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PubMed1991

Mapping of the C3b-binding site of CR1 and construction of a (CR1)2-F(ab')2 chimeric complement inhibitor.

CR1/CR2 chimeric receptors in which various short consensus repeats (SCRs) of CR1 were attached to CR2 were transiently expressed on COS cells, and assessed for the binding of polymerized C3b (pC3b) and anti-CR2 by immunofluorescence. Of COS cells expressing chimeras containing SCR 1-4, 1-3, 2-4, 1-2, and 2-3 of the long homologous repeats (LHRs) -B or -C, 96%, 66%, 23%, 0%, and 0%, respectively, bound pC3b. K562 cells were stably transfected with wild-type CR1, deletion mutants of CR1, and the CR1/CR2 chimeras, respectively, and assayed for binding of 125I-pC3b. The dissociation constants (Kd) for pC3b of wild-type CR1 and the LHR-BD and -CD constructs were in the range of 1.0-2.7 nM, and of the CR1/CR2 chimeras containing SCRs 1-4, 1-3, and 2-4 of LHR-B or -C were 1.8-2.4, 6-9, and 22-36 nM, respectively. The factor I-cofactor function of the CR1/CR2 chimeras paralleled the C3b-binding function of the constructs. A CR1/immunoglobulin (Ig) chimeric protein was prepared by fusing SCRs 1-4 of LHR-B to the heavy chains of a murine F(ab')2 anti-nitrophenacetyl (NP) monoclonal antibody. The (CR1)2-F(ab')2 chimera, which retained its specificity for NP, was as effective as soluble, full-length CR1 in binding pC3b, serving as a cofactor for factor I-mediated cleavage of C3b, and inhibiting activation of the alternative pathway, indicating that the bivalent expression of these SCRs reconstitutes the alternative pathway inhibitory function of CR1. The feasibility of creating CR1/Ig chimeras makes possible a new strategy of targeting complement inhibition by the use of Ig fusion partners having particular antigenic specificities.

Animals↗
PubMed1993

Functional dissection of the CD21/CD19/TAPA-1/Leu-13 complex of B lymphocytes.

The CD21/CD19/TAPA-1 complex of B lymphocytes amplifies signal transduction through membrane immunoglobulin (mIg), recruits phosphatidylinositol 3-kinase (PI3-kinase), and induces homotypic cellular aggregation. The complex is unique among known membrane protein complexes of the immune system because its components represent different protein families, and can be expressed individually. By constructing chimeric molecules replacing the extracellular, transmembrane, and cytoplasmic regions of CD19 and CD21 with those of HLA-A2 and CD4, we have determined that CD19 and TAPA-1 interact through their extracellular domains, CD19 and CD21 through their extracellular and transmembrane domains, and, in a separate complex, CD21 and CD35 through their extracellular domains. A chimeric form of CD19 that does not interact with CD21 or TAPA-1 was expressed in Daudi B lymphoblastoid cells and was shown to replicate two functions of wild-type CD19 contained within the complex: synergistic interaction with mIgM to increase intracellular free calcium and tyrosine phosphorylation and association with the p85 subunit of PI3-kinase after ligation of mIgM. The chimeric CD19 lacked the capacity of the wild-type CD19 to induce homotypic cellular aggregation, a function of the complex that can be ascribed to the TAPA-1 component. The CD21/CD19/TAPA-1 complex brings together independently functioning subunits to enable the B cell to respond to low concentrations of antigen.

Antigens, CD↗
PubMed1996

Antibody response to a T-dependent antigen requires B cell expression of complement receptors.

Several lines of evidence indicate that antibody responses to T-dependent antigens require complement receptors expressed on either B lymphocytes or follicular dendritic cells. We have used RAG-2 deficient blastocyst complementation to create mice specifically lacking B cell complement receptors. Despite normal expression of complement receptor 1 (CR1[CD35]) and CR2 (CD21) on follicular dendritic cells, these mice have a profound defect in their capacity to mount a T-dependent antibody response. This is the first direct demonstration in vivo that B cell expression of complement receptors is required for a humoral immune response. This is the first direct demonstration in vivo that B cell expression of complement receptors is required for a humoral immune response. This suggests that CD21 and/or CD35 on B lymphocytes may be required for cellular activation, adsorptive endocytosis of antigen, recruitment to germinal centers, and/or protection from apoptosis during the humoral response to T-dependent antigens.

Animals↗
PubMed2000

Complement C4 inhibits systemic autoimmunity through a mechanism independent of complement receptors CR1 and CR2.

The complement system enhances antibody responses to T-dependent antigens, but paradoxically, deficiencies in C1 and C4 are strongly linked to autoantibody production in humans. In mice, disruption of the C1qa gene also results in spontaneous autoimmunity. Moreover, deficiencies in C4 or complement receptors 1 and 2 (CR1/CR2) lead to reduced selection against autoreactive B cells and impaired humoral responses. These observations suggest that C1 and C4 act through CR1/CR2 to enhance humoral immunity and somehow suppress autoimmunity. Here we report high titers of spontaneous antinuclear antibody (ANA) in C4(-/)- mice. This systemic lupus erythematosus-like autoimmunity is highly penetrant; by 10 mo of age, all C4(-)(/)- females and most males produced ANA. In contrast, titers and frequencies of ANA in Cr2(-)(/)- mice, which are deficient in CR1 and CR2, never rose significantly above those in normal controls. Glomerular deposition of immune complexes (ICs), glomerulonephritis, and splenomegaly were observed in C4(-)(/)- but not Cr2(-)(/)- mice. C4(-)(/)-, but not Cr2(-)(/)-, mice accumulate activated T and B cells. Clearance of circulating ICs is impaired in preautoimmune C4(-)(/)-, but not Cr2(-)(/)-, mice. C4 deficiency causes spontaneous, lupus-like autoimmunity through a mechanism that is independent of CR1/CR2.

Animals↗
PubMed2002

B lymphocyte memory: role of stromal cell complement and FcgammaRIIB receptors.

To dissect the influence of CD21/CD35 and FcgammaRIIB in antigen retention and humoral memory, we used an adoptive transfer model in which antigen-primed B and T lymphocytes were given to sublethally irradiated wild-type mice or mice deficient in CD21/CD35 (Cr2(-/-)) or FcgammaRIIB receptors (FcgammaRIIB(-/-)). Cr2(-/-) chimeras showed impaired memory as characterized by a decrease in antibody titer, reduced frequency of antibody secreting cells, an absence of affinity maturation, and significantly reduced recall response. The impaired memory in Cr2(-/-) chimeras corresponded with the reduced frequency of antigen-specific memory B cells. Interestingly, FcgammaRIIB(-/-) chimeras showed a differential phenotype with impaired splenic but normal bone marrow responses. These data suggest that CD21/CD35 on stroma, including follicular dendritic cells, is critical to the maintenance of long-term B lymphocyte memory.

Animals↗
PubMed2005

Characterization of marginal zone B cell precursors.

Selection of recently formed B cells into the follicular or marginal zone (MZ) compartments is proposed to occur by way of proliferative intermediates expressing high levels of CD21/35 and CD23. However, we show that CD21/35(high) CD23(+) splenocytes are not enriched for proliferative cells, and do not contribute substantially to the generation of follicular B cells. Instead, ontogenic relationships, steady-state labeling kinetics, and adoptive transfer experiments suggest that CD21/35(high) CD23(+) splenocytes serve primarily as precursors for MZ B cells, although their developmental potential seems to be broader and is influenced by environmental cues that are associated with lymphopenia. Furthermore, CD21/35(high) CD23(+) splenocytes share several key functional characteristics with MZ B cells, including their capacity to trap T-independent antigen and a heightened proliferative response to LPS. These observations challenge previous models of peripheral B cell maturation, and suggest that MZ B cells develop by way of CD21/35(high) CD23(+) intermediates.

Animals↗
PubMed1998

A further link between innate and adaptive immunity: C3 deposition on antigen-presenting cells enhances the proliferation of antigen-specific T cells.

Murine cells of the B lymphoblastoid line A20 and concanavalin A-elicited peritoneal macrophages are shown to activate and fix C3 fragments covalently when incubated in fresh, autologous serum under conditions allowing the initiation of the alternative complement pathway. For the detection of cell-bound C3, cytofluorimetry was performed using FITC-labeled F(ab')2 fragments of anti-mouse C3. Cell-bound C3 fragments are not internalized or shed by the cells under culture conditions for at least two hours. When the antigen-presenting capacity of serum-treated cells was tested using various antigens and experimental systems, augmentation of the proliferation of antigen-specific T cells was found. This enhancing effect was particularly pronounced at suboptimal antigen doses. The elevation of T cell proliferation induced by C3-opsonized antigen-presenting cells (APC) could be abrogated by F(ab')2 fragments of goat anti-mouse C3, suggesting the involvement of C3 receptors expressed by T cells in the process. Using the 7G6 mAb recognizing murine CR1/CR2, the presence of these complement receptors on activated T cells is demonstrated by cytofluorimetry and immunoprecipitation, as well. These results point to the role of C3 bound to acceptor sites on APC in the facilitation of antigen presentation, providing a further link between innate and adaptive immunity.

Animals↗
PubMed2002

Modeling the presentation of C3d-coated antigen by B lymphocytes: enhancement by CR1/2-BCR co-ligation is selective for the co-ligating antigen.

We have used a set of single-chain variable fragment antibodies (sc) genetically fused with an influenza hemagglutinin-derived peptide as a means to investigate the role of CR1 and CR2 in antigen presentation by B cells. When incubated with the B cell lymphoma 2PK3, peptide-containing sc specific for either CR1 or CR1/2 mediated activation of the hemagglutinin peptide-specific T cell line IP-12-7, as assessed by IL-2 production. Efficient presentation was dependent on the binding of the constructs to CR1/2, implying that receptor-mediated endocytosis is responsible for the effect. Cross-linkage of CR1/2 or CD19 by mAb did not increase the extent of T cell activation. However, when CR1/2 was co-ligated with the BCR--using either polyclonal goat anti-mouse IgG or recombinant protein LA--the antigen concentration required to activate T cells decreased by two orders of magnitude. Moreover, this enhancement was selective for the antigen included in these complexes and did not affect the presentation of a free peptide or of antigen bound to CR1/2 excluded from the complexes. These results suggest that B cells may bind various C3d-coated antigens at a time, but only the one which reacts with the BCR will be processed with high efficiency. This mechanism may ensure the specificity of cognate T cell help.

Animals↗
PubMed1990

Characterization of murine complement receptor type 2 and its immunological cross-reactivity with type 1 receptor.

We have previously demonstrated that some mAbs prepared against mouse complement receptor type 1 (CR1) bind a 150,000 Mr protein in addition to the 190,000 Mr CR1 protein. We now identify the 150,000 Mr murine protein as complement receptor type 2 (CR2), since: (i) one of the monoclonal antibodies that bind this protein inhibits rosette formation between mouse B cells and C3d-bearing sheep erythrocytes; (ii) as is known for human CR2, this protein is present on B lymphocytes but not T lymphocytes; and (iii) this protein must have affinity for C3b, since it has weak factor I cofactor activity. In addition, this protein resembles the 145,000 Mr human CR2 molecule in size. Since four of the five mAbs that were produced by immunization with CR1 also bound CR2, and they bind to different CR1 epitopes, it seems that murine CR1 and CR2 share multiple epitopes. Injection of mice with one of the CR1-CR2 cross-reactive mAbs almost eliminated both CR1 and CR2 expression, but did not decrease B cell numbers or the expression of B cell IgM, Ia, or B220 antigens. In contrast, injection of mice with a non-cross-reactive anti-CR1 antibody only modulated CR1 expression. These antibodies should thus provide useful tools for the study of the in vivo roles of B cell complement receptors.

Animals↗
PubMed1993

Ligand specificities of mouse complement receptor types 1 (CR1) and 2 (CR2) purified from spleen cells.

Murine complement receptor type 2 (MCR2) is homologous to human CR2, whereas murine CR1 (MCR1) is structurally and evolutionary different from human CR1. Since ligand specificities of MCR1 and MCR2 are not completely clarified, we analyzed their functional characteristics to correlate them with structural information obtained in molecular biological studies. MCR1 and MCR2 purified from spleen cells were incubated with thiol-Sepharose bearing murine C3b, iC3b, or C3d in the presence or absence of various anti-MCR1 or -MCR1/MCR2 mAbs. Bound and free MCR1 and MCR2 were quantitated by Western blotting or two-site immunoradiometric assay. MCR2 bound to C3d and iC3b similarly efficiently, and 5-fold less efficiently to C3b. These bindings were completely inhibited by MCR1/MCR2-crossreactive antibodies 7G6 and 4E3. MCR1 bound to C3b efficiently and this was partially inhibited by MCR1-monospecific antibody 8C12, but not by 7G6 and 4E3. Combinations of 8C12 and 7G6 or 4E3 completely inhibited MCR1 binding to C3b. Therefore, two binding sites, one unique to MCR1 and the other shared with MCR2, are involved in MCR1 binding to C3b. MCR1 bound also to C3d and this was completely inhibited by 7G6 and 4E3. The binding of this solubilized MCR1 to C3d was as efficient as that of MCR2 to C3d. It seems, therefore, that the site shared by MCR1 and MCR2 that is recognized by both 7G6 and 4E3 binds to C3d and less efficiently to C3b. These results clarify the ligand specificities of MCR1 and MCR2.

Animals↗
PubMed2004

Antigen localization within the splenic marginal zone restores humoral immune response and IgG class switch in complement C4-deficient mice.

Defects of early complement components (C1, C4 and C2) are associated with the development of systemic lupus erythematosus (SLE). The availability of complement knockout mice has increased our knowledge on the role of complement in the regulation of adaptive immunity. An impaired removal of apoptotic bodies, a disturbed clearance of IgG immune complexes (ICs) and an insufficient B-cell regulation via complement receptors CD21/CD35 have been discussed as explanations for the induction of autoimmunity; however, a unifying hypothesis for the loss of B-cell tolerance in the absence of C1 or C4 is still lacking. Using IgM-containing ICs, we observed a significant accumulation of antigen within the splenic marginal zone (MZ) of C4-deficient mice but not in C3-deficient or complement receptors CD21/CD35-deficient mice. The targeting of antigen toward the MZ restored adaptive immunity (antibody response and class switch) in C4-deficient animals. A new explanation for the association of SLE and complement C4 deficiency would be that in the absence of C4, natural antibodies (IgM type) localize more self-antigen toward the MZ so that the auto-antibody response is increased and autoimmune disease ensues. As such, an inadequate localization of self-antigens might be responsible for the annulment of peripheral B-cell tolerance in the absence of C4.

Animals↗
PubMed2001

Follicular dendritic cells in reactive and neoplastic lymphoid tissues: a reevaluation of staining patterns of CD21, CD23, and CD35 antibodies in paraffin sections after wet heat-induced epitope retrieval.

Structural alterations in the meshwork of follicular dendritic cells (FDCs) are frequently found in malignant lymphomas. Formaldehyde fixation and paraffin embedding, however, have long prevented consistent detection of FDCs. Wet heat-induced epitope retrieval in Dako Target Retrieval Solution (TRS) (pH 6.0) enabled the reliable detection of FDCs through CD21, CD23, and CD35 antigens in routinely processed tissues from 11 reactive and 69 neoplastic lymphoproliferations, thus allowing the distribution of the FDCs to be reevaluated. Germinal center FDCs in lymphoid hyperplasias and expanded FDC meshworks in the 8 mantle cell lymphomas, 7 low-grade MALT lymphomas, and 6 low-grade follicular lymphomas were intensely stained with all these markers. In 6 cases of B cell chronic lymphocytic leukemia, tumor cells were CD23+. In four cases of nodular lymphocyte predominance Hodgkin's disease (HD), expanded FDC meshwork's sharply delineating negative tumor cells and their rosetting T cell, were revealed mainly with the CD21 and CD35 antibodies. Follicular dendritic cells were also demonstrated in 11 cases of grade I nodular sclerosing HD, including follicular HD. Striking dendritic cell clusters were revealed with all 3 antibodies in 9 angioimmunoblastic T cell lymphomas. Sparse or no FDC meshworks were detected in the 4 cases of grade II nodular sclerosing HD, 5 follicular lymphomas with high-grade transformation, and 5 T cell-rich B cell lymphomas. CD35 immunostaining showed the most consistent labeling in the four FDC sarcomas studied in the current article. Reproducible demonstration of FDCs in routinely processed paraffin sections with CD21, CD23, and CD35 antibodies, as presented here, provides invaluable pieces of information in the diagnosis of lymphoproliferative disorders.

Antigens, CD↗
PubMed1983

The Epstein-Barr virus receptor is distinct from the C3 receptor.

Polyvalent serum directed against C3 receptors was employed in an attempt to block Epstein-Barr virus (EBV) binding to virus receptor-containing cell lines. The serum eliminated 90% of virus binding to Daudi and BJAB, lines which express only the C3d receptor. Raji and Ramos cells, which express the C3d, C3b and C3bi receptors, still adsorbed 70% of their virus capacity in the presence of excess antiserum. These effects were independent of the virus strain. In the light of previous reports, these data imply that, although the two receptors, EBV and C3d, are closely associated, the binding sites of EBV and complement are distinct. Additionally, an unusual EBV substrain-specific receptor found on U698 and P3HR-1/ASNP lines was shown to be independent of complement receptors.

Animals↗
PubMed1985

Human complement receptors for C3b (CR1) and C3d (CR2).

The human C3b receptor (CR1) is a polymorphic glycoprotein comprised of a single polypeptide chain. Of the 4 allotype forms of CR1 that have been described, the 2 most common have Mr's of 250,000 and 260,000, and are regulated by alleles having frequencies in a Caucasian population of 81.5% and 18.5%, respectively. CR1 is present on erythrocytes, neutrophils, eosinophils, monocytes, macrophages, B lymphocytes, some T lymphocytes, mast cells, and glomerular podocytes. CR1 number on erythrocytes is genetically regulated, and ranges from less than 100 sites per cell to greater than 1000 sites per cell, the average in the normal population being 500-600 sites per cell. A model accounting for this wide distribution proposes the existence of 2 codominant alleles determining low and high receptor number respectively; CR1 number is not affected by the structural polymorphism, so that the loci for these two phenotypic characteristics are distinct. The function of CR1 on erythrocytes may be to promote the clearance of immune complexes from the circulation. CR1 number on myelomonocytic cells is regulated by chemotactic factors which can rapidly transfer CR1 sites from a latent, presumably intracellular, site to the plasma membrane of these cells, thereby enhancing their ability to interact with opsonized foreign material. The receptor is involved in the endocytic reactions of these cells, and recent findings have demonstrated that this function can be modulated by T cell-derived factors, fibronectin, and phorbol esters. The role of CR1 on lymphocytes remains to be fully explored, although the receptor may enhance the differentiation of B cells into antibody-secreting cells.

Alleles↗
PubMed1991

Anti-inflammatory and immunosuppressive effects of recombinant soluble complement receptors.

CR1 and CR2 have served as unusual probes for the analysis of the two major functions of the immune system involving inflammation and the immune response, respectively. CR1, or some construct containing its active site SCRs, may find a role in the therapy of complement-dependent tissue injury, and may be used to define which diseases are caused by the inappropriate or excessive activation of this system. Although soluble forms of CR2 may be shown to have potential clinical utility when foreign antigen is given prospectively, as in monoclonal antibody therapy, perhaps the most important finding emanating from the analysis of this receptor is the recognition of a previously unrecognized membrane protein complex whose role in B cell development is yet to be determined. It is reasonable to predict that the function of the CD19 complex will be significant as it serves as the link between two evolutionarily distinct systems that share a common purpose of anti-microbial host defense.

Animals↗
PubMed2005

Complement receptors regulate lipopolysaccharide-induced T-cell stimulation.

Complement receptors type 1 and 2 (CR1 (CD35)/CR2 (CD21)) are known to enhance the adaptive immune response. In mice, CR1/CR2 are expressed on B cells, follicular dendritic cells, and activated granulocytes. Recently, we showed that a subset of CD44high and CD62Llow T cells also expresses CR1 and CR2. We now report that CR1/CR2 are detectable on both CD4+ and CD8+ subsets of T cells. Lipopolysaccharide (LPS) from Gram-negative bacteria causes polyclonal activation of B cells and stimulation of macrophages and other antigen-presenting cells. We further demonstrate that LPS induced marked up-regulation of CD25 and CD69 on T cells from CR1/CR2 sufficient (Cr+/+), but significantly lower up-regulation on T cells from CR1/CR2 deficient (Cr-/-) mice. These findings point to a novel mechanism by which CR1/CR2 modulates the activation of T cells by LPS.

Animals↗
PubMed1983

Complement (C3)-receptor-mediated phagocytosis of agarose beads by mouse macrophages. I. Intracellular degradation of agarose-bound C3bi and C3b by lysosomal enzymes.

The phagocytosis by macrophages of C3bi-coated agarose beads reached a plateau after 15 min, compared with 30 min for C3b-coated beads. By using 125I-labelled C3bi or C3b coupled to the agarose beads, we found that 70% and 95% of total radioactivity were removed from the beads after 12 h and 36 h of intracellular digestion, respectively. Intracellular degradation of C3bi linked to agarose beads was also demonstrated by testing binding of monoclonal antibodies against human C3c, C3g and C3d to beads extracted from the cells after phagocytosis. Such extracted beads also showed reduced attachment to new macrophages compared with non-ingested beads. Treatment of the cells with leupeptin, an inhibitor of the lysosomal enzyme cathepsin B, or with dextran sulphate to inhibit phagosome-lysosome fusion greatly reduced the release of labelled protein from the agarose during the first 12 h. These findings show that C3bi and C3b on agarose is destroyed intracellularly by lysosomal enzymes.

Animals↗