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PubMed1997

Complement receptors in HIV infection.

The complement system plays an important role in the antimicrobial defense of the organism. Its components recognize a large variety of pathogens and target them for destruction, either directly by formation of a membrane attack complex or indirectly by recruiting phagocytic cells. In addition, it has several functions in cell activation, clearance of immune complexes, control of inflammatory reactions, chemotaxis and autoimmunity. For mediation of all these tasks of the complement system, complement receptor molecules on the cell surface play a key role. Current knowledge on structure, function, signal transduction and associated molecules is briefly summarized here. The role of complement receptors for human immunodeficiency virus (HIV)-associated pathogenesis is ambiguous and varies depending on cell type. On the one hand, complement receptors support the infected host to manage HIV infection and to defend itself, at least partially, against viral spreading throughout the organism. Such complement receptor-mediated supporting mechanisms are activation of immune cells and lysis of viral particles and infected host cells. On the other hand, HIV employs complement receptors to intrude more easily into various cell types, to become localized into lymph follicles and to activate viral replication in latently infected cells. This review summarizes the complex interaction of virus and complement receptors in HIV infection for different cell types.

Animals↗
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↗
PubMed1998

Prevention of hyperacute rejection by phosphatidylinositol-anchored mini-complement receptor type 1.

Complement receptor type 1 (CR1, CD35) contains both factor I cofactor activity and convertase decay accelerating activity, but is, in general, thought to be an extrinsic regulator of complement activation. In this study, we prepared a phosphatidylinositol (PI)-anchored mini-CR1, which is composed of the short consensus repeat (SCR) 8-11 of CR1 and the PI anchor of DAF, and expressed it stably on a swine endothelial cell (SEC) line. We then examined the intrinsic regulatory activity of the mini-CR1, with respect to complement-mediated cell lysis as an in vitro hyperacute rejection model of a swine to human discordant xenograft. Flowcytometric profiles of the stable SEC lines with mini-CR1 showed a moderate level of expression for this molecule. Mini-CR1 blocked human complement-mediated cell lysis by approximately 50-70% on SEC. From the data of this study and our previous studies, mini-CR1 was more effective than membrane cofactor protein (MCP, CD46), and as effective as decay accelerating factor (DAF, CD55) in this system. The results suggest that PI-anchored mini-CR1 represents a useful molecule for clinical xenotransplantation.

Animals↗
PubMed1999

Co-operativity between modules within a C3b-binding site of complement receptor type 1.

Complement receptor type 1 (CR1) has 30 modules in its extracellular portion. An understanding of structure-function relationships within CR1 is being assembled gradually from studies of overlapping protein fragments. A CR1 fragment corresponding to modules 16 and 17 was expressed recombinantly as a non-glycosylated protein and its stability and unfolding characteristics studied using biophysical techniques. The results were compared with data collected previously on a CR1 fragment encompassing modules 15, 16 and 17 which together constitute a C3b-binding site (Kirkitadze, M.D., Krych, M., Uhrin, D. , Dryden, D.T.F., Smith, B.O., Wang, X., Hauhart, R., Atkinson, J.P. and Barlow, P.N. (1999) Biochemistry 38, 7019-7031). Modules within CR1 were found to co-operate during unfolding. The folding, stability and flexibility of this protein is therefore likely to be a complex function, and not just the sum, of contributions from individual modules.

Binding Sites↗
PubMed1995

Erythrocyte complement receptors.

Primate erythrocytes express complement receptors (E-CR), which can extrinsically bind C3b and Cb4. This interaction allows primate erythrocytes to bind complement opsonized particles and immune complexes, a phenomenon historically referred to as immune adherence. The binding of C3b and C4b by E-CR also leads to inhibition of complement activation. The human E-Cr is the complement activation. The human E-CR is the complement receptor type 1, or CR1, which is codominantly expressed as four polymorphic allotypes, ranging in size from 190,000 to 280,000 M(r). Non-human primate E-CR are similar to CR1 in function and antigenicity and are likely homologous to CR1 in structure; however, they are one third to one half the size of CR1. The physiological role of E-CR, determined from studies in monkeys and humans, is to allow erythrocytes to perform as inert shuttles for circulating immune complexes (IC), safely directing IC to the organs of the monocyte phagocytic system, thus preventing indiscriminate IC deposition in vulnerable tissue. In IC-mediated diseases, such as systemic lupus erythematosus (SLE), detectable erythrocyte CR1 levels are reduced, an abnormality that in part is acquired during disease activity. The loss of erythrocyte CR1 may be an important pathogenic factor in the development and severity of SLE.

Animals↗
PubMed1999

Elastase and metalloproteinase activities regulate soluble complement receptor 1 release.

Complement receptor 1 (CR1) is cleaved from the surface of polymorphonuclear cells (PMN) in the membrane-proximal region to yield a soluble fragment (sCR1) that contains the functional domains. The enzymes involved in this cleavage are produced by the PMN itself, since in vitro stimulation of purified PMN is followed by sCR1 release. Purified human neutrophil elastase (HNE) cleaved CR1 from erythrocytes and urinary vesicles originating from podocytes and enhanced tenfold the cleavage of CR1 from activated PMN. The largest fragment released from PMN by HNE was identical in size to CR1 shed spontaneously. The CR1 fragments cleaved from erythrocytes were functional. The shedding of sCR1 by activated PMN was inhibited by phenylmethylsulfonyl fluoride (80 +/- 10%), alpha1-antiprotease (50 +/- 5%) and elafin (60 +/- 5%). Furthermore the cleavage was blocked by the metalloprotease inhibitor 1,10-phenanthroline (70 +/- 6 %) as well as by a monoclonal antibody against human neutrophil collagenase MMP8 (40 +/- 10%). Maximal inhibition of sCR1 shedding was obtained by a combination of 1,10-phenanthroline with elafin (86 +/- 6%). These inhibitors had no effect on L-selectin shedding, indicating that the cleavage of CR1 was specific. In conclusion, elastase or elastase-like activity may be responsible for the shedding of functional sCR1 in vivo, and this activity is controlled by the local release of PMN metalloproteases and alpha1antiprotease.

Complement C3b↗
PubMed1991

Determination of the structural basis for selective binding of Epstein-Barr virus to human complement receptor type 2.

Epstein-Barr virus (EBV) is an oncogenic herpesvirus that selectively infects and immortalizes human B lymphocytes. One determinant of this narrow tropism is human CR2, the only viral receptor within the superfamily of proteins that contain short consensus repeats (SCRs). Human CR2 serves as a receptor for both C3dg and the gp350/220 glycoprotein of EBV, and binds the monoclonal antibody (mAb) OKB7, which blocks binding of both ligands to the receptor. In contrast, although murine CR2 is capable of binding human C3dg and this interaction can be blocked with the mAb 7G6, it does not bind OKB7 or EBV. We have determined the structural basis for absolute specificity of EBV for human CR2 through characterization of a panel of 24 human-murine chimeric receptors, all of which bind human C3dg. The results indicate that preferential binding of EBV to human CR2 is not due to unique amino acids that are capable of binding the virus, but reflects a distinct receptor conformation that can be achieved in murine CR2 with single amino acid substitutions in two discontinuous regions of the primary structure: replacement of proline at position 15 with the corresponding serine from human CR2, and elimination of a potential N-linked glycosylation site between SCR-1 and SCR-2. Furthermore, species-specific binding of EBV, OKB7, and 7G6 can all be manipulated through substitutions among residues 8-15, suggesting that this octapeptide is part of a structural determinant that is critical for binding of both viral and natural ligands to CR2.

Amino Acid Sequence↗
PubMed1987

Specificity of membrane complement receptor type three (CR3) for beta-glucans.

The binding of the iC3b receptor (CR3) to unopsonized zymosan was shown to result from CR3 attachment to cell wall beta-glucans. A specificity of neutrophil responses for beta-glucan was first suggested by a comparison of yeast (Saccharomyces cerevisiae) cell wall components for stimulation of a neutrophil superoxide burst. Neutrophils responded poorly to heat-killed yeast, but gave increasingly better responses to cell wall polysaccharides devoid of proteins (zymosan) and nearly pure beta-glucan particles derived from zymosan. Zymosan triggered a burst that was 29% as great as that stimulated by phorbol myristate acetate (PMA), and beta-glucan particles stimulated a burst that was 72% as great as that produced by PMA. Phagocytic responses to yeast were also inhibited by soluble glucans but not by soluble mannans. Three types of experiments demonstrated a role for CR3 in these responses. First, neutrophil ingestion of either yeast or yeast-derived beta-glucan particles was blocked by monoclonal anti-CR3, fluid-phase iC3b, or soluble beta-glucan from barley. Monocyte ingestion of beta-glucan particles was also blocked by anti-CR3, but not by anti-CR1 or anti-C3. Second, the neutrophil superoxide burst response to either zymosan or beta-glucan particles was blocked by anti-CR3 or fluid-phase iC3b, and was completely absent with neutrophils from 3 patients with an inherited deficiency of CR3. Third, CR3 was isolated from solubilized neutrophils by affinity chromatography on beta-glucan-Sepharose.

Glucans↗
PubMedDate not supplied

Clearance of blood-borne pathogens mediated through bispecific monoclonal antibodies bound to the primate erythrocyte complement receptor.

The primate erythrocyte complement receptor facilitates both the immune adherence reaction and the immune complex clearance properties of primate erythrocytes. These phenomena have been studied for more than 40 years. However, it has only recently become apparent that these characteristics of primate erythrocytes may be useful in the generation of a therapy based on bispecific monoclonal antibodies. Our approach uses bispecific monoclonal antibody constructs (heteropolymers) that promote binding of specific target pathogens to primate erythrocytes via the complement receptor. Once bound to the erythrocytes, the pathogen-heteropolymer complex should be cleared from the circulation, phagocytosed and destroyed in the liver. Results with several prototype target pathogens in monkey models indicate it may be possible to use this technology to develop a robust and general therapy for the treatment of diseases associated with blood-borne pathogens.

Animals↗
PubMed1992

Distinct receptor and regulatory properties of recombinant mouse complement receptor 1 (CR1) and Crry, the two genetic homologues of human CR1.

The relationship between the characterized mouse regulators of complement activation (RCA) genes and the 190-kD mouse complement receptor 1 (MCR1), 155-kD mouse complement receptor 2 (MCR2), and mouse p65 is unclear. One mouse RCA gene, designated MCR2 (or Cr2), encodes alternatively spliced 21 and 15 short consensus repeat (SCR)-containing transcripts that crosshybridize with cDNAs of both human CR2 and CR1, or CR2 alone, respectively. A five SCR-containing transcript derived from a second unique gene, designated Crry, also crosshybridizes with human CR1. We have previously shown that the 155-kD MCR2 is encoded by the 15 SCR-containing transcript. To analyze the protein products of the other transcripts, which are considered the genetic homologues of human CR1, we have expressed the 21 and the 5 SCR-containing cDNAs in the human K562 erythroleukemia cell line. We demonstrate that cells expressing the 21 SCR transcript express the 190-kD MCR1 protein. These cells react with five unique rat anti-MCR1 monoclonal antibodies, including the 8C12 antibody considered to be monospecific for MCR1. In addition, these cells efficiently form rosettes with mouse C3b-bearing sheep erythrocytes. In contrast, cells expressing the five SCR-containing Crry transcript are strongly recognized by an anti-human CR1 antibody that also defines the mouse p65 protein. Using a functional assay that measures the surface deposition of C3 activated via the classical complement pathway, we show that Crry/p65-expressing cells have a markedly decreased amount of C3 deposited on them as compared with control cells expressing the antisense construct or cells expressing MCR1 or MCR2. This suggests that Crry has intrinsic complement regulatory activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1975

Complement receptor in synchronized cultures of human hematopoietic cell lines.

Three previously established human lymphoid cell lines (HLV-1, SWB-16A, and B-1) were synchronized by double thymidine block and the lymphocyte surface receptor for complement was studied by the EAC-rosetting technique during the cell cycle. It was found that the proportion of cells with EAC rosettes remained unchanged throughout the various stages, indicating that the presence of the complement receptor in cultured lymphoid cells is independent of the cell cycle.

Animals↗
PubMed1985

Modulation of complement receptors of a human monocyte cell line, U-937, during incubation with phorbol myristate acetate: expression of an iC3b-specific receptor (CR3).

The human monocyte line, U-937, derived from an individual with histiocytic lymphoma was studied for the expression of surface C3 receptors, after cultivation in the presence of phorbol myristate acetate (PMA) or T lymphocyte-conditioned medium. Receptors were detected by using EAC4b, EAC3b, EC3b, EAC3bi and EAC3d intermediates. U-937 cells, in exponential growth phase, poorly bound the intermediates; after exposure to PMA or T lymphocyte-conditioned medium, U-937 cells strongly bound both EAC3b and EAC3bi since about 50% of cells rosetted with these intermediates. This binding was totally inhibited by EDTA and by Mac-1 monoclonal antibody, suggesting the presence of only CR3 receptor types on these cells. Although U-937 cells formed rosettes with EAC3b, there was no evidence for the presence of CR1 receptors since no rosette was observed either with EAC4b or with EC3b intermediates (EC3b were prepared by coupling purified C3b to erythrocytes with N-succinimidyl 3-(2-pyridyldithio)propionate. As small amounts of factor H were present on EAC3b intermediates, incubation of EAC3b with U-937 cells induced their transformation into EAC3bi and their binding to CR3. Moreover, U-937 cells did not promote the cleavage of C3b in the presence of factor I alone, suggesting that these cells did not bear a sufficient amount of functionally active CR1. These results demonstrated that U-937 cells predominantly expressed CR3. The study of the kinetics of EAC3bi rosette formation demonstrated that CR3 expression is closely related to PMA activation. We suggest that CR3 activity could result from a phosphorylation of existing receptors.

Antibodies, Monoclonal↗
PubMed1988

Ontogeny of human complement receptors CR1 and CR3: expression of these molecules on monocytes and neutrophils from maternal, newborn and fetal samples.

Higher levels of the expression of CR1 and CR3 molecules were detected on the surface of monocytes and neutrophils from maternal and newborn (cord) blood samples than in adult controls. Chemotactic factors such as formyl-methionyl-leucyl-phenylalanine or leukotriene B4 induced an increase of the expression of CR1 and CR3 which was more pronounced on cells from maternal and cord samples than from nonpregnant adult controls. CR1 and CR3 molecules were detected in monocytes and neutrophils from peripheral blood obtained from fetuses more than 14 weeks old and on subpopulations of cells in bone marrow, spleen and thymus.

Antibodies, Monoclonal↗
PubMed1987

Aggregation of complement receptors on human neutrophils in the absence of ligand.

C3bi receptors (CR3) on human polymorphonuclear leukocytes (PMN) bind ligand-coated particles and promote their ingestion. The binding activity of CR3 is not constitutive but is transiently enabled by phorbol esters (Wright, S. D., and B. D. Meyer, 1986, J. Immunol. 136:1759-1764). Our observations indicate that the capacity of CR3 to bind ligand is tightly correlated with the degree of ligand-independent aggregation of the receptor in the plane of the membrane. Fixed PMN were labeled with anti-CR3 monoclonal antibodies and streptavidin colloidal gold before viewing in the electron microscope either en face or in thin section. On unstimulated PMN, gold particles marking CR3 were dispersed randomly. Stimulation of PMN for 25 min with phorbol myristate acetate (PMA) dramatically enhances binding of C3bi-coated particles, and the CR3 on such stimulated cells was observed in clusters containing more than six gold particles. CR3 was not aggregated over coated pits. After 50 min in PMA, the binding activity of CR3 falls, and the distribution of CR3 was again observed to be disperse. If a hydrophilic phorbol ester was washed away after a 20-min stimulation, binding activity remains elevated for at least 50 min, and CR3 remained aggregated. Thus, clustering of CR3 was temporally correlated with its ability to bind ligand and initiate phagocytosis. Unlike CR3, Fc receptors and HLA did not exhibit changes in their aggregation state in response to PMA. Treating PMN with formyl-methionyl-leucyl-phenylalanine, which enhances expression of CR3 but not its function, did not lead to aggregation of CR3. These observations suggest that a clustered configuration is a precondition necessary for binding ligand and signaling phagocytosis.

Antigens, Surface↗