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PubMed1997

Dendritic cells generated from human blood in granulocyte macrophage-colony stimulating factor and interleukin-7.

Dendritic cells (DC), with potentially important clinical applications, have been generated from human peripheral blood monocytes in the presence of GM-CSF and IL-4 (G4 DC). In the present report we show that DC with a novel phenotype can be generated from blood adherent mononuclear cells in the presence of GM-CSF and IL-7 (G7 DC). Adherent cells from PBMC, cultured in GM-CSF (600 U/ml) and IL-7 (6 U/ml), were transformed over 7 days into cells with DC morphology, at a yield of 1.2-1.6 x 10(6) per 10(7) PBMC. G7 DC not only expressed class I and class II MHC, CD1a, CD11c, CD23, CD40, CD54, CD58, CD80, CD86 and CD95, like G4 DC, but also CD21, which is the complement receptor type 2, a ligand for CD23 and a receptor for EBV and IFN-alpha. G7 DC were at least one log more effective in the autologous MLR and at least two logs more effective in the allogeneic MLR, than PBMC. They elicited proliferative responses of CD4 T cells to tetanus toxoid and CD8 T cells to an EBV peptide, and stronger T-cell cytotoxicity to EBV peptide than G4 DC. Expression of CD21 by G7 DC suggests that IL-7 delivers a distinct signal to DC precursors and that G7 DC may be functionally distinct.

Antigen Presentation↗
PubMed2003

Protection against influenza virus infection by intranasal administration of C3d-fused hemagglutinin.

For the induction of mucosal immune responses by intranasal vaccination, cholera toxin B subunits (CTB) and Escherichia coli heat-labile toxin (LT) are often administered as mucosal adjuvants in order to enhance immune responses to mucosally co-administered bystander antigens. However, these toxin also are the causative agents of diarrhea. There is a demand for the establishment of an effective and safer adjuvant or vaccine that elicits mucosal immunity, but does not require the use of CTB or LT adjuvants. In order to induce protective mucosal immune responses in the nasal area against influenza virus infection, we have examined the recombinant protein composed of the complement component, C3d, which is fused to the secreted form of hemagglutinin (sHA-mC3d3) in the influenza-BALB/c mouse model. The fusion protein sHA-mC3d3, the secretory form of hemagglutinin, and the transmembrane form of HA (tmHA) from the influenza virus were intranasally administered to the mice with or without CTB containing a trace amount of holotoxin (CTB*) as an adjuvant. After intranasal administration of these proteins with CTB*, all mice produced nasal IgA and serum IgG antibodies (Abs) against the viral HA. In addition, viral infection was completely inhibited in these mice. In contrast, in the absence of the adjuvant, only sHA-mC3d3-induced locally secreted IgA and serum IgG Abs and provided complete protection against the influenza virus challenge. Thus, C3d fused to the influenza HA antigen is an effective and safe tool for mucosal vaccination.

Adjuvants, Immunologic↗
PubMed1997

Characterization of lymphocyte subtypes in scabietic skin lesions of naive and sensitized dogs.

We delineated the density of cells expressing CD4, CD8, CD21 and CD45RA antigens in the cellular infiltrates in the epidermis, dermis and follicular epithelium in scabietic skin lesions of naive hosts and sensitized hosts that expressed resistance to scabies infestation. No cells expressing CD21 (B-lymphocytes and follicular dendritic cells) were present in the epidermis and only a few were occasionally present in the dermis during both the first and second infestations. Naive T-cells (CD45RA+) and CD8+ cells (cytotoxic and suppressor T-lymphocytes) were present in varying densities in the infiltrates throughout the epidermis, dermis and follicular epithelium with no apparent differences in density and the rate of appearance between sensitizing and challenge infestations. CD4+ cells were abundant in fluctuating densities in the dermis, epidermis, and follicular epidermis during the sensitizing infestation and these cells became the dominant cell type early during the challenge infestation. The density of CD4+ cells in the infiltrate was much greater during the challenge than during the sensitization infestation. This population of CD4+ cells consisted of both T-helper/inducer cells and neutrophils and the large increase in their numbers during the challenge suggested they played a key role in the successful immune/inflammatory response that resulted in resistance to scabies infestation.

Animals↗
PubMed1993

Immunohistologic detection of the primary follicle (PF) in human fetal and newborn lymph node anlages.

The primary follicle (PF) emerges as a globular nest of follicular dendritic cells (FDC) and lymphocytes in the lymph node anlage in the 16th gestational week. It increases in size with age but no germinal center is found until several months later, after birth. Using a panel of monoclonal antibodies, the authors have defined phenotypes of component cells of the PF. The PF contains a B-cell population including IgM+, CD20+, CD21+, and CD24+ cells, together with a T-cell population including CD3+, CD4+, CD5+, and CD8+ but no IgG+ cells. It also contains many CD5+ B cells and several IgD+ and alkaline phosphatase-positive cells but few CD15+, CD25+, CD30+, CD38+, and Ki-67+ cells. CD24+ and dendritic reticulum (DRC)-1+ cells show an irregular meshwork pattern in the PF. CD5+ B cells appear even before the formation of the PF and increase after formation of the PF. The lymphocytic phenotype of the PF is similar to that of the mantle zone of the secondary follicle. The phenotypic characteristics indicate that the PF appears as an aggregation of CD5+ B cells and plays an important role as the ancestor of the secondary follicle as well as helper T cells and FDC.

Antigens, CD↗
PubMed1998

Epstein-Barr virus and CD21 expression in gastrointestinal tumors.

Epstein-Barr virus (EBV) was found in 7-17% of gastric adenocarcinomas, including lymphoepithelioma-like carcinomas, although its significance has not been clear. In addition, 20-30% of malignant lymphomas arising in the gastrointestinal tract have been known to express the EBV genome. Several lines of evidence indicate that EBV has been shown to infect both B lymphocytes and squamous epithelial cells via CD21 molecule in vivo and in vitro. The expression of CD21 in EBV-associated gastrointestinal tumors, however, has remained controversial. To determine the presence of CD21, an EBV receptor, in the EBV-associated gastrointestinal tumors, we, first, examined the EBV genome in sixty seven patients with either gastrointestinal adenocarcinomas or malignant lymphomas using in situ hybridization (ISH) for EBV-encoded small RNAs (EBERs) and PCR for EBNA-1. Then, the investigation of CD21 expression was performed only in the EBV-positive tumors with immunohistochemical method for CD21 antigen on paraffin sections. EBERs were detected in 6 out of 26 gastric adenocarcinomas, 2 of 24 colonic adenocarcinomas, and 8 of 17 malignant lymphomas. EBERs were more prevalent in the malignant lymphomas originating from the small and large intestine (6/6) than from the stomach (2/11), and were detected in both B and T cell phenotypes. EBNA-1 was amplified in 11 of 16 EBERs-positive cases. Interestingly, however, none of the EBV-positive six gastric adenocarcinomas and eight malignant lymphomas expressed the CD21 on the cell surfaces or cytoplasm of both tumor cells and adjacent normal epithelial cells. These results suggest that EBV infection in the gastrointestinal malignancies would be mediated via different routes besides the CD21 or a new receptor distinct from CD21.

Adenocarcinoma↗
PubMed2003

Complement and autoimmunity.

The complement system is comprised of a number of serum and membrane-bound proteins that play an important role in the elimination of foreign microorganisms while protecting the host organism from complement-related damage. Complement has also been shown to participate in the generation of normal humoral immune responses to foreign antigens. Recent studies suggest that the functions of complement may be extended to include the maintenance of B cell tolerance. Complement receptor 2 (CR2/CD21) has been implicated in lupus susceptibility in both humans and animal models of disease. Located primarily on B cells and follicular dendritic cells, CR2 binds C3 degradation products that have become covalently bound to antigen or immune complexes in the process of complement activation. The mechanism by which CR2 might regulate B cell reactivity to autoantigens has not been elucidated, but may involve direct effects on B cell tolerance or indirect effects on T cell tolerance.

Animals↗
PubMed1997

Complement and the immune response.

This past year has seen a major advance in our understanding of how the complement system enhances the adaptive immune response. The use of in vivo models has revealed that direct coupling of C3d to antigen is sufficient to dramatically reduce the amount of antigen required for a secondary response. At least one important requirement for the enhancing effect was determined to be expression of the CD21 (C3d receptor) on B cells.

Animals↗
PubMed2000

Human complement regulators: a major target for pathogenic microorganisms.

The C3 convertases of the human complement system are controlled by fluid-phase and membrane proteins in the RCA (regulators of complement activation) family. Accumulated data show that many pathogenic microorganisms interact with these complement regulators. Recent advances in this field include determination of the crystal structure of the binding domains in the measles virus receptor CD46 and identification of a CD46 transgenic mouse line that is sensitive to measles virus. Moreover, recent findings support the hypothesis that pathogenic bacteria binding fluid-phase RCA proteins exploit these proteins to escape complement attack. These studies provide novel insight into the interplay between pathogens and the innate immune system and may have implications for the plans to use animals expressing an RCA protein for xenotransplantation.

Antigens, CD↗
PubMed2004

A complement C3 fragment equivalent to mammalian C3d from the common carp (Cyprinus carpio): generation in serum after activation of the alternative pathway and detection of its receptor on the lymphocyte surface.

A terminal degradation product (C3d) of mammalian complement component C3 plays an important role in modulation of the adaptive immune response through the interaction with complement receptor type 2 (CR2) on B cells. The present study is aimed at determining whether this is a functional bridge between the innate and adaptive immune systems in bony fish. The fragmentation of the complement component C3 in carp (Cyprinus carpio) serum, activated with zymosan, was analysed to ascertain if carp C3 also generates a mammalian C3d-like fragment under physiological conditions. A 35 kDa peptide reactive to the anti-carp C3 alpha-chain was detected on the zymosan particles and in the activated serum. Its N-terminal amino acid sequence identified it as carp C3d derived from the C3-H1 isoform. Another C3 isoform, C3-S, of carp was found to yield a C3d fragment at lower efficiency than C3-H1. Recombinant C3d fragments derived from C3-H1 and C3-S were produced in Escherichia coli as fusion proteins with glutathione-S-transferase (GST), and used for ligands to examine the presence of a possible CR2-like C3d receptor on carp lymphocytes. An enzyme-linked immunoadsorbent assay system, using the recombinant C3d proteins and anti-GST on a microplate to which was attached carp peripheral lymphocytes, detected a significant binding of carp C3d to the lymphocyte. The degree of binding of C3-H1-derived C3d was higher than that of C3-S-derived C3d. In addition, the binding of both ligands was inhibited by anti-C3 alpha-chain, but not by EDTA or EGTA, indicating that the putative C3d receptor does not require divalent cation. These properties agree well with those reported for mammalian CR2.

Amino Acid Sequence↗
PubMed2003

CR2 units of CR2 complexes are possibly associated with nucleophilic agents through reactive covalent links.

The human complement receptor type 2 (CR2/CD21), a transmembrane glycoprotein, associates with a variety of surface antigens and proteins in the cell membrane. We examined the possibilities that the CR2 units of CR2 complexes are associated through internal covalent links reactive with nucleophilic agents, e.g. H(2)O or methylamine, and that CR2-positive cells process anti-CR2 monoclonal antibodies (MoAbs). Data from immunoblotting and cytofluorimetry with CR2-binding site-specific MoAbs show that: (i) CR2-positive Raji cells release soluble CR2 isoforms into the medium when incubated in phosphate buffered saline; (ii) despite affecting the detection of one soluble CR2 isoform, methylamine treatment of soluble CR2 allows the detection of another of its isoforms; (iii) limited pre-treatment of cells with methylamine reveals a more heterogeneous CR2-positive cell population or enhances the detection of CR2; (iv) cell treatment with CR2-binding site-specific MoAbs enhances the detection of CR2 isoform(s). The data suggest that CR2 is shed mainly as a soluble CR2 complex, in which the CR2 units link covalently and react with nucleophilic agents. Raji cells may process bound fragments (145 kDa) that are recognised by and become bound by anti-CR2 MoAb.

Antibodies, Monoclonal↗
PubMed2003

Redistribution and unmasking of Annexin V binding sites in apoptotic Raji cells.

The complement receptor type 2 (CR2) associates with other surface antigens and proteins and its redistribution and/or unmasking occurs through still unknown mechanism(s). The data presented demonstrate that high-density cultured CR2-positive cells undergo apoptosis and that the redistribution and unmasking of Annexin V binding sites occurs in a fashion similar to the redistribution and unmasking of CR2. Therefore, apoptotic and non apoptotic cells from the same lineage may share a similar mechanism for the exposition of neo-surface markers

Annexin A5↗
PubMed1996

Disruption of the Cr2 locus results in a reduction in B-1a cells and in an impaired B cell response to T-dependent antigen.

Covalent attachment of activated products of the third component of complement to antigen enhances its immunogenicity, but the mechanism is not clear. This effect is mediated by specific receptors, mCR1 (CD35) and mCR2 (CD21), expressed primarily on B cells and follicular dendritic cells in mice. To dissect the role of mCR1 and mCR2 in the humoral response, we have disrupted the Cr2 locus to generate mice deficient in both receptors. The deficient mice (Cr2-/-) were found to have a reduction in the CD5+ population of peritoneal B-1 cells, although their serum IgM levels were within the range of normal mice. Moreover, Cr2-/- mice had a severe defect in their humoral response to T-dependent antigens that was characterized by a reduction in serum antibody titers and in the number and size of germinal centers within splenic follicles. Reconstitution of the deficient mice with bone marrow from MHC-matched Cr2+/+ donors corrected the defect, demonstrating that the defect was due to B cells themselves. These results indicate an obligatory role of B cell complement receptors in responses of the B cells to protein antigens.

Animals↗
PubMed2001

The CD19/CD21 complex functions to prolong B cell antigen receptor signaling from lipid rafts.

The CD19/CD21 complex functions to significantly enhance B cell antigen receptor (BCR) signaling in response to complement-tagged antigens. Recent studies showed that following antigen binding the BCR translocates into plasma membrane lipid rafts that serve as platforms for BCR signaling. Here, we show that the binding of complement-tagged antigens stimulates the translocation of both the BCR and the CD19/CD21 complex into lipid rafts, resulting in prolonged residency in and signaling from the rafts, as compared to BCR cross-linking alone. When coligated to the BCR, the CD19/CD21 complex retards the internalization and degradation of the BCR. The colocalization and stabilization of the BCR and the CD19/CD21 complex in plasma membrane lipid rafts represents a novel mechanism by which a coreceptor enhances BCR signaling.

Animals↗
PubMed2001

Marginal zone and B1 B cells unite in the early response against T-independent blood-borne particulate antigens.

The rate of pathogen elimination determines the extent and consequences of an infection. In this context, the spleen with its highly specialized lymphoid compartments plays a central role in clearing blood-borne pathogens. Splenic marginal zone B cells (MZ), by virtue of their preactivated state and topographical location, join B1 B cells to generate a massive wave of IgM producing plasmablasts in the initial 3 days of a primary response to particulate bacterial antigens. Because of the intensity and rapidity of this response, combined with the types of antibodies produced, splenic MZ and B1 B cells endowed with a "natural memory" provide a bridge between the very early innate and the later appearing adaptive immune response.

Animals↗
PubMed2001

The follicular versus marginal zone B lymphocyte cell fate decision is regulated by Aiolos, Btk, and CD21.

Most splenic B cells in mice that lack Aiolos are mature IgD(hi)IgM(lo) follicular lymphocytes, suggesting that maturation signals delivered via the BCR are enhanced in the absence of Aiolos. The enhanced maturation of follicular B cells is accompanied by the absence of MZ B lymphocytes and the downregulation of CD21 expression in follicular B cells, all of which depend on the generation of signals via Btk, which is in epistasis to Aiolos. The inverse relationship between the strength of BCR signaling and MZ B cell development is supported by an examination of MZ B cells in CD21 null mice. These data support the view that antigens (in contrast to "tonic" signals) drive the development of naive B cells.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed2001

Cr2, a candidate gene in the murine Sle1c lupus susceptibility locus, encodes a dysfunctional protein.

The major murine systemic lupus erythematosus (SLE) susceptibility locus, Sle1, corresponds to three loci independently affecting loss of tolerance to chromatin in the NZM2410 mouse. The congenic interval corresponding to Sle1c contains Cr2, which encodes complement receptors 1 and 2 (CR1/CR2, CD35/CD21). NZM2410/NZW Cr2 exhibits a single nucleotide polymorphism that introduces a novel glycosylation site, resulting in higher molecular weight proteins. This polymorphism, located in the C3d binding domain, reduces ligand binding and receptor-mediated cell signaling. Molecular modeling based on the recently solved CR2 structure in complex with C3d reveals that this glycosylation interferes with receptor dimerization. These data demonstrate a functionally significant phenotype for the NZM2410 Cr2 allele and strongly support its role as a lupus susceptibility gene.

Alleles↗
PubMed2002

Complement receptors CD21/35 link innate and protective immunity during Streptococcus pneumoniae infection by regulating IgG3 antibody responses.

The CD21/35 receptor provides an important link between innate and adaptive immunity. Its importance during protective immune responses to encapsulated extracellular bacteria was assessed using a new line of mice completely deficient in CD21/35 expression (CD21/35(-/-)). CD21/35 expression was essential for the rapid trapping of C3dg-antigen complexes by B cells in vivo, especially in splenic marginal zones. Despite normal B cell development in CD21/35(-/-) mice, T cell-independent and -dependent antibody responses to low-dose antigens were significantly decreased, with a striking impairment in IgG3 responses. Accordingly, CD21/35(-/-) mice were more susceptible to acute lethal Streptococcus pneumoniae infection. Thus, CD21/35 expression is critical for early protective antibody responses to lethal pathogens that rapidly multiply and quickly overwhelm the immune system.

Animals↗