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PubMed1999

Decay accelerating activity of complement receptor type 1 (CD35). Two active sites are required for dissociating C5 convertases.

The goal of this study was to identify the site(s) in CR1 that mediate the dissociation of the C3 and C5 convertases. To that end, truncated derivatives of CR1 whose extracellular part is composed of 30 tandem repeating modules, termed complement control protein repeats (CCPs), were generated. Site 1 (CCPs 1-3) alone mediated the decay acceleration of the classical and alternative pathway C3 convertases. Site 2 (CCPs 8-10 or the nearly identical CCPs 15-17) had one-fifth the activity of site 1. In contrast, for the C5 convertase, site 1 had only 0.5% of the decay accelerating activity, while site 2 had no detectable activity. Efficient C5 decay accelerating activity was detected in recombinants that carried both site 1 and site 2. The activity was reduced if the intervening repeats between site 1 and site 2 were deleted. The results indicate that, for the C5 convertases, decay accelerating activity is mediated primarily by site 1. A properly spaced site 2 has an important auxiliary role, which may involve its C3b binding capacity. Moreover, using homologous substitution mutagenesis, residues important in site 1 for dissociating activity were identified. Based on these results, we generated proteins one-fourth the size of CR1 but with enhanced decay accelerating activity for the C3 convertases.

Amino Acid Sequence↗
PubMed2000

Interaction between complement receptor gC1qR and hepatitis C virus core protein inhibits T-lymphocyte proliferation.

Hepatitis C virus (HCV) is an important human pathogen that is remarkably efficient at establishing persistent infection. The HCV core protein is the first protein expressed during the early phase of HCV infection. Our previous work demonstrated that the HCV core protein suppresses host immune responses, including anti-viral cytotoxic T-lymphocyte responses in a murine model. To investigate the mechanism of HCV core-mediated immunosuppression, we searched for host proteins capable of associating with the core protein using a yeast two-hybrid system. Using the core protein as bait, we screened a human T cell-enriched expression library and identified a gene encoding the gC1q receptor (gC1qR). C1q is a ligand of gC1qR and is involved in the early host defense against infection. Like C1q, HCV core can inhibit T-cell proliferative responses in vitro. This core-induced anti-T-cell proliferation is reversed by addition of anti-gC1qR Ab in a T-cell proliferation assay. Furthermore, biochemical analysis of the interaction between core and gC1qR indicates that HCV core binds the region spanning amino acids 188 to 259 of gC1qR, a site distinct from the binding region of C1q. The inhibition of T-cell responsiveness by HCV core may have important implications for HCV persistence in humans.

Animals↗
PubMed1988

Opsonin-dependent and independent surface phagocytosis of S. aureus proceeds independently of complement and complement receptors.

We examined the mechanism of surface phagocytosis of Staphylococcus aureus by human polymorphonuclear leucocytes (PMN). Surface phagocytosis of unopsonized bacteria occurred, but was significantly enhanced by the presence of serum. The serum requirement was low, and a maximal effect occurred with serum concentrations of 0.25-0.5%. The opsonic effect of serum was not removed by heat inactivation of complement but was adsorbed, at low serum concentrations, by protein A, indicating that opsonin-dependent surface phagocytosis requires IgG but not C3. The requirement of opsonin-dependent surface phagocytosis for IgG was demonstrated further with purified IgG preparations as the sole opsonin. Activation of PMN by N-formyl-methionyl-leucyl-phenylalanine (FMLP) or phorbol myristate acetate (PMA) increased opsonin-independent surface phagocytosis by 47% and 66%, respectively, but had no effect on opsonin-dependent surface phagocytosis. Blockade of the PMN iC3b receptor (CR3), which has lectin-like properties, by a panel of monoclonal antibodies against the alpha- and beta-chains of CR3 did not inhibit the surface phagocytosis of opsonized or unopsonized S. aureus, and one antibody (NIMP-R10) enhanced opsonin-independent surface phagocytosis. These results indicate that the mechanism of surface phagocytosis is quite different to that observed in suspension assays. Opsonin-independent surface phagocytosis occurs and is enhanced by PMN activation, opsonin-dependent surface phagocytosis is dependent on IgG and not complement, and neither opsonin-independent nor -dependent surface phagocytosis proceeds through CR3.

Antibodies, Monoclonal↗
PubMed1979

Immune responsiveness of irradiated mice reconstituted with complement receptor positive CLR+ or negative CLR--lymphocytes from spleen or bone marrow.

Spleen and bone marrow cells depleted of CRL cannot restore immune reactivity of irradiated mice to sheep red blood cells SRBC. The response to anti-SIII, a T-independent antigen does not change when irradiated animals are repopulated with spleen cells or spleen cells depleted of CRL. Spleen cells of 6-day-old mice having low number of CRL, in contrast to spleen cells of adult animals, could not reconstitute irradiated recipients.

Age Factors↗
PubMed1983

Capping of complement receptors on human neutrophils induced by group A streptococcal cell walls.

Peptidoglycan-polysaccharide polymers derived from group A streptococcal cell walls (PG-PS) were opsonized with either purified C3 or normal human serum and were used as a probe to investigate the mobility of CR1 and CR3, the C3b and iC3b receptors, respectively, on human neutrophils. Incubation of monolayers or cell suspensions of neutrophils with PG-PS opsonized with C3b or serum resulted in capping of PG-PS, as detected by fluorescein-labeled antibody to PS. No binding of PG-PS to neutrophils was observed with heat-inactivated serum. By 30 min the cell walls were internalized and observed in one to three vacuoles. Capping was totally inhibited when PG-PS opsonized with C3b or serum was preincubated with Fab'-anti-C3b. Similar inhibition was observed when C3b-opsonized PG-PS was incubated with neutrophils that were preincubated with anti-CR1 or fluid-phase C3b; only partial inhibition of neutrophil capping was observed by using serum-opsonized PG-PS. Because anti-CR1 blocks only the C3b receptor, the cap formation observed with serum-opsonized PG-PS is probably due to CR3. These results suggest that both CR1 and CR3 on neutrophils cap after stimulation by group A streptococcal cell wall fragments.

Animals↗
PubMed1986

Ligand binding by the p150,95 antigen of U937 monocytic cells: properties in common with complement receptor type 3 (CR3).

U937 cells (a monocytic cell line) grown in the presence of phorbol myristate acetate were surface labeled with 125I and the iC3b-binding proteins isolated by affinity chromatography on iC3b-Sepharose in the presence of divalent cations. Three polypeptides of 170, 150 and 95 kDa were found to bind specifically to iC3b-Sepharose. The polypeptides of 170 and 95 kDa were identified as the alpha and the beta subunits of CR3 by immunoprecipitation with OKM1 monoclonal antibody. The 150-kDa polypeptide was not immunoprecipitated by antibodies to the alpha subunit of CR3 or LFA-1. However, the 150-kDa polypeptide, together with the 95-kDa polypeptide, was immunoprecipitated with an anti-beta subunit-specific antibody IB4, which immunoprecipitates LFA-1, CR3 and p150,95. These results indicated that the 150-kDa polypeptide is the alpha subunit of the p150,95 antigen. The binding of p150,95 and CR3 to iC3b-Sepharose is specific as neither binds to C3u-Sepharose. A monoclonal antibody, 3.9, which immunoprecipitated the 150 and a 95-kDa polypeptide from U937 cells was characterized as being directed against the alpha-subunit of the p150,95 antigen. Phorbol myristate acetate-stimulated U937 cells from rosettes with EAC3b and EAiC3b but not with EAC3d cells. Monoclonal antibody 3.9 does not inhibit either type of rosetting, but we were unable to exclude a role for p150,95 in adherence of iC3b-coated particles. Since there is no rosetting with C3d-bearing particles it is unlikely that p150,95 is a receptor for C3d, a role for p150,95 which has been suggested by others (Wright, S.D., Licht, M.R. and Silverstein, S.C., Fed. Proc. 1984. 43: 413).

Antibodies, Monoclonal↗
PubMed1986

Human eosinophils express CR1 and CR3 complement receptors for cleavage fragments of C3.

The functional and antigenic characteristics of C3 receptors expressed on human eosinophils were investigated using rosette assays with sheep erythrocytes coated with C3 fragments and flow cytometric analysis of cells stained with anti-receptor antibodies. Purified peripheral blood eosinophils from 13 patients with hypereosinophilia expressed CR1 antigens. In 8 patients, a mean of 14 + 9.5% eosinophils formed C3b-dependent rosettes that were inhibited by F(ab')2 anti-CR1 antibodies. This number increased to 33% following stimulation with leukotriene B4 (LTB4) (10(-7) M). Similar numbers of C3b rosettes were formed by hypodense and normodense eosinophils. Eosinophils from 2 patients from this group expressed 20,000 125I-labeled monoclonal anti-CR1 antibody binding sites/cell. In another group of patients, 55 +/- 9% eosinophils spontaneously formed C3b-dependent rosettes that could not be enhanced by LTB4. In all patients, a mean of 16 +/- 9% eosinophils formed cation-dependent rosettes with C3bi-bearing intermediates that were inhibited by anti-CR3 antibody OKM1. All eosinophils stained with monoclonal antibodies against the alpha chain of CR3. There was no C3d-dependent rosette formation with eosinophils and no eosinophils stained with monoclonal anti-CR2 antibody. Thus, human eosinophils express CR1 and CR3. Since CR3 is required for the adhesion of granulocytes to surfaces and antibody-dependent cellular cytotoxicity of neutrophils, the interaction of C3 fragments with CR3 and CR1 on eosinophils may be of importance in eosinophil-mediated damage of opsonized targets.

Antibodies, Monoclonal↗
PubMed1992

Markers of inflammatory activation: upregulation of complement receptors CR1 and CR3 on synovial fluid neutrophils from patients with inflammatory joint disease.

Expression of the C3 receptors CR1 and CR3 was investigated on neutrophils from paired peripheral blood and synovial fluid samples from 34 patients with inflammatory joint disease (21 patients with rheumatoid arthritis (RA) and 13 patients with other articular diseases (OAD)). Using monoclonal antibodies (anti-CD35, anti-CD11b) and immunofluorescence flow cytometric analyses the percentages of positively labeled cells and the relative fluorescence intensities (as a measure of receptor number) were determined. CR1 and CR3 were found to be present on the majority (> 85%) of circulating neutrophils from normal subjects, RA and OAD patients, and on synovial fluid neutrophils from both patient groups. A strong correlation between neutrophil CR1 and CR3 expression was observed in peripheral blood samples from normal subjects (r = 0.81; P = 0.001), RA (r = 0.79; P = 0.001), and OAD patients (r = 0.83; P = 0.001); in each case the levels of CR3 expression were approximately twice those recorded for CR1. Both CR1 and CR3 expression was upregulated on synovial fluid neutrophils compared with that observed on the corresponding peripheral blood cells. Mean percentage increases observed were: RA patients: CR1, 16.5% (P < 0.001) and CR3, 28.7% (P < 0.001); and OAD patients: CR1, 4.1% and CR3, 26.9% (P = 0.001). Correlation of serum and synovial fluid IL-6, IL-8, and immune complex levels with neutrophil CR1 and CR3 expression failed to demonstrate any significant relationship between the concentrations of these soluble factors and receptor expression. Upregulation of CR1 and CR3 receptors, reflecting neutrophil activation within the inflamed joint, is a consistent finding in patients with inflammatory arthropathies.

Adult↗
PubMed1995

Identification of complement receptor type 1-related proteins on primate erythrocytes.

The purpose of this study was to characterize the structure and function of the immune adherence receptor (CR1, CD35, C3b/C4b receptor) of primates. Western blotting, immunoprecipitation, ELISA, and affinity chromatography with homologous C3b and C4b were utilized. The major cross-reactive E membrane protein of ten species of primates tested was lower in m.w. than was human CR1 and fell into two size groups of 55 to 75 and 130 to 165 kDa. There was 10- to 100-fold more CR1 per primate E than human E. Five species also expressed lesser quantities of a protein similar in m.w. (approximately 200 kDa) to human CR1. In contrast to E, the major cross-reactive protein on PBMC was similar in size to human CR1. Four species also expressed lesser amounts of a lower m.w. protein on their PBMC of the same M(r) as that found on their E. Affinity chromatography demonstrated that the approximately 200-kDa form, if present, was recovered with a similar efficiency to that of human CR1. Three patterns of binding, however, were identified among the lower m.w. proteins: 1) C3b > or = C4b; 2) C4b > C3b; and C3b only or predominantly. The fact that these E proteins cross-react with Ab to human CR1, bind homologous C3b and, in most cases, C4b, and for some species represent the only such protein expressed on their E identifies them as immune adherence receptors. The 70-kDa CR1 of the chimpanzee E seems to arise by alternative splicing of the mRNA encoding the 200-kDa protein. These data raise interesting questions relative to the evolution of CR1 in primates and provide a basis for analysis of structure-function relationships among these size forms of CR1.

Animals↗
PubMed1979

Complement receptor binding of C3b-coated cells treated with C3b inactivator, beta 1H globulin and trypsin.

Treatment of 125I-C3b bound to EAC1423b with C3b inactivator (C3bINA) and beta 1H globulin (beta 1H) cleaved the alpha-chain of C3b into 65,000- and 42,000-dalton fragments, both of which remained disulfide-bonded to the intact beta-chain (C3bi). Subsequent treatment with trypsin (0.1 microgram/ml) released 125I into the supernatant and yielded cells coated with a 33,000-dalton fragment of alpha-chain, presumably C3d. These results are in agreement with those obtained by others using fluid phase C3b. C3b-coated cells (EAC1423b) adhered to complement (C) receptors on human erythrocytes, glomeruli, and monocytes. C3bi-coated cells adhered to the receptors on glomeruli and monocytes, but not to those on human erythrocytes. C3d-coated cells adhered only to the monocyte receptors. The findings suggest that the glomerular C receptor recognizes portions of the C3 molecule different from those recognized by either the erythrocyte or monocyte receptors.

Animals↗
PubMed1975

Spleen-cell reactivity against transplanted neurogenic rat tumors induced by ethylnitrosourea: uncovering of tumor specificity after removal of complement-receptor-bearing lymphocytes.

Spleen cells from BDIX-rats bearing either GVlAl-tumor (a syngeneic mixed glioma) or NVlAc-tumor (a cloned syngeneic neurinoma of the peripheral nervous system) were cytotoxic to both tumor cells in vitro. However, the tumors displayed individually distinct antigenic specificities by in vivo rejection tests. Their in vitro cross-reactivity disappeared when a particular subpopulation of the spleen cells was used. The procedure of lymphocyte purification included three consecutive steps: treatment with carbonyl iron and magnetism, passage through a nylon wool column, and finally removal of complement receptor-bearing cells present in the colum-excluded population. Cross-reactivity between the syngeneic tumors persisted after the first two steps of lymphocyte purification. In contrast, specific cytotoxic reactions were observed against each individual tumor subsequent to the removal of the remaining C3 receptor-positive but surface Ig-negative cells. While killer cells were present in normal spleen-cell populations, these were almost completely eliminated by passage through the nylon wool column.

Animals↗
PubMed1997

Immune complexes bound to the primate erythrocyte complement receptor (CR1) via anti-CR1 mAbs are cleared simultaneously with loss of CR1 in a concerted reaction in a rhesus monkey model.

In the circulation of primates, C3b-opsonized immune complexes (IC) bound to erythrocyte (E) CR1 are taken to the liver and spleen where IC are removed and destroyed without lysis or sequestration of E. Individuals with diseases associated with IC processing often have decreased E CR1 levels, and in previous primate animal models of IC disease, E CR1 was shown to be reduced, but the relationship between IC processing and CR1 loss remained to be clarified. We have developed a simple model to study this question. In naive (nonimmunized) rhesus monkeys, E-bound mouse anti-CR1 mAbs (1500 IgG/E) are not rapidly cleared from the circulation. Infusion of monkey anti-mouse IgG leads to rapid indirect binding of this second antibody to E CR1. Subsequently, in what appears to be a concerted reaction, CR1-bound nascent IC are rapidly cleared from the circulation and CR1 is removed from E at the same rate. Clearance of bound IC and loss of CR1 were both independently followed by RIA. Imaging studies localized the cleared anti-CR1 mAbs to the liver. Western blots indicated that the loss of CR1 was not due to a conformational change, and E CR1 levels returned to normal in 2-3 weeks, suggesting that the return was associated with synthesis of new E. Our findings suggest that the key step in the clearance mechanism requires recognition (possibly by Fc receptors) of IC-like material associated with E CR1, and this leads to loss of CR1 and uptake of the CR1-IC substrate by liver phagocytic cells.

Animals↗
PubMed1998

Mam33p, an oligomeric, acidic protein in the mitochondrial matrix of Saccharomyces cerevisiae is related to the human complement receptor gC1q-R.

Mam33p (mitochondrial acidic matrix protein) is a soluble protein, located in mitochondria of Saccharomyces cerevisiae. It is synthesized as a precursor with an N-terminal mitochondrial targeting sequence that is processed on import. Mam33p assembles to a homo-oligomeric complex in the mitochondrial matrix. It can bind to the sorting signal of cytochrome b2 that directs this protein into the intermembrane space. Mam33p is encoded by an 801 bp open reading frame. Gene disruption did not result in a significant growth defect. Mam33p exhibits sequence similarity to gC1q-R, a human protein that has been implicated in the binding of complement factor C1q and kininogen.

Amino Acid Sequence↗