cells. Role in stimulation of autocrine IL-6 secretion by a human myeloma cell line.

Myeloma is a neoplasia characterized by the accumulation of malignant plasma cells in the bone marrow. In these studies, we have demonstrated that CD40 is expressed in human myeloma cells and have used a recently established IL-6-dependent myeloma cell line, ANBL-6, to examine the potential function of CD40 expression in myeloma cells. In addition to its expression on the ANBL-6 cells, we show that CD40 is expressed on freshly isolated myeloma cells from seven of seven patients tested. To address the role of CD40 expression in myeloma cells, we have examined the responsiveness of the ANBL-6 cell line to a CD40-specific mAb, G28-5. This cell line has previously been shown to proliferate only in response to IL-6. Of interest in this study, G28-5 also induced proliferation of the ANBL-6 cells. This proliferation was substantially inhibited by an IL-6-neutralizing mAb. Analysis of ANBL-6 cell culture supernatants by ELISA demonstrated that G28-5-stimulated cells secreted significant levels of IL-6, whereas unstimulated cell culture supernatants contained undetectable levels of IL-6. Furthermore, CV-1/EBNA cells expressing the human CD40 ligand also induced the proliferation of the ANBL-6 cell line, an effect that was inhibited by the anti-IL-6 mAb. Lastly, RNA blot analysis demonstrated an increase in IL-6 message in G28-5-stimulated ANBL-6 cells over unstimulated cells. These results indicate that the primary mechanism of anti-CD40-stimulated proliferation of the ANBL-6 cells is the induction of autocrine IL-6 production. Moreover, these data suggest that the expression of CD40 in malignant plasma cells may play a role in tumor cell expansion, possibly by stimulating the induction of autocrine IL-6 secretion.

Antibodies, Monoclonal↗
PubMed1994

CD40 expression in Hodgkin's disease.

CD40 is a transmembrane protein that belongs to a superfamily of proteins related to nerve growth factor receptor. CD40 is expressed on B cells and some B cell malignancies. It appears to be involved in B cell proliferation and the prevention of apoptosis in germinal center cells, which is accompanied by expression of bcl-2. Its expression is up-regulated by the EBV protein latent membrane protein-1 and cytokines interleukin-4 and interferon-gamma. The expression of CD40 in 37 cases of Hodgkin's disease and 23 cases of non-Hodgkin's lymphoma (11 T cell lymphomas and 12 B cell lymphomas) was examined by paraffin section immunohistochemistry using the BB-20 monoclonal antibody. In 26 of 37 cases of Hodgkin's disease the Reed-Sternberg cells showed strong membrane or cytoplasmic expression of CD40. Only 3 of 23 non-Hodgkin's lymphomas showed any expression of CD40 and then only weakly. There was no correlation between expression of bcl-2 or latent membrane protein-1 with CD40 expression. These results show that there is probable hyperexpression of CD40 in Hodgkin's disease and suggest that dysregulation of CD40 expression may play a role in the pathogenesis of Hodgkin's disease.

Antigens, CD↗
PubMed1994

Cross-linking CD40 on human B cell precursors inhibits or enhances growth depending on the stage of development and the IL costimulus.

The function of the cell surface molecule CD40 on B cell precursors (BCP) is not well understood. We now report studies using the L cell/CD40 system (anti-CD40 mAb immobilized on CD32+ mouse L cells) to assess the potential function of CD40 during human B cell ontogeny. Stimulation of human B lineage cells with IL-4 in the L cell/CD40 system yielded a hierarchy of responsiveness: high density tonsillar B cells > fetal splenic B cells > fetal bone marrow surface Ig+ immature B cells > fetal bone marrow surface Ig- BCP. Using a microsphere/flow cytometry growth quantitation assay, we found that substituting IL-3 for IL-4 in the L cell/CD40 system provided a stronger growth stimulus for fetal bone marrow BCP and immature B cells. We also found that FACS-purified fetal bone marrow CD10+/CD34+/CD40+/cytoplasmic mu- pro-B cells responded maximally to IL-3 plus IL-7. Surprisingly, anti-CD40 inhibited the pro-B cell response to IL-7. In contrast, FACS-purified fetal bone marrow CD10+/CD34-/CD40+/cytoplasmic mu+ pre-B cells were essentially nonresponsive to IL-3, IL-7, or anti-CD40 alone, but were uniquely responsive to IL-3 plus anti-CD40. B-lineage cells derived after 14 days from IL-7-stimulated pro-B cells were predominantly CD19+/L chain-, whereas pre-B cells stimulated with IL-3 plus anti-CD40 were predominantly CD19+/L chain+. The L chain+ cells from pre-B cell cultures were both mu+/delta+ and mu-/delta+. Our results demonstrate that the response to CD40 signaling depends upon the BCP developmental stage and the IL costimulus, and indicate that normal human pro-B cells and pre-B cells have different growth factor requirements.

Antigens, CD↗
PubMed1993

CD40 plays an essential role in the activation of human B cells by murine EL4B5 cells.

A mutant subclone of the murine thymoma EL-4, known as EL4B5, can strongly activate human B cells to proliferate and differentiate in a cell-cell contact-dependent manner. We have investigated whether interaction via CD40 plays a role in this helper activity. For this purpose, three newly generated anti-CD40 monoclonal antibodies (mAb) were used. In contrast with other anti-CD40 mAb described in the literature, these mAb did not co-stimulate proliferation of human B cells. On the other hand, these novel mAb could inhibit the co-stimulatory effect of the previously described anti-CD40 mAb S2C6 on anti-IgM-induced human B-cell proliferation. It was found that addition of these non-stimulatory anti-CD40 mAb could completely inhibit EL4B5-induced human B-cell proliferation. Maximal inhibition occurred already at a mAb concentration of 10 ng/ml. Similarly, a fusion protein, consisting of the extracellular portion of CD40 and human IgM constant domains CH2, CH3 and CH4, could completely inhibit EL4B5-induced human B-cell proliferation. Induction of human B-cell proliferation by EL4B5 cells was also inhibited by anti-CD40 mAb S2C6 and G28.5, but less effectively. In contrast, mAb against B-cell surface antigens CD20 or B7 had no inhibitory effects. It is concluded that interaction via CD40 is essential for the induction of human B-cell proliferation by EL4B5 cells.

Animals↗
PubMed1996

CD40 ligation results in protein kinase C-independent activation of ERK and JNK in resting murine splenic B cells.

CD40 is a 45- to 50-kDa transmembrane glycoprotein that plays an important role in B cell proliferation, survival, memory, and Ig isotype switching. How CD40 engagement couples to these distal events in B cell activation remains poorly understood. In this study, we have examined signal transduction events mediated by CD40 cross-linking in resting murine splenic B cells. In comparison to signaling via the B cell Ag receptor (BCR), CD40 cross-linking was less effective at activating protein tyrosine kinases. Interestingly, however, CD40 engagement resulted in the phosphorylation of both extracellular signal-regulated protein kinase (ERK) and the Ras guanine nucleotide exchange factor, Son of sevenless. In addition, both ERK and c-Jun NH2-terminal kinase activities were increased after both CD40 and BCR ligation. Overnight treatment of cells with phorbol ester as well as pharmacologic inhibitors of protein kinase C abrogated these signaling events after BCR treatment; however, no effect was seen on CD40-mediated activation of ERK or c-Jun NH2-terminal kinase, suggesting that the BCR and CD40 differentially utilize protein kinase C to couple with these signaling pathways.

Animals↗
PubMed1996

CD40-mediated signaling in B cells. Balancing cell survival, growth, and death.

Multimerization of CD40 molecules on B cells by binding CD40 ligand on activated T cells initiates signaling events essential for B cell differentiation. In mature B cells, CD40 mediates stimulation and costimulation of cell growth, switch recombination, and transcriptional regulation. CD40-mediated signaling also regulates cell death, rescuing B cells from anti-Ig-induced apoptosis and inducing the expression of the Fas surface molecule. Recent efforts to elucidate the biochemistry of CD40-mediated signaling pathways have identified members of the TRAF protein family that are associated with the cytoplasmic tail of CD40. CD40 cross-linking probably multimerizes TRAF proteins which may act as direct transcriptional regulators. Modulation of protein tyrosine kinase and protein tyrosine phosphatase activity also occurs after CD40-mediated signaling; however, a connection to the TRAF pathway has not been established. Multiple pathways of B cell triggering are probably integrated at the level of transcriptional activation to produce differentiation stage-specific B cell responses.

Animals↗
PubMed1996

Activation of the Ras signaling pathway by the CD40 receptor.

The CD40 receptor is an important molecule regulating B lymphocyte proliferation, maturation, Ab class switching, and cell survival. In the present study, we identified signal transduction events triggered by cross-linking the CD40 receptor. Stimulation of Daudi B cells with anti-CD40 resulted in activation of p21ras, an important switch point in the regulation of cell growth and differentiation. Ras activation correlated with a stimulation of Rac1 and MEK-1 as well as tyrosine phosphorylation of phosphatidylinositol 3-kinase. Inhibition of endogenous Ras by transfection of transdominant inhibitory Ras prevented tyrosine phosphorylation or stimulation of phosphatidylinositol 3-kinase, Rac1, or MEK-1 upon CD40 receptor triggering, proving an activation of the Ras pathway by CD40. Ras activation was partially inhibited by either herbimycin A or calphostin pretreatment and completely inhibited by preincubation with a combination of both inhibitors, indicating a synergistic role for protein tyrosine kinases and diglycerides in Ras activation after CD40 stimulation. In support of a role for diglycerides, we detected a 30 +/- 5% decrease of cellular phosphatidylcholine content, correlating with a threefold increase of diacylglycerol synthesis induced by CD40. Supporting a role for protein tyrosine kinase, we measured a five- to eightfold stimulation of p56lyn and p58blk kinase activity. These results suggest the activation of the Ras pathway via an additive function of src kinases and phospholipases that may be important in the mediation of biologic effects after CD40 receptor engagement.

Antibodies, Monoclonal↗
PubMed1997

CD40 ligand induces an antileukemia immune response in vivo.

Leukemia cells may express tumor specific antigens in association with Class I and II major histocompatability complex (MHC) molecules. However, lack of expression of conventional costimulator molecules means that these cells tend to induce specific T-cell anergy rather than activation. CD40 ligand (CD40L) is a costimulator molecule that directly activates T cells and may promote antigen presentation by CD40-expressing cells, which include professional antigen presenting cells and B-acute lymphoblastic leukemia (ALL) cells from many patients. We determined whether transgenic expression of CD40L could enhance an antileukemia immune response using a CD40+ murine lymphoblastic (A20) leukemia and a CD40- myeloblastic (WEHI-3) leukemia in a tumor treatment model. Injection of otherwise nonimmunogenic A20 cells in the presence of CD40L induced an immune response active against preexisting A20 tumor at a distant site. Moreover, concomitant local secretion of transgenic interleukin-2 (IL-2) further amplified the antileukemic response induced and increased protection against preexisting tumor. In ex vivo studies, CD40 activation of A20 cells enhances the antigen presenting potential of A20 cells by upregulating expression of B7.1 (CD80), Class I and II MHC molecules, and increases expression of fas antigens. The importance of CD40 activation to the resulting antitumor response is further emphasized by the failure of transgenic CD40L to protect against the CD40- WEHI myeloblastic leukemia. Depletion studies showed the protective effects against A20 cells to be mediated by a combination of CD4+ and CD8+ T lymphocytes and by natural killer (NK) cells. These results suggest a means by which CD40+ leukemia cells may be rendered immunogenic in vivo.

Animals↗
PubMed1998

Differential coupling of membrane Ig and CD40 to the extracellularly regulated kinase signaling pathway.

Coupling of membrane Ig (mIg) and CD40 to the extracellularly regulated kinase (ERK) signal transduction pathway was examined in the WEHI-231 B lymphoma and normal mouse B cells. Cross-linking mIg induces ERK activation in both WEHI-231 and normal B cells. In contrast, CD40 cross-linking failed to induce ERK activation in WEHI-231, but signals through CD40 were more effective than mIg as a stimulus for ERK activation in normal B cells. However, several lines of evidence suggest that CD40 and the B cell Ag regulate ERK through distinct pathways that converge at the level of MEK-1, mitogen-activated protein kinase kinase. Abs to mIg or CD40 induced MEK-1 activation with different kinetics. Cross-linking of mIg, but not CD40, induced tyrosine phosphorylation of the SHC adapter molecule that couples receptors to Ras-dependent signaling pathways. Finally, agents that elevate cAMP, causing protein kinase A-mediated inhibition of Raf-1, inhibited activation of ERK in response to mIg cross-linking, but had no affect on ERK activation in response to anti-CD40 or Jun N-terminal kinase activation by signals through either receptor. Thus, CD40 uses an unidentified protein kinase A-insensitive MEK kinase, rather than Raf-1, to regulate ERK activity.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Expression and function of CD40 in rheumatoid arthritis synovium.

OBJECTIVE: To determine the involvement of CD40 in chronic activation of rheumatoid arthritis (RA) synovial monocytes. METHODS: CD40 expression on RA synovial monocytes was examined by immunostaining. Involvement of CD40 in tumor necrosis factor-alpha (TNF-alpha) secretion from RA synovial fluid mononuclear cells (SFMC) was examined by blocking with anti-CD40 antibody. RESULTS: CD40 was expressed on RA synovial monocytes. TNF-alpha secretion from RA SFMC was enhanced by CD40 ligand stimulation. Spontaneous secretion of TNF-alpha from RA SFMC was inhibited by anti-CD40 antibody. CONCLUSION: CD40 was involved in the activation of RA synovial monocytes that leads to TNF-alpha production.

Adult↗
PubMed1998

Regulation of cytoplasmic, surface and soluble forms of CD40 ligand in mouse B cells.

CD40 and CD40 ligand (CD40L) form one of most important receptor-ligand pairs that dock during T-B cell interactions as part of T-dependent antibody responses. It has been reported that among other cell types, B cells can express CD40L. Here we show that a large proportion of mouse B cells express CD40L in their cytoplasm, but not on the surface and that this is readily released as a soluble molecule. Thus, in their resting state up to 50% of mouse B cells express CD40L within their cytoplasm and both the proportion of cells expressing and the amount of CD40L is increased by signaling through immunoglobulin (Ig) or CD38. In contrast, T cell-derived signals such as CD40L (anti-CD40) or Th2-type cytokines cause a decrease in CD40L expression that is related to a release of a soluble form of the molecule from the cell. Supernatants from B cells activated with anti-Ig and anti-CD40 contain CD40L in a variety of forms (18 kDa, 33 kDa and 66 kDa) that are readily detectable by immunoprecipitation with CD40-Fc gamma fusion protein (CD40-Ig) followed by Western blotting with anti-CD40L antibody (MR1). The 33-kDa species is distinct from the 39-kDa membrane-bound molecule found in activated T cells or in resting B cells and appears to be a novel soluble form of CD40L. Inhibition of T cell-independent in vitro stimulation of B cells with CD40-Ig or anti-CD40L suggests that the B cell-derived soluble CD40L or CD40L expressed on the B cell surface can play a positive role in B cell proliferation.

Animals↗
PubMed1998

Diminished expression of CD40 ligand may contribute to the defective humoral immunity in patients with MHC class II deficiency.

Major histocompatibility complex (MHC) class II deficiency (bare lymphocyte syndrome, BLS) is a rare primary immunodeficiency classified as a subgroup of severe combined immunodeficiency. We studied T and B lymphocyte function by examining the CD40 ligand/CD40 system in three BLS patients from two unrelated families. CD40 ligand expression by maximally activated BLS T cells was diminished. This abnormality may represent immunological naïveté rather than a general T cell defect, since expression of activation marker CD69 and proliferative responses to PHA or anti-CD3 were normal, and BLS T cells primed and restimulated in vitro expressed normal amounts of CD40 ligand. BLS B cells proliferated and produced IgE if stimulated with anti-CD40 or soluble CD40 ligand and IL-4. Activation of BLS B cells with soluble CD40 ligand and IL-4 induced normal expression of activation markers, although MHC class II expression remained absent. Depressed antibody titers, lack of amplification and failure to undergo isotype switching in response to immunization with bacteriophage phi x 174 demonstrated defective T cell help. We conclude that BLS B cells are functionally normal if appropriately stimulated, and that the defective humoral immunity observed may be related to diminished expression of CD40 ligand on BLS T cells.

Antibodies, Viral↗
PubMed1999

Differential activation and regulation of mitogen-activated protein kinases through the antigen receptor and CD40 in human B cells.

In human B cells, antigen receptor ligation and CD40 ligation are known to activate the extracellular-regulated kinases (ERK) and c-Jun N-terminal kinase (JNK) pathways, which in turn regulate many important B cell functions. We previously reported that antigen receptor ligation activated the ERK pathway whereas CD40 ligation activated the JNK/stress-activated protein kinase (SAPK) pathway. Here, we demonstrate that another SAPK, p38/Hog1, is activated by both antigen receptor ligation or CD40 ligation in a human B-lymphoblastoid cell line and tonsillar B cells. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase, partially inhibited ERK2 and p38 activation triggered through the B cell receptor whereas activation of JNK1 and p38 through CD40 was not affected. PD98059, a specific inhibitor of mitogen-activated extracellular response kinase kinase (MEK), significantly inhibited ERK2 activation and partially inhibited p38 activation triggered by anti-IgM antibody treatment, but did not affect CD40-dependent signaling events. In addition, anti-IgM antibody-induced signaling pathways were shown to be PKC-dependent in contrast to the CD40-induced signaling pathways. Thus, the B cell receptor and CD40 recruit the ERK, JNK and p38 pathways by using different upstream effectors.

Antigens, Differentiation, T-Lymphocyte↗
PubMed2002

Cellular responses to murine CD40 in a mouse B cell line may be TRAF dependent or independent.

Engagement of CD40 by its ligand induces IKK and mitogen-activated protein kinase (MAPK) phosphorylation and transcriptional activation, leading to activation and differentiation of B cells. These events are most likely transduced by adaptor molecules that are recruited to the CD40 cytoplasmic domain, called TNF receptor-associated factors (TRAF). We have engineered a chimeric CD40 molecule using the human extracellular sequence and the murine cytoplasmic domain to assess the contribution that specific TRAF binding domains provide to the cytoplasmic signaling functions of CD40. The data presented here show that the shared binding site for TRAF2 and TRAF3 accounts for receptor internalization, and the majority of signaling through CD40, but is redundant with the TRAF6 binding site for activation of p38 and NFkappaB signaling pathways. Disruption of the TRAF2/3 binding site results in a delayed and diminished kinase pathway induction, but complete preclusion of all signals requires the disruption of more than the two known TRAF binding sites. The specific TRAF dependency of CD40-induced growth arrest, TNF-alpha production, and phosphorylation of signaling molecules are shown, while p38 MAPK activation and cell surface antigen modulation suggest TRAF independent CD40 signaling in B cells.

Animals↗
PubMed2003

CD40 and CD40L expression in the chicken embryo aorta: possible role in the endothelial-mesenchymal transdifferentiation process.

Endothelial-mesenchymal transdifferentiation (EMT) is believed to play a crucial role in embryonic vascular development and intimal thickening, which contributes to the pathogenesis of atherosclerotic lesions. However, the mechanisms by which it occurs, as well as the signals that control it, have not yet been elucidated. Given the important role played by the CD40-CD40 ligand (CD40L) system during the initiation and progress of atherosclerosis, we investigated whether both CD40 and CD40L were present in the aortic wall during EMT and the advanced stages of chicken embryo development. CD40-CD40L expression was found on endothelial cells (ECs), mesenchymal cells, and smooth muscle cells (SMCs) at all stages examined, and appeared to be distributed across the aortic wall. However, some notable differences between the expression patterns were observed. CD40 had a more restricted distribution compared to CD40L, and did not stain every cell type of the aortic wall. According to immunoblotting and enzyme-linked immunosorbent assay (ELISA) analyses, the CD40L content was highest at day 7 of development. An important and novel finding was the expression of CD40L in areas where ECs transdifferentiate into mesenchymal cells. Specifically, CD40L was associated to the surface of cells that were detaching and migrating from the monolayer of ECs, whereas for CD40 a very diffuse subcellular localization was seen at the monolayer and the detaching and migrating cells. These data suggest a possible role for CD40-CD40L interactions during EMT and the remodeling of the aorta.

Actins↗
PubMed1995

A cytotoxic CD40/p55 tumor necrosis factor receptor hybrid detects CD40 ligand on herpesvirus saimiri-transformed T cells.

The B cell activation molecule CD40 and the p55 tumor necrosis factor receptor (p55TNFR) belong to the same family of structurally conserved proteins. We constructed a chimeric receptor consisting of the CD40 extracellular and transmembrane domains and the p55TNFR intracellular domain. This receptor hybrid retained the biological activity and the ligand specificity of the respective wild-type receptor domains. Thus it exerted a marked cytotoxic effect in three different transfected cell lines after activation not only with anti-CD40 antibody but also with CD40 ligand (CD40L) in soluble and membrane-bound forms. Using hybrid-transfected baby hamster kidney cells we demonstrated that herpesvirus saimiri-transformed human CD4+ T lymphocytes constitutively express bioactive CD40 ligand on their surface. The hybrid receptor-based assay was highly specific for CD40 activating reagents and more sensitive than an assay measuring CD40-mediated B cell rescue from apoptosis. Hence CD40/p55TNFR transfectants may be useful for dissecting CD40L-mediated events in T-B cell interactions, and also to detect a defective CD40L molecule in putative hyper-IgM syndrome patients.

Animals↗
PubMed2005

CD154-CD40 interactions drive hepatocyte apoptosis in murine fulminant hepatitis.

The CD154-CD40 interaction is a critical costimulatory pathway modulating the cellular immune response. Moreover, fulminant hepatitis of various etiologies is characterized by a hepatic influx of CD154-expressing T cells and an upregulation of CD40 expression on Kupffer cells and hepatocytes, implicating this pathway in the pathogenesis of fulminant hepatitis. In this study, we used a murine model of fulminant hepatitis induced by concanavalin A (con A) and documented a significant influx of CD154-expressing T cells into the livers of mice treated with con A, in association with markedly increased expression of CD40 restricted mainly to hepatocytes in damaged areas of the liver. Furthermore, con A hepatitis in CD154-deficient mice was significantly attenuated compared with that in wild-type controls and was associated with a decrease in hepatic tumor necrosis factor alpha (TNF-alpha) levels and hepatocyte death. We next determined the role of the CD154-CD40 pathway in hepatocyte death in vitro. These in vitro studies demonstrated that TNF-alpha induces CD40 expression in hepatocytes and that subsequent activation of CD40 results in hepatocyte apoptosis mediated at least in part by enhanced hepatocyte expression of FasL. In conclusion, CD154 stimulation of CD40 plays a central role in hepatocyte death in fulminant hepatitis through direct and indirect pathways that may have direct therapeutic implications in humans. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).

Animals↗