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Results for “Receptors, Complement 3d”

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PubMed2004

Allergen extracts directly mobilize and activate human eosinophils.

Allergic diseases are characterized by the presence of eosinophils, which are recruited to the affected tissues by chemoattractants produced by T cells, mast cells and epithelium. Our objective was to evaluate if allergens can directly activate human eosinophils. The capacity of purified allergen extracts to elicit eosinophil chemotaxis, respiratory burst, degranulation and up-regulation of the adhesion molecule complement receptor 3 (CR3) was determined in eosinophils isolated from healthy blood donors. Eosinophils stimulated with an extract from house dust mite (HDM) released the granule protein major basic protein (MBP) and up-regulated the surface expression of CR3. Cat allergen extracts also induced the up-regulation of CR3, but not the release of MBP; instead cat, as well as birch and grass allergens, elicited the release of eosinophil peroxidase (EPO). In addition, grass pollen extract caused the secretion of MBP. None of the allergens stimulated eosinophilic cationic protein release, nor production of free oxygen radicals. Both HDM and birch extracts were chemotactic for eosinophils. These findings establish that common aeroallergens can directly activate eosinophils in vitro. We propose that eosinophil activation in vivo is not exclusively mediated by cytokines and chemokines of the allergic inflammatory reaction, but could partly be the result of direct interaction between allergens and eosinophils.

Allergens↗

PubMed2006

Antibody-independent B cell-intrinsic and -extrinsic roles for CD21/35.

Mice lacking C3, C4 or complement receptor 1/2 (Cr) have defective germinal centers (GC). The requirement for C4 implicates complement fixation by immune complexes (IC) via the classical pathway. Yet, transgenic (Tg) mice that lack circulating antibody but still express membrane IgM (mIgM) have normal GC responses. We showed previously that cross-linking mIgM leads to the deposition of C3 on the B cell surface and that disruption of this pathway diminishes GC responses. Here, we investigate the role of Cr in this process by generating mIgM-Tg mice that lack Cr and serum Ig. These mIgM/Cr-/- mice have smaller, transient GC, with incomplete B cell receptor down-regulation and peanut agglutinin up-regulation, compared to mIgM/Crwt counterparts. BM chimera experiments showed that Cr on B cells is required for normal GC responses. These results establish that Cr ligands generated at the B cell surface are sufficient for normal GC responses and function by signaling Cr on B cells. Unexpectedly, chimera experiments also showed a critical role for Cr on follicular dendritic cells (FDC), even in the absence of IC, indicating novel functions for FDC-expressed Cr beyond the capture of C3-coated IC.

Animals↗

PubMed1988

Establishment and characterization of three transplantable EBV-containing nasopharyngeal carcinomas.

Three transplantable nasopharyngeal carcinoma (NPC) tumors, designated C15, C17 and C18, have been obtained and characterized. C15, derived from a primary NPC tumor, has been propagated in nude mice for 30 passages. C17 and C18, derived from metastatic NPC tissue, have been passaged 10 times. Desmosomes, present in every case, provided confirmation of the epithelial origin of all 3 tumors. The Epstein-Barr virus (EBV) genome is contained in C15, C18 and C17 tumor cells with 30, 12 and 3 copies, respectively. The Epstein-Barr virus nuclear antigen (EBNA) was stained by the classical anti-complement immunofluorescence (ACIF) technique. Fluorescence intensity was strong in C15, moderate in C18, and hardly detectable in C17 cells. No expression of the EA and VCA antigens was detected. Flow cytometry analysis performed on monocellular suspensions showed the absence of detectable CR2 molecules (the EBV receptor on B lymphocytes) in all 3 tumors, and the constitutive expression of HLA class-II antigens in C15 and C17 cells. IL-1 activity was demonstrated in the supernatant of C15 and C17 cells cultivated in vitro for 3 days. These data confirm that the constitutive synthesis of MHC class-II molecules and the release of IL-1-like activities are frequent features of NPC cells. These characteristics could be of importance in relation with the T-cell infiltrate found in NPC primary tumors.

Adolescent↗

PubMed1989

Identification of a human epithelial cell surface protein sharing an epitope with the C3d/Epstein-Barr virus receptor molecule of B lymphocytes.

This work examines the basis for our earlier observation that certain monoclonal antibodies (MAbs) specific for the B-cell-associated C3d/Epstein-Barr virus (EBV) receptor molecule CD21 also react with the surface of some epithelial cells. Of 9 proven anti-CD21 MAbs now examined on frozen sections of human nasopharynx, tonsil and ecto-cervix, only 3 (HB5, anti-B2, AB1) showed staining of stratified epithelium; 2 of these (HB5, anti-B2) also reacted with the surface of epithelial cells freshly dispersed from these sites. The proportion of HB5- and anti-B2-reactive cells in primary epithelial cultures fell to a low but stable level within days of explantation, while almost all permanently established epithelial cell lines, whether SV40 virus-transformed or of malignant origin, were not reactive with either MAb. This contrasts with the pattern of expression of another surface marker also found selectively on cells of the lymphoid and epithelioid lineages, the CDw40 antigen. Staining with CDw40 MAbs on epithelial sections was usually restricted to the basal (proliferating) layer, but the proportion of CDw40-positive cells increased to a relatively high level in normal epithelial cultures; furthermore, most epithelial cell lines expressed this antigen. Immunoprecipitation from the surface of metabolically labelled epithelial cells with the anti-CD21 MAb HB5 yielded a protein of approximate MW 200 kDa, clearly different in size from the 145 kDa CD21 molecule on B cells. This 200 kDa protein was identified on fresh ecto-cervical epithelium, on primary cultures of a laryngeal carcinoma and on one unusual SV40-transformed epithelial cell line. We conclude that stratified human epithelial cells express a 200 kDa surface molecule which is antigenically related to, but not identical with, the CD21 antigen on B cells. It remains to be seen whether this epithelial cell protein can function as an EBV receptor.

Antibodies, Monoclonal↗

PubMed1990

Epstein-Barr virus internalization and infectivity are blocked by selective protein kinase C inhibitors.

Selective protein kinase C inhibitors can either block or significantly reduce Epstein-Barr virus infectivity: inhibition of transformation and decreased 3H-thymidine (3H-TdR) incorporation in human B lymphocytes infected with B95-8 EBV, as well as a significant reduction in the induction of early antigens in Raji cells superinfected by P3HRI EBV was achieved by pre-treating the cells with the inhibitors. The inhibitors do not act by blocking binding of the virus to its cellular receptor CR 2, but rather are effective in the viral internalization process. Our results suggest that protein kinase C may be involved in the process of viral entry into cells.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1993

Epstein-Barr virus and gastric cancer: data and unanswered questions.

Sixty-five unselected cases of gastric cancer have been analysed for EBV DNA by polymerase chain reaction, in situ hybridization and immunohistochemistry for CD21 antigen expression. Four cases were found EBV-positive by PCR, while ISH yielded positive results in 3 of these cases, demonstrating EBV in the nuclei of cancerous cells. CD21 antigen was expressed in cancerous cells in all 3 ISH-positive cases. All the EBV-positive cancers of the present series were poorly to moderately differentiated adenocarcinomas with prominent lymphoid infiltration. These results are discussed also on the basis of the literature.

Adenocarcinoma↗

PubMed1998

Binding of the endogenously expressed Epstein-Barr virus (EBV) envelope glycoprotein gp350 with the viral receptor masks the major EBV-neutralizing epitope and affects gp350-specific ADCC.

The major neutralizing epitope (MNE) for the Epstein-Barr virus (EBV) is present on its envelope glycoprotein gp350/220 (hereafter referred to as gp350) in close proximity to the virus-receptor (CR2) binding site and is recognized by the neutralizing murine monoclonal antibody (mAb) 72A1. We studied the reactivities of 72A1 and another anti-gp350 mAb 2L10 (which does not neutralize EBV) with gp350 expressed on three different lymphoid cell lines (Raji, CEM.NKr and BJA-B). Our results indicate that gp350 expressed on the surface of CR2-positive cells interacts with the viral receptor and that this interaction masks the major EBV-neutralizing epitope. The interaction was reversible and the masked epitope was revealed on incubation with an excess of anti-CR2 mAb OKB7. Gp350-expressing CEM-NKr cells with intact MNE exhibited significantly higher (P < or = 0.05) lysis in gp350-specific antibody-dependent cellular cytotoxic assays compared with its Raji counterpart. The present results may have important implications for the use of soluble viral receptors as therapeutic agents in acute and chronic EBV and other viral infections (e.g., HIV-1).

Antibodies, Blocking↗

PubMed2003

Epstein-Barr virus infection of rat lymphocytes expressing human CD21 results in restricted latent viral gene expression and not in immunoblastic transformation.

Transgenic rats expressing human CD21 gene (hCD21) driven by the mouse immunoglobulin enhancer were generated. hCD21 was expressed in lymphoid tissues, especially in the spleen and in the brain. Flow cytometric analysis indicated that about 20% of spleen cells, most having a B-lymphocyte marker, expressed hCD21. After Epstein-Barr virus (EBV) infection of spleen cells, EBV-determined nuclear antigen (EBNA) was first detected on Day 4 and reached a maximum of 0.3% on Day 5, but the infection was abortive and was not followed by blastogenesis, cellular DNA synthesis or proliferation. Reverse transcription-polymerase chain reaction (RT-PCR) analyses demonstrated that EBV-infected spleen cells expressed EBNA1 and EBV-encoded small RNA (EBER), but not other latent EBV products. EBNA promoter analysis by RT-PCR indicated that the Q promoter was active, whereas C and W promoters were not active. The present findings indicate that human and rat lymphocytes respond to EBV infection differently in vitro.

Animals↗

PubMed1989

Predilection of a nasopharyngeal carcinoma-derived isolate of Epstein-Barr virus for infection of specific subsets of B lymphocytes.

It is important to know whether there are variants of Epstein-Barr virus (EBV) with biological properties that are different from the prototype viruses that have been studied in detail, such as P3HR-1 and B95-8. We have studied an EBV isolate derived from a nasopharyngeal carcinoma (NPC) tumor, designated NPC-EBV. We have examined the target B lymphocytes infected and growth-transformed with NPC-EBV as compared with two common EBV isolates, B95-8 and AG876 EBV, for stage of maturation using antibodies to several immunoglobulin chains. Typing of the NPC-EBV transformed lymphoblastoid cell lines revealed the predilection of the NPC-EBV isolate to infect immature B lymphocytes. This was not the case for the B95-8 and AG876 isolates. The reason for the predilection of NPC-EBV for immature B lymphocytes remains to be explored further. However, these results may be important in understanding the pathophysiology of EBV-associated diseases.

Animals↗

PubMed2006

Multiplex detection of surface molecules on colorectal cancers.

A technique of fluorescence multiplexing is described for analysis of the plasma membrane proteome of colorectal cancer cells from surgically resected specimens, enabling detection and immunophenotyping when the cancer cells are in the minority. A single-cell suspension was prepared from a colorectal tumour, and the mixed population of cells was captured on a CD antibody microarray. The cancer cells were detected using a fluorescently tagged antibody for carcinoembryonic antigen (CEA-Alexa647) or epithelial cell adhesion marker (EpCAM-Alexa488). Using this multiplexing procedure, dot patterns from colorectal cancers were distinct from those of adjacent normal tissue. Subtraction of the expression levels for each antigen from normal tissue from those for the cancer shows differential expression in the cancer of CD66c, CD15s, CD55, CD45, CD71, CD45RO, CD11b and CEA, in descending order. Cells captured on the same microarray were also labelled with fluorescent CD3-phycoerythrin antibody revealing the presence of tumour-infiltrating lymphocytes. The immunophenotypes of T lymphocytes from the tumour samples showed differential expression of HLA-DR, TCR alpha/beta, CD49d, CD52, CD49e, CD5, CD95, CD28, CD38 and CD71, in descending order. Fluorescence multiplexing of mixed cell populations captured on a single antibody microarray enables expression profiling of multiple sub-populations of cells within a tumour sample.

CD4 Antigens↗

PubMed1994

On interleukins 4, 6 and 10 and their interrelationship with immunoglobulins G and M in common variable immunodeficiency.

Following culture of human peripheral blood mononuclear cells (PBMNC) from 25 normal donors and 15 patients with common variable immunodeficiency (CVID), we were unable to identify any IL10-defective patients. Clear-cut effects of IL4 could be demonstrated in controls, while in CVID all effects are less pronounced. While in both controls and CVID baseline levels of IL6, IgG and IgM were found to be correlated, this was altered by the addition of either IL4 or Poke Weed Mitogen (PWM). We therefore conclude that the inability of PBMNC to produce IL10 is not the cause of CVID in our patients. In CVID, the regulating circuitry triggered by IL4 remains principally intact, however, some subgroups of CVID behave significantly differently.

Adult↗

PubMed1999

Contribution of the innate immune system to autoimmune diabetes: a role for the CR1/CR2 complement receptors.

B lymphocytes are required for diabetogenesis in nonobese diabetic (NOD) mice. The complement component of the innate immune system regulates B cell activation and tolerance through complement receptors CR1/CR2. Thus, it is important to assess the contribution of complement receptors to autoimmune diabetes in NOD mice. Examination of the lymphoid compartments of NOD mice revealed striking expansion of a splenic B cell subset with high cell surface expression of CR1/CR2. This subset of B cells exhibited an enhanced C3 binding ability. Importantly, long-term in vivo blockade of C3 binding to CR1/CR2 prevented the emergence of the CR1/CR2(hi) B cells and afforded resistance to autoimmune diabetes in NOD mice. These findings implicate complement as an important regulatory element in controlling the T cell-mediated attack on islet beta cells of NOD mice.

Animals↗

PubMed2001

Cytokine dependency of human B cell cycle progression elicited by ligands which coengage BCR and the CD21/CD19/CD81 costimulatory complex.

Coengagement of BCR and the C3dg binding CD21/CD19/CD81 costimulatory complex can profoundly reduce the BCR binding threshold for eliciting B cell S phase entry, provided cytokine is present. IL-4 is substantially better than IL-2, IL-13, and TNF-alpha at exhibiting synergy with BCR:CD21 coengaging ligand (anti-IgM:anti-CD21:dextran) in promoting B cell DNA synthesis. Synergy between IL-4 and anti-IgM:anti-CD21:dextran (a) is not explained by the viability-promoting function of IL-4, (b) occurs when the anti-CD21 moiety engages either C3dg binding or non-C3dg binding domains, (c) does not reflect reversal of FcgammaRII-mediated negative regulation, and (d) involves differing temporal requirements for BCR and IL-4R signal transduction during the activation process. The IL-4R signaling pathway appears to synergize directly with the BCR:CD21 signaling pathway(s) in promoting the progression of resting B cells past an early G1 checkpoint, as well as to promote independently the progression of activated B cells past a later G1 to S checkpoint.

Antigens, CD↗

PubMed1993

Expression and functional characteristics of the complement receptor type 2 on adult and neonatal B lymphocytes.

In vivo antibody synthesis against thymus-independent type 2 (TI-2) antigens such as type-specific polysaccharides of pneumococci is low or absent during the first 2 years of life. Recently, we described a role for CR2 in the in vitro antibody response of B cells of adults to the TI-2 antigen type 4 pneumococcal polysaccharide. In the present study a decreased expression of CR2 is described on cord blood B cells using HB5 and OKB7 anti-CR2 MAb. Crosslinking of HB5 anti-CR2 antibodies on the B cell membrane leads to increases in intracellular calcium ([Ca2+]i) in both adult and neonatal B cells. In adult B cells, a synergism between CR2 and sIgM could be demonstrated on the level of calcium mobilization by occupying CR2 and crosslinking of sIgM with substimulatory concentrations of anti-IgM antibodies. This synergistic action between CR2 and sIgM could not be demonstrated in neonatal B cells. In addition, it is demonstrated that HB5 MAb cannot induce B cell differentiation in neonatal B cells, while adult B cells can be induced to differentiate into Ig-producing cells by this MAb.

Adult↗

PubMed1995

Decreased levels of complement receptor 1 (CD35) on B lymphocytes in persons with HIV infection.

Previous studies have shown that complement receptor 1 (CR1) expression on erythrocytes is decreased under several conditions including HIV infection and autoimmune diseases. The goal of this study was to determine whether expression of CR1 on peripheral blood B cells, where this receptor plays a role during immune responses, is altered in persons with HIV infection. The B cells from rheumatoid arthritis (RA) patients were also assessed since this represents a group with known complement and B cell abnormalities. The CD19+ B cells from persons with either HIV infection or RA had significantly reduced levels of CR1 when compared with control donors (75 and 72% CR1+ versus 94% CR1+ for control donors). The reduction of B cell CR1 occurred in both the percentage of B cells positive for CR1 and the levels of CR1 found on positive cells. In contrast, CR1 on monocytes was not reduced. As shown in previous studies, CR2 was also found to be reduced on B cells from the HIV-infected persons and there was extensive overlap between the B cell subsets which lacked expression of CR1 and CR2. The complement receptor-negative B cells found in HIV-infected persons were not immature or activated as defined by their lack of expression of CD10 or B7, respectively. Elevated levels of C4d, a classical complement pathway-activation product, were detected in plasma from both HIV-infected and RA patients. These studies suggest that chronic complement activation occurring in persons with HIV infection or RA can affect the complement receptor phenotype of peripheral blood B cells. Since complement receptors are involved in activation of B cells, the subset that lacks CR1 may represent cells that have encountered immune complexes and may therefore be stimulated. Additionally, the downregulation of complement receptors may have significant effects on the ability of B cells to capture and present opsonized antigens.

Antigen-Antibody Complex↗

PubMed1998

Complement receptor 2 in the regulation of the immune response.

Antigens coated with split products of C3, the result of complement activation, are capable of crosslinking the complement receptor 2 (CR2, CD21) and the antigen receptor on the surface of B cells simultaneously. This dual recognition leads to increased cell proliferation and differentiation and enhanced antibody production. CR2 is also considered to be a regulator of the B cell response to antigen. In this review we summarize the biology of the CR2 and focus on its essential role in generating an effective B cell response to antigenic stimuli. The involvement of CR2 in the pathophysiology of infectious and autoimmune diseases is also discussed.

Antibody Formation↗

PubMed2000

Molecular cloning of the critical region for glomerulopathy with fibronectin deposits (GFND) and evaluation of candidate genes.

Glomerulopathy with fibronectin deposits (GFND, MIM 601894) is an autosomal dominant kidney disease that leads to terminal renal failure at a median age of 47 years. It represents a distinct entity of membranoproliferative glomerulonephritis (MPGN) type III and is characterized by the unique feature of massive glomerular deposits of fibronectin. We have recently localized a gene locus for GFND to human chromosome 1q32 by total genome linkage analysis in a large kindred, within a 4.1-cM critical interval between markers D1S2872 and D1S2891. This interval contains a cluster of genes for "regulators of complement activation" (RCA), which represent strong candidates for GFND. To identify positional candidate genes for GFND within the critical genetic interval, we here report the cloning of the entire critical GFND region in a complete YAC and partial PAC contig. We constructed a high-resolution transcriptional map, thereby defining positional and functional candidate genes for the disease. To evaluate their role in GFND, we performed functional studies on RCA proteins in GFND patients from the large kindred, as well as mutational analysis of the genes for complement receptor-2 (CR2), membrane cofactor protein (MCP), and decay accelerating factor (DAF). Although no loss-of-function mutation has been identified as yet, these data provide a basis for the examination of candidate genes for GFND and other genes for MPGN, which localize to the vicinity of the GFND region.

Adult↗

PubMed1993

Antibody feedback regulation in MRL/lpr mice.

MRL/Mp-lpr/lpr (MRL/l) mice spontaneously develop autoimmune disease, characterized by glomerulonephritis, polyarteritis and polyarthritis. The lpr mice have defects in the Fas antigen, which plays a role in apoptosis, and it has been suggested that lack of negative selection of autoreactive T cells explains the initiation of the disease. The extremely high amount of autoantibodies may reflect additional immunoregulatory abnormalities. Antibody feedback regulation is an efficient way of up- or downregulating antibody responses. We have for the first time determined whether IgG-mediated suppression as well as IgM-mediated enhancement operates normally in these mice. MRL/l and MRL/Mp(-)+/+ (MRL/n) mice of different ages were therefore immunized with sheep erythrocyte (SRBC)-specific IgG or IgM antibodies followed by SRBC. Control groups received antigen alone. Five days later, the antigen-specific plaque-forming cell response was measured. IgG induced more than 90% suppression in both MRL/l and MRL/n in mice of all ages tested. This degree of suppression is in the same range as for other, normal mouse strains. In contrast, IgM-mediated enhancement was completely absent in 12-week-old MRL/l mice but normal in 8-week-old MRL/l as well as in MRL/n mice of all ages tested. When spleens and lymph nodes were immunohistochemically studied using a mAb specific for complement receptors 1 and 2 (CR1/CR2), an abnormal follicular structure was demonstrated in 12-week-old MRL/l mice. The antibody response of both 8- and 13-week-old MRL/l mice in vivo, after downregulation of these receptors, was inhibited by 85-96%. Thus, the presented data demonstrate that MRL/l mice with overt autoimmune disease are refractory to IgM-mediated enhancement of antigen-specific antibody production. We believe that this abnormal antibody feedback regulation is due to abnormal follicular structure in lymphoid organs of old MRL/l mice, hence the inability to localize and present antigen in a normal way.

Animals↗