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PubMed1988

The role of C3 and its fragments in the control of S phase entry of activated mouse B lymphocytes via the complement receptor type 2.

Complement component C3 and receptors for its activated fragments have been recognized as regulators of humoral immune responses. Cross-linked C3b and C3d will substitute for alpha B cell growth factors (alpha BCGF) produced by macrophages by stimulating activated murine B lymphocytes to enter S phase. In contrast, soluble C3d and synthetic oligopeptides--containing the amino acid sequence of the binding site of C3d to its receptor, the complement receptor type 2--inhibit the entry into S phase of alpha BCGF-stimulated B cells. There is evidence supporting the hypothesis that a portion of the C3 gene at the 3' end, encoding parts of the alpha chain, encodes an alternate C3 product with alpha BCGF activity.

Amino Acid Sequence↗
PubMed1991

Modulation of mouse complement receptors 1 and 2 suppresses antibody responses in vivo.

A mAb, 7G6, that binds to mouse CR1 and CR2 and down-modulates their expression on splenic B cells in vivo, was used to determine whether a decrease in CR1 and CR2 expression affects antibody responses to different T-dependent and T-independent Ag. Injection of mice with the mAb 7G6 prior to immunization with FITC haptenated Salmonella typhimurium (SH5771), Salmonella montevideo (SH5770), SRBC, or Ficoll dramatically decreased subsequent antibody responses to FITC. Although both IgM and IgG primary antibody responses were affected similarly, the antibody levels were most inhibited during early phases of the response. In contrast, down-modulation of the CR did not affect memory antibody responses, because injection of mice with 7G6 before a second immunization with FITC-SH5771 had no effect on subsequent anti-FITC antibody production. Moreover, polyclonal in vivo activation of the mouse immune system by anti-mouse IgD antibodies was not affected by previous administration of 7G6, because anti-IgD-induced increases in Ia expression and serum IgG1 levels were not affected. Taken together, these observations suggest that CR1 and CR2 may play an important role in enhancing primary antibody responses to many T-dependent and T-independent Ag and may contribute to a host's response to naturally occurring antigens such as bacteria.

Animals↗
PubMed1977

Complement receptors and cell associated complement components.

Membrane receptors for activated complement components are widely distributed amongst tissue cells of most mammalian species. Common amongst these are receptors for C3b which mediate many of the biological functions of C3. In addition, the genetic control of certain complement components is linked to the genes which code for the major histocompatibility complex. Many of these components are also present on cell surfaces. This suggests that the function of the complement system and the major histocompatibility complex may be related.

Animals↗
PubMed1993

Receptor-receptor interactions of complement receptor type 3 in neutrophil membranes.

The leukocyte integrin CR3 (CD11b/CD18) is known to participate in a variety of cell functions. Recent studies have indicated that CR3 may communicate with other plasma membrane receptors to carry out several cell functions. In this review we discuss these potential receptor-receptor interactions of CR3 and present a unifying model of CR3's diverse functions.

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↗
PubMed1992

Expression, molecular association, and functions of C3 complement receptors CR1 (CD35) and CR2 (CD21) on the human T cell line HPB-ALL.

We have investigated the expression, molecular association, ligand binding properties, and ability to transduce intracellular signals of CR1 and CR2 C3 receptors on cells of the human HPB-ALL T cell line. CR1 and CR2 on HPB-ALL cells bound polymeric C3b and C3dg and several anti-CR1 and anti-CR2 mAb recognizing different epitopes of the receptors on normal peripheral blood cells. Immunoprecipitated CR1 and CR2 exhibited similar m.w. to those of the receptors on normal peripheral blood T and B lymphocytes. CR1 and CR2 were partially associated in the form of CR1/CR2 complexes in the cell membrane as assessed by the ability of the receptors to cocap and cointernalize and to form a detergent-sensitive complex upon immunoprecipitation analysis. Triggering of CR2 with mAb OKB7 that recognizes an epitope associated with the ligand binding site of the receptor induced an increase in intracellular free calcium concentration in HPB-ALL cells. The signal provided by mAb OKB7 did not synergize with that triggered by anti-CD3 mAb UCHT1. Triggering of CR1 did not result in changes in intracellular free calcium concentration. Our observations have significance for the biology of normal human T cells because the majority of peripheral blood T cells that express CR1 also expressed CR2 and because a change in (Ca2+)i was induced by mAb OKB7 in purified normal T cells. These functions may be relevant for the regulatory role of C3 fragments on the immune response to T-dependent Ag and for the penetration into T cells of lymphocytotropic viruses.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1991

Differential effects of the stimulation of complement receptors CR1 (CD35) and CR2 (CD21) on cell proliferation and intracellular Ca2+ mobilization of chronic lymphocytic leukemia B cells.

The regulatory role of CR1 and CR2 on B cell activation and proliferation has been investigated by using B cells from patients with chronic lymphocytic leukemia. The chronic lymphocytic leukemia B cells are clonal expansions of B lymphocytes frozen at specific stages of activation. They displayed two patterns of response upon surface Ig (sIg) cross-linking in terms of in vitro proliferation and intracellular free Ca2+ mobilization: cells from patient F (first pattern) proliferated in the presence of mitogenic anti-mu antibodies, whereas cells from patient A (second pattern) did not respond to sIg cross-linking but proliferated in the presence of low m.w. B cell growth factor and IL-2. Coculture of A or F cells with C3b-bearing SRBC led to a two- to four-fold increase in thymidine incorporation in cultures containing low m.w. B cell growth factor but not in cultures containing rIL-2. This enhanced proliferation was inhibited by F(ab')2 polyclonal rabbit antihuman CR1 antibodies. Only cells which proliferated in the presence of anti-mu (cells F) responded to cross-linking of sIg with a rise in intracellular Ca2+. No increase in calcium mobilization was observed after co-cross-linking of CR1 and sIg on A and F cells with mAb or polyclonal anti-CR1 antibodies. Co-cross-linking of CR2 with sIg only led to an enhanced intracellular Ca2+ rise in F cells but not in A cells. The lack of CR2-mediated synergy in Ca2+ rise in A cells indicates that the synergy occurs only if there is a proper coupling of sIg to phospholipase C. CR1-induced proliferation of B cells does not involve the signaling pathways of sIg. These results provide additional evidences for the role of C3 fragments in modulation of human B cell activation.

Antigens, CD↗
PubMed1990

A molecular and immunochemical characterization of mouse CR2. Evidence for a single gene model of mouse complement receptors 1 and 2.

The relationships between functional, biochemical, and genetic homologues of human and mouse C receptors 1 (CR1) and 2 (CR2) are incompletely understood. We have isolated and characterized a partial mouse CR2 cDNA clone and determined the exon-intron organization of the gene encoding it. Together they predict a form of mouse CR2 highly identical to the 15 short consensus repeat form of human CR2. Strong similarities in genomic organization and exon-intron junctions indicate that this mouse gene and human CR2 are evolutionary homologues. A polyclonal rabbit anti-mouse CR2 fusion protein, BRN-1, was prepared. BRN-1 immunoprecipitates bands of 155 to 160 kDa under nonreducing conditions in mouse CR2 expressing B cell lines. In mouse spleen a doublet of 155 kDa and 190 kDa under nonreducing and 165 and 205 kDa under reducing conditions is recognized by immunoprecipitation and Western blot analysis. Staphylococcus aureus V8 protease maps of these two proteins show many shared bands. Crossed immunoprecipitation using BRN-1 and 7E9, a previously described mAb reported to identify the 190-kDa mouse CR1 and a smaller 150-kDa protein, indicates that both antibodies react with the same proteins. Therefore, by using BRN-1 we have now linked the genetic mouse CR2 to its functional, biochemically characterized gene product. The observation that BRN-1 also recognizes a second 190-kDa mouse protein defined functionally as a homologue of human CR1, and that these proteins have very similar peptide maps, provides strong evidence that these two proteins are expressed by a single mouse CR2/CR1 transcription unit.

Amino Acid Sequence↗
PubMed1990

Deficiencies of human C3 complement receptors type 1 (CR1, CD35) and type 2 (CR2, CD21).

CR1 (CD35) and CR2 (CD21) are structurally related integral transmembrane glycoproteins that function as cellular receptors for human C3b and C3dg, respectively. The primary sequence of the most common structural allotype of CR1 and that of CR2 have been established, and ligand binding on the molecules has been mapped. CR1 and CR2 genes are located in close vicinity in the RCA locus of chromosome 1. CR1 has a wide cellular/tissular distribution and mediates a variety of biologic functions, including the transport of C3-bearing immune complexes on erythrocytes, enhancement of phagocytosis, induction of IL-1 secretion and enhancement of B-cell differentiation. Expression of CR2 is restricted to B lymphocytes and follicular dendritic cells. The receptor modulates B-cell growth. CR2 also serves as the receptor for EBV and determines the cellular tropism of the virus. This review discusses the molecular biology and functional characteristics of CR1 and CR2. It focuses on alterations of expression of the receptors in disease, with particular emphasis on the genetic and acquired factors that contribute to the defective expression of CR1 in patients with systemic lupus erythematosus.

Amino Acid Sequence↗
PubMed1995

Characterization of rat complement receptors and regulatory proteins. CR2 and Crry are conserved, and the C3b receptor of neutrophils and platelets is distinct from CR1.

In the mouse, CR1 and CR2 on B lymphocytes are encoded by alternatively spliced Cr2 gene transcripts. Immune adherence receptors that bind C3b are present on mouse platelets and unstimulated neutrophils, but they are not CR1. In this study, rabbit anti-mouse CR1/CR2 Ab immunoprecipitated a 145- to 150-kDa CR2 protein from rat platelets, neutrophils, and splenocytes, but not a approximately 200-kDa CR1 protein. By Northern analysis, cDNA for mouse CR2 hybridized to mRNA of 3.7 and 5.2 kb from both mouse and rat splenocytes. The murine decay-accelerating factor and membrane cofactor protein analogue Crry was present in rat platelets, neutrophils, E, and splenocytes as two distinct proteins of 65 to 70 kDa and 75 to 85 kDa. Rat platelets, neutrophils, and splenocytes contained a novel 200-kDa cell membrane protein that specifically bound to a rat C3b-Sepharose column. We have named this protein C3bR-200. C3bR-200 was not identified by anti-mouse CR1/CR2 or anti-human CR1 Ab. Rat E lacked C3bR-200. Rat neutrophils and splenocytes also contained an 80-kDa C3b-binding protein that was distinct from Crry, which we have named C3bR-80. Therefore, CR2 and Crry are present in the rat, and have similar qualities to those from the mouse, except that CR2 is located on rat platelets and neutrophils, which is not the case in the mouse. Rat platelets, neutrophils, and splenocytes have a 200-kDa C3b-binding protein, C3bR-200, that is likely to be the rodent immune adherence receptor.

Animals↗
PubMed1994

Cooperation between Fc gamma receptor II and complement receptor type 3 during activation of platelet-activating factor release by cytokine-primed human eosinophils.

After priming with cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-3, or IL-5, eosinophils are stimulated potently by opsonized particles like serum-treated zymosan (STZ), resulting in activation of the respiratory burst and production of lipid mediators, such as platelet-activating factor (PAF) and leukotriene C4 (LTC4). In the present study, the role of the opsonin receptors Fc gamma RII and CR3 during both STZ-induced activation of the respiratory burst and PAF release by human eosinophils was investigated. Inhibition studies with blocking mAbs (alpha hFc gamma RII: AT10, IV.3; alpha CR3: B2.12, 44a) showed that both Fc gamma RII and CR3 are important for STZ-induced PAF release by cytokine-primed eosinophils. In contrast, CR3 is involved in activation of the respiratory burst, whereas Fc gamma RII seems not to be important, because blocking anti-Fc gamma RII mAbs had no effect. Subsequently, experiments were performed with zymosan particles coated with IgG, iC3b, or a combination of both. IgG-coated particles poorly activated both responses in GM-CSF primed and unprimed cells. iC3b-Zymosan activated the respiratory burst as well as zymosan expressing both opsonins (IgG/iC3b-zymosan). In contrast, iC3b-zymosan induced significantly less PAF release by GM-CSF-primed eosinophils than did IgG/iC3b-zymosan, suggesting synergism between Fc gamma RII and CR3. This synergistic effect was not observed when IgG-zymosan and iC3b-zymosan were added simultaneously. Therefore, these data indicate that on human eosinophils, Fc gamma RII and CR3 act synergistically to activate PAF release, provided that their ligands are in close proximity.

Cytokines↗
PubMed1993

Soluble complement receptor type 1 inhibits the complement pathway and prevents contractile failure in the postischemic heart. Evidence that complement activation is required for neutrophil-mediated reperfusion injury.

BACKGROUND: Complement-mediated neutrophil activation has been hypothesized to be an important mechanism of reperfusion injury. It has been proposed that soluble complement receptor 1 (sCR1), a potent inhibitor of both classical and alternative complement pathways, may prevent the complement-dependent activation of polymorphonuclear leukocytes (PMNs) that occurs within postischemic myocardium and thereby inhibit PMN-derived free radical generation and prevent postischemic contractile failure. Therefore, we performed studies to determine the effects of sCR1 on contractile function, PMN adhesion, complement deposition, and PMN-derived free radical generation in the postischemic heart. METHODS AND RESULTS: Studies were performed in an isolated rat heart model in which the isolated effects of given cellular or humoral factors could be determined. Plasma and PMNs were present to study the effects of sCR1 on contractile function, coronary flow, leukocyte adhesion, complement deposition, and PMN-derived free radical generation. Isolated rat hearts were perfused by the method of Langendorff (n = 10 in each group) and subjected to 20 minutes of global ischemia and reperfusion with PMNs and plasma in the presence or absence of sCR1. Left ventricular developed pressure (LVDP), coronary flow (CF), left ventricular end-diastolic pressure (LVEDP), and rate-pressure product (RPP) were measured during the preischemic period, during 1-minute control infusion of PMNs and plasma, and on reflow following 20 minutes of global ischemia. During the preischemic control infusion, no significant alterations in the physiologic parameters were observed, and there was no measurable free radical generation. Reperfusion with sCR1 markedly improved the recovery of postischemic contractile function. LVDP after 45 minutes of reperfusion was 76 +/- 9.8% compared with 32 +/- 6.2% (P < .001). In addition, significant improvements in LVEDP, RPP, and CF were observed in hearts treated with sCR1. Additional experiments were also performed to determine the effect of sCR1 on complement-mediated PMN activation. Measurements of PMN-derived free radical generation were performed in both isolated PMNs and the coronary effluent of hearts using electron paramagnetic resonance spectroscopy (EPR) with the spin trap 5,5-dimethyl-1-pyrroline-N-oxide (DMPO). EPR measurements in both isolated PMNs and coronary effluent demonstrated that sCR1 blocked complement-mediated free radical generation from the PMNs. Increased accumulation of PMNs was observed both in hearts treated with sCR1 and in those not treated with sCR1. Immunohistochemical staining of the postischemic myocardial tissue demonstrated marked complement deposition on the endothelial surface of small arterioles and capillaries, which was prevented by sCR1 treatment. Thus, sCR1 did not prevent PMN adhesion but did prevent complement deposition with activation of the PMN oxidative burst. CONCLUSIONS: The potent complement inhibitor sCR1 was found to be effective at preventing postischemic myocardial contractile dysfunction and enhancing the recovery of coronary flow. This study demonstrated that complement activation occurs in postischemic myocardium and is necessary for activation of the neutrophil oxidative burst with the generation of reactive oxygen free radicals. The process of neutrophil adhesion, however, was not affected by sCR1 and was independent of complement factors. These findings demonstrate the sCR1 is a highly potent agent at preventing complement-mediated PMN activation and secondary free radical generation in the postischemic heart. This genetically engineered protein appears to be a promising therapeutic agent in the prevention of myocardial reperfusion injury.

Animals↗
PubMed1991

Inhibition of immunological memory and T-independent humoral responses by monoclonal antibodies specific for murine complement receptors.

The importance of the complement system for mounting an antibody response in vivo was investigated by down-regulating and blocking the complement receptors (CR) in mice with three different monoclonal rat antibodies (mAb): mAb 8C12 recognized the C3b-binding site of CR1, mAb 7G6 recognized another site of CR1 and the C3d-binding site of CR2 and mAb 7E9 again recognized other epitopes on CR1 and CR2. We have earlier shown that 7G6, is the only mAb that completely suppresses the primary antibody response to horse erythrocytes. This antibody was also shown to suppress induction of immunological memory and a secondary antibody response. In contrast to what seems to be the case for thymus-dependent antibody responses, all three mAb could inhibit the antibody response to a thymus-independent antigen, dextran B 1355S.

Animals↗
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↗
PubMed1990

Duplication and divergence of the amino-terminal coding region of the complement receptor 1 (CR1) gene. An example of concerted (horizontal) evolution within a gene.

Human C3b/C4b receptor or complement receptor type one (CR1) is one of a family of receptor and regulatory glycoproteins that are encoded at a single genetic region (1q32) and are composed largely of a tandemly repeated motif (short consensus repeat or SCR) of approximately 60 amino acids. In addition, CR1 features an internal homology of seven SCRs in length, known as a long homologous repeat, that is reiterated four times, in the major polymorphic size variant, from SCR-1 to SCR-28, and may be reiterated three, five, and six times in other polymorphic forms. In the course of studying CR1, we detected sequences closely related to CR1 on several overlapping genomic clones. We have characterized a 40-kilobase CR1-like genomic region containing 10 potential exons that are 95% homologous to the amino-terminal coding portion of CR1. This region appears to be a partial duplication of CR1 and may encode a related gene. A comparison of CR1 and CR1-like sequences suggests that unequal crossing-over and concerted evolution have occurred within the most precisely reiterated subregion of CR1. Similar mechanisms have been important in the evolution of tandemly repeated genes and could provide the means for generation of the CR1 polymorphic size variants.

Amino Acid Sequence↗
PubMed1985

The selective localization of B lymphocytes in the spleen and the role of complement receptors.

The role of complement receptors on the localization of T and B cells in the spleen of mice was studied using short-term homing experiments in cobra venom factor (CoF)-treated animals. The localization ratio of B and T cells in the spleen of CoF-treated mice decreased significantly compared to control recipients. No changes could be found in the relative distribution of resident T and B cells in the spleen or other lymphoid organs of CoF-treated animals and when their spleen or lymph node cells were transferred, the localization pattern was normal. When cells were incubated in serum prior to transfer a disturbed localization ratio in the spleen of untreated recipients was observed. This was due to a blockade of complement receptors as determined by the inability of the incubated cells to form EAC rosettes. No blockade of EAC rosettes and no changes in localization ratios upon transfer could be observed when the cells were incubated in functionally C3-depleted serum. The results suggest a role for the complement-receptor on B cells in the initial localization in the spleen, whereas no influence upon the selective localization in high endothelial venules-bearing organs was found.

Animals↗
PubMed1984

Activation of macrophage complement receptors for phagocytosis.

Macrophage complement receptors, while innately incapable of promoting phagocytosis, can be activated to do so by a number of inflammatory stimuli and by several immunologic mechanisms. Studies with a complement receptor-activating lymphokine reveal that activation occurs as a result of mobilization of innately immobile receptors and suggest that receptor mobility is a prerequisite for phagocytosis. Since Fc receptors are susceptible to blockade by immune complexes at inflammatory sites, phagocytosis mediated by macrophage complement receptors may be of prime importance in vivo.

Animals↗