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R A van Lier

Publications and source records attributed to R A van Lier.

At least 19 recordsLinked to original sources
PubMed1997

AICL: a new activation-induced antigen encoded by the human NK gene complex.

The NK gene complex on mouse chromosome 6 and its human homologue on chromosome 12 encode type II transmembrane proteins with a C-type lectin domain which trigger or inhibit target cell lysis by NK cells (NKR-P1, Ly49, NKG2, CD94) or function as cellular activators of various hematopoietic cells (CD69). We herein report the cDNA cloning of a new molecule, designated activation-induced C-type lectin (AICL), whose gene maps to the human NK gene complex proximal to the CD69 gene. AICL is a 149-amino acid (aa) polypeptide with a short cytoplasmic part of seven aa and a C-type lectin domain separated from the transmembrane region by only nine aa. The highest sequence similarity is found to the C-type lectin domains of CD69 and the chicken lectin 17.5. The presence of AICL transcripts in different cell types of hematopoietic origin, a rapid increase of gene transcription during lymphocyte activation, and a short half-life of the mRNA characterize AICL as a new, broadly expressed activation antigen.

Amino Acid Sequence↗
PubMed1997

Antigen-presenting cell-derived signals determine expression levels of CD70 on primed T cells.

Interaction between CD27 and its ligand CD70 provides a second signal for T-cell proliferation and tumour necrosis factor-alpha (TNF-alpha) production. Whereas CD27 is broadly expressed during T-cell development, expression of CD70 in vivo is restricted. To determine when CD27 CD70 interactions can occur in immune reactions, we here analysed the regulation of CD70 expression on activated T cells. Mitogenic stimulation of purified T cells with either immobilized CD3 monoclonal antibody (mAb) or a combination of CD2 mAb induces only low levels of CD70 membrane expression. Markedly expression of the CD27-ligand is strongly enhanced by antigen-presenting cells (APC) and APC-associated signals such as interleukin-1 alpha (IL-1 alpha). IL-12, TNF-alpha and CD28-ligation. In contrast, T-cell derived cytokines, such as IL-4, counteract CD70 up-regulation on activated T cells. Analysis of the small subset of circulating CD70+ T cells revealed that these cells have a primed phenotype as they express CD45RO and HLA-DR antigens and are in high frequency able to secrete interferon-gamma (IFN-gamma). We conclude that T-T interactions involving CD27 and CD70 are likely to occur relatively early in immune reactions, after productive T-cell priming by APC and that expression of CD70 on circulating T cells is a reflection of recent priming by antigen.

Antibodies, Monoclonal↗
PubMed1996

Alteration of B-cell antigen receptor signaling by CD19 co-ligation. A study with bispecific antibodies.

The activation of B-cell antigen receptor-associated protein tyrosine kinases is an early and crucial event in B-cell signaling. Apart from the B-cell antigen receptor (BCR), the B-cell-specific transmembrane glycoprotein CD19 has also been shown to directly activate intracellular signaling cascades. In addition, because CD19 and the BCR are associated on the surface of activated B-cells, it has been proposed that close approximation between these two entities is crucial for optimal B-cell triggering. To test this hypothesis, bispecific antibodies were generated that bind membrane IgM and CD19 simultaneously. Although CD19 bispecific antibodies strongly induced tyrosine phosphorylation, they were, in contrast to muF(ab)2 fragments, unable to induce a proliferative response. Detailed analysis of the early signaling events showed that compared with muF(ab)2 fragments CD19 bispecific antibodies potently raised the intracellular [Ca2+], which was correlated with an efficient tyrosine phosphorylation of syk. Strikingly, the assembly of Grb2 complexes that may couple the BCR to p21(ras) was clearly altered by the CD19 bispecific antibody. In addition to the reported Shc and 145-kDa phosphoproteins, a prominent 90-95-kDa phosphoprotein resembling CD19 was detected in the Grb2 complexes. Thus, studies with CD19 bispecific antibodies show that CD19 co-ligation both quantitatively and qualitatively alters BCR signaling.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Elevation of cerebrospinal fluid soluble CD27 levels in patients with meningeal localization of lymphoid malignancies.

Diagnosis of meningeal localization of lymphoid malignancies by means of cytologic examination of the cerebrospinal fluid (CSF) can be difficult. Thus far no reliable CSF tumor markers have been identified. CD27 is a transmembrane disulfide-linked 55-kD homodimer present on most peripheral blood T cells and on a subset of B cells. CD27 is also expressed on human malignant B cells and high levels of soluble CD27 can be present in the serum of patients with B-cell malignancies. The aim of this study is to determine prospectively the diagnostic value of CSF sCD27 as a tumor marker in patients with meningeal localization of lymphoid malignancies. CSF sCD27 levels were determined by sandwich enzyme-linked immunosorbent assay. The optimal cut-off value using receiver operator characteristics curves was found to be 10 U/mL. sCD27 levels were normal in all 50 control patients (lumbar disc protrusion) and in 39 of 40 samples obtained from patients with either solid tumors or acute myeloid leukemia. Of 104 CSF samples from 70 children with acute lymphoblastic leukemia (ALL) or non-Hodgkin's lymphoma (NHL) undergoing routine central nervous system (CNS) staging, sCD27 was false positive and false negative in only one sample each. In 70 samples from 45 patients suspected of meningeal localization of ALL or NHL, the sCD27 test had an excellent sensitivity (100%) and specificity (82%). In 7 patients with positive CSF studied longitudinally, sCD27 levels correlated very well with remission and relapse. sCD27 levels were not nonspecifically increased by the administration of cytostatic drugs. Finally, sCD27 was also elevated in the 4 patients studied with primary central nervous system lymphoma (PCNSL). CSF sCD27 is a promising tumor marker in patients with either meningeal localization of lymphoid malignancies or PCNSL, and can be useful in the differential diagnosis of CNS involvement by either lymphoid malignancies or solid tumors.

Adult↗
PubMed1996

Structure of the human CD97 gene: exon shuffling has generated a new type of seven-span transmembrane molecule related to the secretin receptor superfamily.

Recent cDNA cloning of EMR1 and CD97 suggests the existence of a new group of seven-span transmembrane (7-TM) molecules, likely encoded by a gene cluster on the short arm of chromosome 19. The membrane-spanning region of both molecules is homologous to the secretin receptor (SecR) superfamily, a group of receptors with specificity for mammalian and insect peptide hormones. Unlike members of the SecR superfamily known thus far, EMR1 and CD97 have extended extracellular regions that possess several EGF domains at the N-terminus. We herein describe the organization of the human CD97 gene, which consists of 18 exons expanding approximately 12 kb of DNA. Identical exon-intron positions in the transmembrane region indicate that the CD97 gene has evolved from an ancestral gene of the SecR superfamily. Remarkably, exons encoding the 300 amino acids by which CD97 extends the extracellular part from other members of the SecR group are preferentially separated by introns in phase 1. All three EGF domains are encoded by symmetrical class 1-1 exons, suggesting that exon shuffling to the upstream region of a precursor gene from the SecR superfamily has generated this new type of 7-TM receptor.

Antigens, CD↗
PubMed1996

CD30 expression does not discriminate between human Th1- and Th2-type T cells.

CD30 is a member of the TNF receptor superfamily that is commonly used as a marker for Hodgkin and Reed-Sternberg cells in Hodgkin's disease. More recently, it has been proposed that CD30 is preferentially up-regulated on Th2-type human T cells. We analyzed regulation of CD30 expression on both peripheral blood T cells and T cell clones. In short-term culture, CD30 expression could be induced on T cells by Ags that elicit Th2-type responses (Schistosoma haematobium, adult worm Ag, and Toxocaria canis, excretory/secretory Ag) and Th0-type responses (tetanus toxoid), as well as Th1-type responses (tuberculin purified protein derivative). Moreover, simultaneous measurement of membrane phenotype and cytokine production showed that CD30-expressing cells can produce IFN-gamma. Finally, within panels of randomly generated as well as Ag-specific T cell clones, CD30 expression was found on Th0-, Th2-, and Th1-type clones. We conclude that induction of CD30 on activated T cells is not related to differentiation in Th0-, Th1-, or Th2-type cells.

Cell Differentiation↗
PubMed1996

A dual role for both CD40-ligand and TNF-alpha in controlling human B cell death.

Members of the TNF-R family are instrumental in controlling lymphoid cell death and survival. A major role in the regulation of murine and human B cell survival and differentiation has been attributed to CD40/CD40-ligand (CD40-L) interactions, but recent in vitro and in vivo data implicate that other receptor-ligand pairs might also be involved. We have used the human Burkitt lymphoma cell line Ramos as a model system to identify additional TNF-R/TNF family members that are implicated in the regulation of B cell apoptosis. Ligation of B cell receptor (BCR) with anti-IgM mAb for 48 h induced apoptosis in approximately 68% of the Ramos B cells. Interestingly, not only CD40 mAb but also rTNF-alpha could efficiently inhibit BCR-induced B cell death. In addition, activated T cells also prevented BCR-triggered apoptosis, and this effect was inhibited completely by a combination of blocking Abs against CD40-L and TNF-alpha. In contrast to the strong effect of BCR ligation, APO-1 mAb induced apoptosis in only +/- 18% of the Ramos cells after 48 h. Noticeably, addition of CD40 mAb or rTNF-alpha increased the percentage of cells (+/- 46%) undergoing apoptosis, which correlated with an increase of Fas/APO-1 membrane expression induced by CD40 or TNF-R ligation. Taken together, we show that CD40/CD40-L and TNF-R/TNF-alpha interactions not only postpone or prevent B cell death, but are also involved in sensitizing B cells for Fas-ligand (Fas-L)-dependent death.

Antibodies, Anti-Idiotypic↗
PubMed1996

Identification of a novel subpopulation of germinal center B cells characterized by expression of IgD and CD70.

CD27, which belongs to the tumor necrosis factor receptor family, is expressed on germinal center (GC) but not on naive B cells, suggesting an important function of this molecule in the regulation of the GC reaction. We described here the expression of CD70, which is the ligand for CD27. We observed that in most tonsils, CD70 is only expressed on part of the IgD-, CD38- B cell population, which have been described as memory B cells. However, in 10% of the tonsils tested, CD70+ IgD+ GC were found. The CD70+ GC B cells were small cells that also expressed CD44 and CD39, but were CD10- and CD38-, suggesting that they represent very recent immigrants that are in the process of forming a GC. The concordant expression of CD27 and its ligand CD70 on this primordial subset of GC B cells suggests an important role for CD27/CD70 interaction at this stage of GC formation.

Antigens, CD↗
PubMed1996

Increased expression of CD80, CD86 and CD70 on T cells from HIV-infected individuals upon activation in vitro: regulation by CD4+ T cells.

T cells express CD28 and CD27 which transduce co-stimulatory signals after interaction with their ligands on antigen-presenting cells (APC). These ligands, CD80, CD86 and CD70, are also expressed to some extent on activated T cells. Here, we show that in human immunodeficiency virus (HIV)-infected individuals, CD28 and CD27 expression is decreased on CD8+ T cells. On the other hand, T cell stimulation in vitro induced high CD80, CD86 and CD70 expression on T cells from HIV-infected individuals. It appeared that an inverted CD4:CD8 T cell ratio could explain this enhanced expression of co-stimulatory ligands. Indeed, high expression levels of CD80, CD86 and CD70 were found on activated CD8+ T cells from HIV- individuals cultured in the absence of CD4+ T cells. Addition of CD4+ T cells prevented this up-regulation. However, in HIV-infected individuals, addition of excess autologous or healthy control CD4+ T cells did not completely counteract up-regulation of co-stimulatory ligand expression on CD8+ T cells. Thus, to some extent, CD8+ T cells in HIV-infected individuals appeared to be refractory to CD4+ T cell-mediated regulation of ligand expression in vitro. Activated T cells from HIV-infected individuals and activated CD8+ T cells from healthy controls were able to act as accessory cells in CD3-induced T cell proliferation, which was dependent on cell-cell contact. Thus, we showed that T cells from HIV-infected individuals express enhanced levels of co-stimulatory ligands upon activation, which provides them with accessory cell properties. Enhanced stimulatory potential of these nonprofessional APC may contribute to persistently high levels of immune activation in HIV infection related to disease progression.

Antigens, CD↗
PubMed1996

Phenotype and function of human B cells expressing CD70 (CD27 ligand).

CD70, the cellular ligand of the tumor necrosis factor receptor family member CD27, can be found on a limited number of germinal center (GC) B cells in some tonsils, on scattered lymphocytes residing in secondary lymphoid organs, and on a fraction of the circulating B cell population. Due to the restricted expression of CD70 in vivo, we analyzed signals that determine CD70 expression levels and characterized the phenotype and function of CD70+ B cells. Expression of CD70 on B cells activated in vitro was found to be dependent on the continuous presence of a B cell antigen receptor cross-linking agent, and induced or potentiated by CD40 ligation but was down-modulated by the Th2 cytokines interleukin (IL)-4 and IL-13. Both in peripheral blood and tonsil cell suspensions, CD70+ B cell subpopulations were found to be enriched for CD27- and IgG-expressing cells, but contained less IgD+ B cells. Additional analysis of markers which define specific differentiation stages (Bm1-5) of mature B cells within human tonsils did not place CD70-expressing B cells in one of these subsets. Functional experiments revealed that whereas both CD70- and CD70+ B cells can secrete immunoglobulin after activation with a combination of Staphylococcus aureus Cowan strain I and IL-2, only CD70+ B cells can produce large quantities of antibodies when stimulated in a T cell-dependent fashion. Our combined data imply that CD70 is a marker for mature B cells which have recently been primed by antigen in vivo.

Antibody Formation↗
PubMed1996

Expression of the activation antigen CD27 in rheumatoid arthritis.

Differentiation of CD4+ T-cells is reflected by the change from the CD45RA+CD27+ phenotype via CD45RO+CD27+ to the CD45RO+CD27- phenotype. To provide insight into the migration and activation of T-cells at the site of inflammation in rheumatoid arthritis (RA), CD27 expression by T-cells in peripheral blood (PB), synovial fluid (SF), and synovial tissue (ST) as well as the levels of the soluble form of CD27 (sCD27) in plasma and SF were studied in patients with RA. Since CD4+CD27+ T-cells are involved in providing helper activity for B-cells, we also investigated the levels of rheumatoid factors in serum and SF in relation to CD27 expression. The mean level of sCD27, which is produced by CD27+ cells, and the mean percentage of CD27 T-cells within the CD4+CD45RA- subset were higher in SF than in PB. SF sCD27 levels were higher in the patients with RA than in the patients with osteoarthritis, who served as controls. In ST infiltration by CD4+CD45RO+CD27+ T-cells, could be demonstrated in the rheumatoid perivascular lymphocytic aggregates with a relative increase in the percentage of CD27- T-cells in the diffuse lymphocytic infiltrate. The sCD27 levels and the percentages of CD4+CD27+ cells in SF correlated positively with the levels of rheumatoid factors in serum and SF. The findings presented in this study suggest a continuous influx of preactivated CD4+CD45RO+CD27+ cells from the PB into the rheumatoid ST and further activation and differentiation to CD4+CD45RO+CD27- cells in situ, followed by migration to the SF. These activated T-cells are likely to play a role in synovial inflammation.

Adult↗
PubMed1996

Compartmentalization of B-cell antigen receptor functions.

Receptor tyrosine kinases (RTK), like the PDGF-receptor, translate information from the extracellular environment into cytoplasmic signals that regulate a spectrum of cellular functions. RTK molecules consist of ligand binding extracellular domains, cytoplasmic kinase domains and tyrosine phosphorylation sites [Ullrich and Schlessinger, 1990 (Cell 61, 203-212); Heldin, 1992 (EMBO J. 11, 4251-4259)]. Upon ligand-induced RTK oligomerization, the kinase domains will become activated and induce auto(trans)phosphorylation of a number of cytoplasmic tyrosine residues. These phosphorylated tyrosine residues are incorporated in distinct sequence motifs and act as specific docking sites for SH2 domain-containing proteins [Songyang et al., 1993 (Cell 72, 767-778)]. In contrast to single- or oligo-chain RTK, immunological receptors such as antigen receptors, FcR and cytokine receptors are multi-chain complexes in which distinct receptor functions appear to be compartmentalized in distinct polypeptides. Here, we summarize current knowledge on the structural and functional characteristics of the B-cell antigen receptor complex (BCR) and address the specific ability of accessory molecules to recruit intracellular signaling intermediates towards the activated receptor complex.

Amino Acid Sequence↗
PubMed1996

A pilot study investigating the effects of orally administered pentoxifylline on selected immune variables in patients with multiple sclerosis.

Multiple sclerosis is probably mainly mediated by T-helper 1 (TH1)-lymphocytes. TH1-function can be down-regulated in vitro and in animal experiments by pentoxifylline. Therefore, we included 20 multiple sclerosis patients in an open label pilot trial of pentoxifylline. Outcome parameter was the effect of treatment on levels of various cytokines and adhesion molecules in cerebrospinal fluid and serum, on production of TH1- and TH2-cytokines using cell stimulation assays, as well as on measures of T-cell activation and proliferation. Kurtzke's EDSS was a secondary efficacy parameter. A convincing and consistent effect of pentoxifylline could not be demonstrated.

Administration, Oral↗
PubMed1996

Recombinant interferon-beta blocks proliferation but enhances interleukin-10 secretion by activated human T-cells.

Results from recent clinical trials have indicated that recombinant interferon-beta (rIFN-beta) is a promising drug for the treatment of Multiple Sclerosis (MS), a disease of supposed autoimmune etiology. To gain insight into the immunoregulatory properties of this cytokine, we analyzed effects of interferon-beta (IFN-beta) on T-cell functions in vitro. Interferon-beta inhibited T-cell proliferation, as well as T-cell-dependent immunoglobulin secretion, in a dose-dependent manner. IFN-beta did not inhibit upregulations of CD40L on activated T-cells, but blocked induction of CD25 on stimulated T- and B-lymphocytes. Secretion of interferon-gamma (IFN-gamma), tumour necrosis alpha (TNF-alpha) and IL-13 was inhibited by the addition of IFN-beta, whereas IL-4 secretion was unaffected. Interestingly, IFN-beta enhanced secretion of IL-2 about two-fold and secretion of IL-10 nearly four-fold. In summary, these findings suggest that IFN-beta may exert direct effects on T- and beta-cell function in vivo. In addition, enhanced secretion of IL-10 by activated T-cells may interfere with newly initiated and ongoing inflammatory immune reactions.

B-Lymphocytes↗
PubMed1995

Bispecific antibody-mediated target cell-specific costimulation of resting T cells via CD5 and CD28.

Induction of T-cell activation requires multiple signals provided by cell surface receptor interactions and/or cytokines. T-cell stimulation via the T-cell receptor/CD3 complex provides an important initial activation event which, when combined with the proper costimulatory signals, results in an activated effector T cell. In this report, we have investigated the effectiveness of epithelial glycoprotein-2- (EGP-2) positive tumor target cells to induce specific T-cell stimulation via CD3, CD5, and CD28 using various combinations of bispecific monoclonal antibodies (BsMab) directed against CD3, CD5, or CD28 on the one hand and the pancarcinoma-associated antigen EGP-2 on the other. Induction of T-cell activation was investigated by assessment of CD69 expression, induction of proliferation, and acquirement of cytolytic potential. EGP-2-specific induction of T-cell activation was observed using combinations of BsMab which simultaneous ligated CD3/CD5, CD3/CD28, or CD3/CD5/CD28 with EGP-2. Activation with CD3-, CD5-, or CD28-based BsMab alone did not result in significant induction of T-cell activation in the presence or absence of EGP-2-positive target cells. Simultaneous ligation via CD5/CD28 resulted in partial T-cell activation, including CD69 up-regulation and increased cytolytic activity. Stimulation via CD3 and CD5 or CD28 could be further increased by the addition of exogenously added recombinant Interleukin 2. In contrast, T-cell activation by simultaneous ligation of CD3/CD5/CD28 could not be further augmented by addition of exogenous interleukin 2, indicating that T-cell activation via the combination of CD3, CD5, and CD28 results in complete T-cell activation. Our results show that rapid and target cell-specific induction of T cells is possible using combinations of BsMab directed against different costimulatory molecules. Simultaneous costimulation via CD3/CD5/CD28 results in the most complete activation of T cells.

Antibodies, Bispecific↗
PubMed1995

Hematopoietic cell phosphatase is recruited to CD22 following B cell antigen receptor ligation.

Hematopoietic cell phosphatase is a nonreceptor protein tyrosine phosphatase that is preferentially expressed in hematopoietic cell lineages. Motheaten mice, which are devoid of (functional) hematopoietic cell phosphatase, have severe disturbances in the regulation of B cell activation and differentiation. Because signals transduced via the B cell antigen receptor are known to guide these processes, we decided to analyze molecular interactions between the hematopoietic cell phosphatase and the B cell antigen receptor. Ligation of the B cell antigen receptor induces moderate tyrosine phosphorylation of hematopoietic cell phosphatase and the formation of a multi-molecular complex containing additional 68-70- and 135-kDa phosphoproteins. In resting B cells most of the hematopoietic cell phosphatase proteins reside in the cytosolic compartment, whereas after B cell antigen receptor cross-linking, a small fraction translocates toward the membrane where it specifically binds to the 135-kDa phosphoprotein. This 135-kDa glycoprotein was identified as CD22, a transmembrane associate of the B cell antigen receptor complex. Together these findings provide the first direct evidence that this cytoplasmic tyrosine phosphatase is involved in antigen receptor-mediated B cell activation, suggesting that in vivo B cell antigen receptor constituents or associated molecules may serve as substrate for its catalytic activity.

Antibodies, Monoclonal↗
PubMed1995

Activated T cells can induce high levels of CTLA-4 expression on B cells.

Engagement of the TCR/CD3 complex together with ligation of CD28 by its counterstructures B7-1 (CD80) and B7-2 (CD86) on APC are required for mitogenic T cell activation. After activation, T cells not only express B7-1 and B7-2 molecules, but a second receptor for the B7 ligands, CTLA-4, can be found on their surfaces. We here show that B cells can be induced to express CTLA-4 on the plasma membrane. Similar to what has been reported for T cells, CTLA-4 expression on B cells was transient. Purified B cells did not express CTLA-4 when mitogenically activated with alpha IgM and CD40 Ab, but did express the molecule when cultured in the presence of membranes from activated T cells, which suggests that induction of CTLA-4 expression on B cells was dependent on direct cell-cell contact of B lymphocytes and activated T cells. CTLA-4 molecules isolated from either T or B cells were biochemically indistinguishable. Moreover, because the ability of chimeric B7-1/Ig proteins to bind to activated B cells was correlated with CTLA-4 expression levels on these cells, we conclude that B cell-expressed CTLA-4 has ligand binding capacity. These data suggest that costimulatory receptors and their specific ligands not only play a role in T cell stimulation, but contribute in a direct fashion to the regulation of B cell responses.

Abatacept↗