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PubMed2006

Differential mechanisms of microparticle transfer toB cells and monocytes: anti-inflammatory propertiesof microparticles.

Microparticles are small vesicles released from the plasma membrane of various cell types independently of apoptosis or cell death, are transferred between cells, and carry membrane proteins from one cell to another. We have studied the mechanism of uptake of microparticles by monocytes and B cells. The transfer of microparticles to B cells was almost completely dependent on complement. Incubation of microparticles with serum resulted in opsonization of microparticles with the complement cleavage product iC3b. The subsequent transfer to B cells was mediated by the complement receptor CR2. The interaction between iC3b-opsonized microparticles and B cells reduced the activation of B cells as measured by expression of MHC class II, CD86 and CD25. In contrast, transfer of microparticles to monocytes was only partially complement dependent, but involved calcium and annexin V, and was found to change the cytokine profile of monocytes towards a reduced release of the pro-inflammatory cytokines GM-CSF and TNF-alpha and an increased release of the anti-inflammatory cytokine IL-10. These data show that microparticles are taken up by B cells and monocytes by different mechanisms and modulate the activation of monocytes and B cells towards an anti-inflammatory phenotype. Microparticles might be involved in counterbalancing pro-inflammatory signals arising from tissue injury or inflammation.

Annexin A5↗
PubMedDate not supplied

Restrictions upon Epstein-Barr virus infection of the leukemic cell are demonstrated in patients with hairy cell leukemia.

We tested the hypothesis that Epstein-Barr virus (EBV) might actually infect leukemic hairy cells in vivo by examining those cells for the EBV-receptor, EBV nuclear antigen (EBNA) and membrane antigen (MA), for spontaneous transformation and rescue of infectious virus and for presence of EBV genome. EBV-receptors were found on subpopulations of leukemic cells from each of 7 patients with hairy cell leukemia (HCL) tested. MA was present on low numbers (1-5 per cent) of fresh leukemic cells of 7 patients and in some instances occurred with a greater frequency after 3 to 5 days in culture, with or without 12-O-tetradecanoylphorbol-13-acetate. In 11 fresh leukemic cell preparations from 8 HCL patients, no EBNA was demonstrated. However, 2 samples after 4 days in culture expressed low frequencies of EBNA-positive cells. Spontaneous, EBV-positive cell lines were established with a high transformation efficiency from 3 HCL blood samples but not from 8 other specimens. Infectious EBV could be rescued from some hairy leukemic cell preparations by co-cultivation with cord blood lymphocytes. These results demonstrated that leukemic cell populations harbored infectious EBV, that the leukemic cells expressed virus receptors and suggested that a small subpopulation of leukemic cells might become infected in vivo at least transiently and possibly transformed in vitro by EBV. To test for the extent of occult in vivo infection of leukemic cells with EBV, Southern type hybridization studies were performed with a probe for EBV genome (Bam HI W). At a sensitivity level of 0.1 genome per cell, EBV genome was not detected in the leukemic cell populations of 7 patients. We conclude that host defence mechanisms protecting these individuals from EBV also prevent infections of the leukemic cell and/or most hairy leukemic cells are not suitable targets for both infection and transformation.

Antigens, Viral↗
PubMed1986

Epstein-Barr virus status and tumour cell phenotype in sporadic Burkitt's lymphoma.

Burkitt's lymphoma (BL) biopsy cells and derived cell lines can be grouped according to their patterns of reactivity with 6 selected monoclonal antibodies (MAbs) against B cell-associated surface antigens. Group I cells react only with MAbs J5 and 38.13, recognising the common acute lymphoblastic leukaemia antigen and a BL-associated antigen respectively; group II cells react with J5 and 38.13 and with one or more of a set of MAbs (Ki-24, MHM6, AC2, Ki-1) against "lymphoblastoid" antigens; group III cells react only with these anti-"lymphoblastoid" MAbs. Tumour biopsy cells from 17 cases of sporadic BL, 9 positive for the Epstein-Barr (EB) virus genome and 8 negative, have been analysed during the process of cell line establishment in vitro. In early passage the EB virus-negative BL cells showed either a group I phenotype or gave an additional reactivity with MAb Ki-24 which placed them in group II; these phenotypes remained essentially stable with continued growth of the cell lines for up to 50 passages. By contrast the EB virus-positive BL cells were much more susceptible to phenotypic change in vitro. Although such cells displayed a group I or group II phenotype in early passage, many of the lines soon moved into group III whilst retaining the karyotypic markers indicative of their malignant origin. These observations suggest that a resident EB virus genome can drive the in vitro progression of BL cells towards a more "lymphoblastoid" phenotype. This was confirmed in subsequent experiments where virus-negative BL cell lines were converted to EB virus positivity by in vitro infection. Clearly, therefore, phenotypic analysis of long-established lines can lead to false distinctions being drawn between the EB virus-positive and -negative forms of sporadic BL; both may derive from the same sub-population of target B cells in vivo.

Adolescent↗
PubMed1986

EBV-negative and -positive Burkitt cell lines variably express receptors for B-cell activation and differentiation.

The expression of receptors for proliferation and differentiation factors was analyzed by indirect immunofluorescence on 29 Burkitt lymphoma (BL) cell lines previously classified into 3 groups on the basis of their reactivity with 8 monoclonal antibodies (MAbs), including anti-CALLA, BL13 and TU1. BL13 and HB5 antibodies recognize different epitopes of the EBV/CR2 receptors. The determinant recognized by BL13 has been previously shown to be expressed only on cell lines of the first two groups, supposed to derive from the germinal center and to be negative on a third group of lines of putative BM origin and established from sporadic cases of BL. In contrast, and as expected from its reactivity on normal B cells in the BM or in the lymph nodes, HB5 antibody reacts with all BL lines except one. The receptor for transferrin is expressed on the 29 lines. Two new MAbs, Bac-1 and B1H5, could recognize respectively receptors for BCGF1 and BCGF2. Bac-1 reacts with 15 of 17 BL lines belonging to the first two groups and 7 of 12 BL lines of the third group; 14 of 15 EBV + lines express Bac-1. No BL line expresses B1H5. The IL2 receptor is weakly expressed on 5 EBV + cell lines and one EBV (-) line. All delta are BCGF1-positive. The almost constant expression of BCGF1 receptor on EBV + cell lines is the only strict relation between the expression of receptors for growth factors and their characteristics (i.e. EBV association, translocation, ethnic origin and clinical presentation). The maturation stage or the origin of BL cell lines in relation to the expression of growth factor receptors and the functional significance of these receptors will be discussed.

Antigens, Neoplasm↗
PubMed1989

Activation and immortalization of leukaemic B cells by Epstein-Barr virus.

We have studied the responses of chronic leukaemic B cells to infection by Epstein-Barr virus (EBV). Our results define one population of B lymphocytes, represented by prolymphocytic leukaemic (PLL) cells, which are highly susceptible to immortalization by EBV. Another B-cell type, represented by chronic lymphocytic leukaemic (CLL) cells, can be readily infected by the virus but is resistant to immortalization. Comparative studies of viral and cellular related events early after infection in these 2 cell types reveal that both express the EB viral nuclear antigen (EBNA) complex, but the immortalization-resistant CLL cells fail to express the latent membrane protein (LMP), which can be detected in PLL cells 48 hr after infection. Circularization of the linear viral genome could be detected at 7 days post infection in the PLL cells, but only in 2 out of 4 CLL cells tested. Both CLL and PLL cells show increased surface expression of CD23 and HLA-DR molecules after infection but, whereas PLL cells show an increase in size, together with RNA and DNA synthesis indicative of cell cycle progression, CLL cells appear to be arrested in the G1/S phase of the cycle. The results suggest that the outcome of infection by EBV is determined by the nature of the target cell rather than by random virus-related events. The correlation between the block in immortalization of CLL cells and their failure to express LMP suggests that expression of this protein is essential for in vitro immortalization of B cells. The failure to detect circularization in some EBV-infected CLL cells suggests that this, as well as LMP expression, may be dependent on prior activation of the B cell by EBV, an event which may vary between the different CLL samples tested.

Antigens, CD↗
PubMed1993

Epstein-Barr virus (EBV) nuclear-antigen-2-induced up-regulation of CD21 and CD23 molecules is dependent on a permissive cellular context.

The Epstein-Barr virus (EBV) induces unlimited growth of B lymphocytes in vitro, a phenomenon known as immortalization. The elucidation of the mechanisms by which EBV de-regulates B-cell proliferation in vitro will permit an understanding of how the virus contributes in vivo to the genesis of Burkitt's lymphoma (BL) and of lymphoproliferations in immunosuppressed patients. At present, no single EBV immortalizing gene has been identified, and the hypothesis has been made that many viral genes cooperate in establishing an autocrine loop of secretion leading to immortalization. Constitutive expression of B-cell surface molecules such as CD21 and CD23, specifically implicated in the control of B-cell proliferation, is indeed induced at the surface of immortalized B lymphocytes. The expression of the viral nuclear antigen 2 (EBNA2) has been shown to be in part responsible for CD21 and CD23 up-regulation, and EBNA2 is suspected to be a transactivator of cellular genes, although this point remains to be demonstrated. The role of EBNA2 gene, independently of other viral genes, has been investigated by transfection into B-lymphoma lines, but conflicting results have been reported. To further investigate its role in the regulation of CD21 and CD23 molecules, we have compared the effects of EBNA2 expression in 2 sets of B-lymphoma lines infected with P3HR1 EBV strain, and/or transfected with EBNA2 gene. We report here that: (i) EBNA2 expression is not a sufficient condition to induce CD21 and CD23 upregulation, EBNA2's effects are highly dependent on the cellular context, and moreover can be modified by infection with P3HR1 virus; (ii) EBNA2 induces activation of CD23 expression in a very particular way, namely, an increased quantity of CD23 steady-state RNA coding for the form A of the protein, which is not detectable at the cell surface but directly secreted.

Antigens, Viral↗
PubMed1991

Epstein Barr virus/complement C3d receptor is an interferon alpha receptor.

Interferon alpha contains a sequence motif similar to the complement receptor type two (CR2/CD21) binding site on complement fragment C3d. Antibodies against a peptide with the CR2 binding sequence on C3d react with a peptide carrying the IFN alpha CR2 binding motif (residues 92-99) and with recombinant IFN alpha. The IFN alpha-derived peptide, as well as recombinant IFN alpha, inhibits C3bi/C3d interaction with CR2 on the Burkitt lymphoma Raji. The direct interaction of IFN alpha and CR2 is inhibited by polyclonal anti-IFN alpha, anti-CR2 and anti-C3d peptide antibodies as well as by C3bi/C3d, EBV coat protein gp350/220 and IFN but not by IFN gamma. [125I]IFN alpha binding to Raji cells is inhibited by polyclonal anti-IFN alpha and anti-CR2 antibodies, by peptides with the CR2 binding motif and partially by C3bi/C3d. Monoclonal anti-CR2 antibody HB5, but not OKB-7, blocks IFN alpha binding to Raji cells. CR2 or CR2-like molecules may therefore be the major IFN alpha receptors on B lymphocytes.

Amino Acid Sequence↗
PubMed2003

Germinal centre-like versus undifferentiated stromal immunophenotypes in follicular lymphoma.

Follicular dendritic cells (FDCs) in reactive germinal centres (GCs) show modulated expression of antigens indicative of step-wise maturation from more undifferentiated stroma. The present study compared the expression of FDC markers CD21, CD23, CD35, and chemokine CXCL13 and the stromal markers low-affinity nerve growth factor receptor (LNGFR) and CNA.42 in 35 follicular lymphoma (FL) cases with reactive lymphoic tissue. CXCL13 was expressed by follicular stroma in all FLs but most cases showed either partial (11/35 cases, 31%) or complete (10/35 cases, 29%) absence of other FDC antigens, most commonly CD23, followed by CD21 and CD35, with variable patterns of LNGFR and CNA.42 immunostaining. Only a minority of FL cases (14/35, 40%) showed stroma that resembled mature FDCs (CD23+, CD21+, CD35+) and these tumours were always associated with numerous intrafollicular T-cells, similar to reactive GCs. In the 25 FL cases that had identifiable extrafollicular tumour cells, the immunophenotype of follicular stroma showed the same variability but the extrafollicular stroma showed an absence of FDC markers, with the exception of frequent strong LNGFR staining. Stromal phenotypic changes in FL were not correlated with mean follicle size, percentage of diffuse growth, tumour mitotic rate or the proliferation index as determined by PCNA immunostaining. Serial biopsy specimens analysed in a subset of 15 patients showed either a stable stromal phenotype (seven cases, 47%) or loss of FDC antigens in tumour-associated stroma over time (seven cases, 47%). The GC-like subset of FLs, having both abundant intrafollicular T-cells and fully differentiated CD23+ FDCs, comprises a minority of FL cases that likely have different growth requirements from FLs that lack these features. The pattern of FDC antigen loss in stroma of FL is a readily assessable biological feature that appears independent of architectural growth pattern and may serve as a useful surrogate marker of tumour progression.

Biomarkers, Tumor↗
PubMed1996

Structure-based modeling of the ligand binding domain of the human cell surface receptor CD23 and comparison of two independently derived molecular models.

CD23, a type II membrane receptor protein, recognizes four different ligands via its extracellular C-type lectin domain: immunoglobulin E (IgE), CD21, and the beta 2-integrins CD11b and CD11c. CD23 specifically interacts in a calcium-dependent manner, "lectin-like" with carbohydrate moieties expressed on CD21 and CD11b/c, but also "lectin-unlike" with protein epitopes on IgE. As a first step in analyzing the multiple binding specificities associated with CD23 in more detail, we report a detailed molecular model of the lectin-like domain of human CD23 (hCD23). The model was built based on information provided by X-ray structures of mannose binding protein (MBP) and E-selectin, both of which are members of the calcium-dependent (C-type) lectin superfamily. Sequence-structure comparisons suggest that hCD23 is structurally more similar to MBP than to E-selectin. The hCD23 model is compared to an independently derived model. Although the CD23-carbohydrate and CD23-protein interactions are both calcium dependent, analysis of the model suggests the presence of distinct binding sites for these ligands.

Amino Acid Sequence↗
PubMed1993

EBV membrane receptor (CR2) is phosphorylated by protein kinase C (PKC) in the early stages of virus entry into lymphoblastoid cells line (Raji).

Labeling the EBV membrane with octadecylrhodamine-b-chloride (R18) we were able to monitor spectrofluorometrically the early events of EBV fusion, under conditions in which we could affect PKC activity. Binding of EBV to Raji cells induces PKC translocation from the cytosol to the plasma membrane and 32P incorporation into its cellular receptor CR2. CR2 phosphorylation is completely inhibited when cells are preincubated with the PKC inhibitor calphostin c. This treatment also generates a strong inhibition of EBV fusion. Taken together this result suggests a key role of CR2 phosphorylation in the EBV entry into Raji cells.

Adenosine Triphosphate↗
PubMed2001

Ontogeny of the follicular dendritic cell phenotype and function in the postnatal murine spleen.

Follicular dendritic cells (FDCs) represent a unique cell population of antigen trapping cells restricted to follicles within the secondary lymphoid tissues. FDCs appear to be involved in the formation of primary follicles during the ontogeny of lymphoid tissue. We sought to determine the kinetics and tissue distribution of cells in the spleen of newborn mice expressing various differentiation antigens restricted to FDCs using immunohistochemistry with monoclonal antibodies (mAb) against FDCs and in vivo immune complex binding and retention. The earliest FDC-specific marker displayed was the antigenic determinant recognized by the FDC-M1 mAb, which was detectable by Day 3 prior to follicle formation on cells located around the peripheral part of the developing white pulp. The appearance of CD21/35 (complement receptor Type 2 and 1, CR1.2) was observed at the end of the first week, revealing a focal pattern in B-cell-rich areas. In addition, at that time there were some FDC-M1-positive cells in the nonfollicular part of the periarteriolar region. The administration of anti-horseradish peroxidase antibody followed by soluble antigen HRP into 7-day-old newborn mice resulted in the trapping and retention of immune complexes onto FDCs even in the absence of Fcgamma receptors. The appearance of another FDC-specific marker, FDC-M2, was observed during the second week after birth and was restricted on the cells located in the same area as CR1.2 cells. The Fcgamma receptor Type II appeared on FDCs after the second postnatal week. The above sequence of phenotypic maturation could also be observed in newborns after lethal irradiation at Day 3. This indicates that not only mature FDCs but also their precursors are highly radioresistant, and their phenotypic maturation follows a programmed path that requires only a small number of mature B cells.

Animals↗
PubMed1993

Elevated secretory IgA antibodies to Epstein-Barr virus (EBV) and presence of EBV DNA and EBV receptors in patients with cervical carcinoma.

Epstein-Barr virus (EBV) receptors (EBV/C3d receptors) were detected, using the monoclonal antibody HB5, on 23 ectocervical and 5 endocervical biopsies of the uterine cervix. Elevated IgA titers against the viral capsid antigen and early antigen of EBV were also found in the cervical secretions from cervical carcinoma patients (83%), compared with samples from patients with cervical intraepithelial neoplasia (75%), herpes simplex virus-infected patients (0%), and gynecologic patients with nonmalignant conditions (0%). EBV DNA was present in 63% of cervical carcinoma biopsies detected by in situ hybridization. These observations suggest a positive association between EBV and carcinoma of the cervix.

Analysis of Variance↗
PubMed1995

Interaction of Fc gamma receptor type IIIB with complement receptor type 3 in fibroblast transfectants: evidence from lateral diffusion and resonance energy transfer studies.

To explore potential inter-receptor interactions between Fc gamma RIIIB, a GPI-linked protein, and the leukocyte integrin CR3, we have prepared transfected 3T3 fibroblast cell lines expressing Fc gamma RIIIB, CR3, or both Fc gamma RIIIB and CR3. We test the hypothesis that Fc gamma RIIIB and CR3 are physically associated in membranes using fluorescence recovery after photobleaching (FRAP) and resonance energy transfer (r.e.t.) microscopy. Cells expressing Fc gamma RIIIB alone displayed a diffusion coefficient (D) of 3.4 x 10(-9) (+/- 2.9 x 10(-9) cm2/second and a mobile fraction (m.f.) of 0.73 (+/- 0.10). In contrast, Fc gamma RIIIB exhibited D = 2.5 x 10(-9) (+/- 1.4 x 10(-9) cm2/second (n.s.) and a m.f. of 0.48 (+/- 0.08) (p < 0.01) on cells expressing both Fc gamma RIIB and CR3, thus indicating that co-expression of CR3 constrains the lateral diffusion of Fc gamma RIIIB. To further test for a direct physical interaction between these gene products, (r.e.t.) microscopy was performed. Donor-labeled anti-CR3 and acceptor-labeled anti-Fc gamma RIIIB on cells expressing both receptors yielded a r.e.t. photon count rate of 8.9(+/- 6.4) kilocounts/second (kC/s), whereas CR3-to-CR3 measurements gave 1.6(+/- 0.6) kC/s (p < 0.01). Moreover, the addition of exogenous agents such as N-acetyl-D-glucosamine, but not indomethacin, diminished the magnitude of these interactions in transfectant membranes. These data support the notion that a subpopulation of Fc gamma RIIIB is physically associated with CR3 and that this association can be affected by exogeneous compounds.

3T3 Cells↗
PubMed2001

Epstein-Barr Virus and its glycoprotein-350 upregulate IL-6 in human B-lymphocytes via CD21, involving activation of NF-kappaB and different signaling pathways.

Epstein-Barr virus (EBV) is a ubiquitous and highly immunotropic gamma herpesvirus that infects more than 90 % of humans worldwide. Its pathogenicity leads to a number of diseases including tumors that result from EBV's ability to readily transform B-lymphocytes and, to a lesser extent, epithelial cells. EBV utilizes CD21/CR2 as its receptor on B cells to initiate the infection process. EBV binds to CR2 through its major envelope glycoprotein-350 (gp350) and is also a remarkable immunomodulating agent. We had previously shown that EBV is capable of modulating the synthesis of a number of cytokines. We now show that while both purified recombinant gp350 (rgp350) and EBV upregulate IL-6 mRNA synthesis in B cells, EBV-induced IL-6 gene activation occurs for a significantly longer period of time (i.e. 12 hours for EBV as compared to 6 hours for rgp350). Moreover, the half-life of EBV-induced IL-6 mRNA was also significantly longer (10 hours) than that of mRNA induced by rgp350 (about 6 hours). Both EBV and gp350 enhance the binding of the NF-kappaB transcription factor, as determined by band-shift and augment NF-kappaB-mediated activation of a CAT reporter plasmid. Furthermore, we demonstrate that while the activation of IL-6 gene expression by gp350 is mediated primarily by the protein kinase C pathway, EBV can mediate its effects through multiple signaling pathways. To our knowledge this is the first report showing that the binding of a herpesvirus envelope glycoprotein to CR2 on human B cells results in the activation of the NF-kappaB transcription factor leading to the upregulation of IL-6 gene expression in these lymphocytes.

B-Lymphocytes↗
PubMed1998

The complement system and adaptive immunity.

The complement system covalently attaches C3d to microbial antigens which binds to CR2 on B lymphocytes, leading to a markedly enhanced adaptive immune response to that antigen. The enhancement is mediated by the cross-linking of the CR2-CD19 complex to mIg which augments the activation of several intracellular signalling pathways. Two additional receptors of the B lymphocyte, FcgammaRIIB and CD22, have opposing effects when cross-linked to mIg, the former suppressing signalling by recruiting the inositol phosphatase, SHIP, and the latter by activating the phosphotyrosine phosphatase, SHP-1. Two principles emerge from these studies: innate immunity guides the adaptive immune response, and activation of the B lymphocyte is determined by co-receptors which evaluate the biological characteristics of antigen.

Animals↗
PubMed1995

Epstein-Barr virus infection of CR2-transfected epithelial cells reveals the presence of MHC class II on the virion.

Epithelial cell lines transfected with the Epstein-Barr virus (EBV) receptor CR2 are susceptible to infection by EBV. Following infection with certain EBV strains we found that these cells became positive for MHC class II. The class II was confirmed as being of viral and not target cell origin by immunostaining with HLA-specific monoclonal antibodies. Electron microscopic immunogold staining confirmed the presence of MHC class II on the surface of the virion. While some MHC class I was also found on the EB virion, other cell surface molecules were absent. Dual color immunofluorescence and confocal microscopy analysis demonstrated colocalization of class II with EBV-encoded structural proteins (MA and VCA) in infected epithelial cells. However, preincubation of EBV with antibodies against either MHC class I or MHC class II failed to affect either EBV binding or EBV infection. The presence of MHC on the surface of the EB virion may be a consequence of the intracellular pathways through which productive virus exits from the cell and may influence the target cell tropism of EBV.

Animals↗
PubMed2006

Signalling pathways in B cells: implications for autoimmunity.

Following investigations of the pathogenic role of autoantibodies in rheumatic diseases, preclinical and clinical studies suggest a more central role of B cells in the maintenance of the disease process beyond just being precursors of (auto)antibody-producing plasma cells. Detailed analyses have implicated a number of surface molecules and subsequent downstream signalling pathways in the regulation of the events induced by BCR engagement. In this review, we discuss the potential role of molecules involved in altered B cell longevity, especially molecules involved in apoptosis (bcl-2, bcl-x, mutations in the Fas/Fas-L pathway), as well as molecules that might alter activation thresholds of B cells (CD19, CD21, CD22, lyn, SHP, SHIP-1) in the development of autoimmunity. Although focused on intrinsic B cell abnormalities, the complexity of interactions of B cells with other immune cells also makes it possible that increased B cell activation can be induced by distortions in the interaction with other cells. Further delineation of these alterations of B cell function in autoimmune conditions will allow development of more precise B cell-directed therapies beyond drastic B cell depletion, with the potential to improve the risk-benefit ratio of the treatments of autoimmune diseases.

Animals↗