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A defect of a functional epitope of the complement receptor 3 is described in a patient with SLE and immune vasculitis. This defect interferes with the interaction of CR3 with its ligand C3bi.
Molecular definition of the cellular receptor for the collagen domain of C1q has been elusive. We now report that C1q binds specifically to human CR1 (CD35), the leukocyte C3b/C4b receptor, and the receptor on erythrocytes for opsonized immune complexes. Biotinylated or radioiodinated C1q (*C1q) bound specifically to transfected K562 cells expressing cell surface CR1 and to immobilized recombinant soluble CR1 (rsCR1). *C1q binding to rsCR1 was completely inhibited by unlabeled C1q and the collagen domain of C1q and was partially inhibited by C3b dimers. Kinetic analysis in physiologic saline of the interaction of unlabeled C1q with immobilized rsCR1 using surface plasmon resonance yielded an apparent equilibrium dissociation constant (K[eq2]) of 3.9 nM. Thus, CR1 is a cellular C1q receptor that recognizes all three complement opsonins, namely, C1q, C3b, and C4b.
Most of the biological processes depend on cell-to-cell and protein-to-cell interactions, which take place through receptors present on the cell surface. Various physiological systems are linked by such interactions, as is the case for innate and adaptative immune response. There is increasing evidence that two of the main actors involved in host defense, namely, the proteins of the complement system (nonspecific response) and the B lymphocytes (specific response), are strongly connected through the complement receptors displayed on the B-cell surface. Many parameters account for the importance of these molecules: (1) their diversity in terms of binding specificity allows them to interact with different fragments resulting from complement activation and C3 component proteolysis; (2) the structures of their extra- and intracytoplasmic domains differ from one receptor to another, controlling their interactions with other nall surface molecules as well as pathogens and regulating cell signaling; (3) their expression on the majority of the cells involved in immune response, especially B lymphocytes, make them an essential link between specific and nonspecific immune responses. This review deals with these different aspects, taking into account the most recent data.
Fifteen to 16 cell surface proteins which interact with soluble components of the complement system have now been identified. Most of these--CR1, CR2, CR3, "CR4", DAF, HSV-1 c glycoprotein, Gp 45-70, p150,95, cell-surface Factor H, and a 90 kD protein--interact with C3 or C4 and their degradation products. Other receptors for C1q, Factor H, C5a, and the C5b-9 complex have been identified. Receptors for additional complement proteins such as Factor B or its fragments are likely to exist. Complement receptors have a wide tissue distribution and have major roles in controlling the turnover of the complement system, and regulating behaviour and growth of leukocytes.
Treatment of mice with a monoclonal antibody (mAb) designated NIMP-R10, directed against the CD11b polypeptide of the CD18/CD11b heterodimeric type 3 complement receptor (CR3), exacerbates listeriosis by preventing myelomonocytic cells from focusing at sites of infected hepatocytes in the liver. Under these conditions an otherwise sublethal Listeria inoculum grows unrestrictedly within hepatocytes and causes death in 3 days. The results obtained with NIMP-R10 are similar to those previously obtained with a different anti-CD11b mAb (5C6), although mAb NIMP-R10 is more effective at enhancing infection. Therefore, both mAbs can be used to analyze host antibacterial defenses in vivo.
A study of lymphocytes bearing C3b, C4b and C3d complement receptor (CRL) was performed on human peripheral blood from 16 healthy donors and 12 patients affected with Chronic Lymphatic Leukemia (CLL). In the latter group a clear rise of C3dCRL was demonstrated, when compared with immunoadherence receptors bearing lymphocytes. However, when compared with controls, also these latter were slightly augmented. Furthermore in CLL under treatment CRL populations showed the same profile as CLL: so it was suggested that the treatment reduced not selectively all the three types of CRL, within the population of sIg bearing lymphocytes. Here we discuss the hypothesis that, in CLL, the proliferating lymphocytes population is chiefly sIg+, C3d+/C3b-, C4b-, but also sIg+, C3d+/C3b+, C4b+.
Axotomy of the rat facial nerve leads to mitotic divisions of microglial cells without developing into phagocytes. In order to study the functional characteristics of those activated, i.e., proliferating but nonphagocytic, microglia we investigated the expression of monocyte/macrophage antigens by these cells. Our results show that activated microglia lack monocyte/macrophage antigens recognized by the monoclonal antibodies Ox-41, ED1, ED2, and Ki-M2R but express high levels of CR3 complement receptors in situ.
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Complement-dependent activation of immune cells is regulated by cell surface membrane receptors. In this study, expression of complement receptors (CR) on human blood basophils (n = 11), tissue mast cells (lung, n = 7; skin, n = 10; uterus, n = 4; tonsil, n = 3; heart, n = 10), and on respective human cell lines (basophil line KU-812, mast cell line HMC-1) was analyzed by the use of mAbs and indirect immunofluorescence. Normal blood basophils and KU-812 cells were found to express C5aR (CD88), membrane cofactor protein (CD46), decay-accelerating factor (CD55), and membrane attack complex inhibitory factor (CD59), as well as the previously recognized CR1 (CD35), CR3 alpha (CD11b), CR4 alpha (CD11c), and CR3/4 beta (CD18). Mast cells from all organs as well as HMC-1 cells expressed CD46, CD55, and CD59, but not CD11b, CD21, or CD35. The C5aR (CD88) was detectable on skin mast cells, a subset (5 to 15%) of cardiac mast cells, and on HMC-1 cells, but not on lung, uterus, or tonsillar mast cells (< 5%). Moreover, double immunoperoxidase staining (tryptase vs C5aR/CD88) revealed in situ expression of C5aR on skin, but not lung mast cells. Recombinant human (rh) C5a, at 10(-10) to 10(-7) M, induced secretion of histamine from basophils (rhC5a, 10(-8) M: 53.4 +/- 3.1% vs control < 5%) and from skin mast cells (rhC5a, 10(-8) M: 25.8 +/- 16.1% vs control < 10% histamine release), but not from other mast cells (rhC5a or control: < 10%, p > 0.05). The rhC5a-induced secretion of histamine from basophils and skin mast cells was inhibited by S5/1, a blocking Ab against CD88 (basophils: 37.2% to 75.1%; skin mast cells: 39.2% to 83.9% inhibition, p < 0.05). Together, this study shows that a) basophils and mast cells express a different profile of complement receptors, b) C5a-dependent mediator release in skin mast cells and basophils is mediated via CD88, and c) mast cells constitute a heterogeneous lineage in terms of expression of the C5a binding site CD88.
Microglia and macrophages express the alpha(M)/beta(2) integrin complement-receptor-3 (CR3/MAC-1; CD11b/CD18) and scavenger-receptor-AI/II (SRAI/II). Both can mediate myelin phagocytosis. We document that CR3/MAC-1 mediated myelin phagocytosis in microglia is modulated by complement and anti-CR3/MAC-1 mAbs. Complement augmented phagocytosis twofold. Anti-alpha(M) mAbs M1/70 and 5C6 inhibited and anti-beta(2) mAb M18/2 augmented myelin phagocytosis in the presence and absence of active complement. Active complement modulated phagocytosis inhibition by M1/70 and 5C6 and phagocytosis augmentation by M18/2. CR3/MAC-1 mediated myelin phagocytosis may thus be, at least partially, independent of but modulated by complement. Anti-beta(2) mAb Game-46 did not affect phagocytosis. However, combining M18/2 with Game-46 resulted in phagocytosis augmentation that was larger in magnitude than that induced by M18/2 alone. Thus, phagocytosis augmentation induced by one anti-beta(2) mAb was potentiated by another anti-beta(2) mAb. Combining M1/70 or 5C6 with M18/2 inhibited M18/2-induced augmentation. Overall, mAbs-induced phagocytosis modulation ranged three- to sevenfold from inhibition to augmentation. Anti-CR3/MAC-1 mAbs may reveal a mechanism by which native extracellular molecules bind to and modulate CR3/MAC-1 mediated myelin phagocytosis in microglia and macrophages. We further document SRAI/II mediated myelin phagocytosis in microglia and CR3/MAC-1 contributing to myelin phagocytosis two- to threefold more than SRAI/II when the two receptors function together.
Experimental autoimmune neuritis (EAN) in Lewis rats induced by immunization with bovine peripheral nerve myelin in complete Freund's adjuvant is an animal model of the human Guillain-Barré syndrome. In this study myelin-induced EAN was treated with 30 mg/kg per day human soluble complement receptor type 1 (sCR1) beginning on day 8 post immunization (p.i.). Clinical signs of disease were markedly suppressed by application of sCR1 and none of eight treated animals but seven of nine control rats developed paraparesis. Electrophysiologic examination of sciatic nerve function 13 days p.i. revealed faster nerve conduction velocities and significantly higher compound muscle action potentials in sCR1-injected animals. In sections of sciatic nerves acquired 16 days p.i. extended demyelination and axonal degeneration was prevented by treatment with sCR1 in vivo. Our findings underscore the functional importance of complement during inflammatory demyelination in the peripheral nervous system and suggest sCR1 as a potential therapeutic approach in these diseases.
Anti-Mac-1 (M1/70), a rat monoclonal antibody that reacts with mouse and human macrophages, polymorphonuclear leukocytes (PMNL), and natural killer cells, selectively inhibited complement receptor-mediated rosetting by murine macrophages and human PMNL. Preincubation of macrophages with anti-Mac-1 inhibited formation of rosettes with sheep erythrocytes bearing IgM antibody and murine C3 fragments. No inhibition was observed when other monoclonal antibodies that react with macrophages (such as anti-Ly5, anti-H-2, or anti-pan-leukocyte) were tested at 10-fold higher concentrations. Anti-Mac-1 did not affect macrophage Fc receptor-mediated rosetting. Erythrocytes bearing homogeneous human C3 fragments C3b (EC3b) or C3bi (EC3bi) were used to test the specificity of the murine macrophage and human PMNL complement receptor inhibited by anti-Mac-1. In both cases, anti-Mac-1 inhibited CR3-mediated rosetting of EC3bi but not CR1-dependent rosetting of EC3b. The results show that Mac-1 is either identical to CR3 or closely associated with CR3 function. This is one of the first cases in which a monoclonal antibody-defined differentiation antigen has been associated with a specific cell surface function.
Nonopsonized Bordetella pertussis bind to human monocytes by means of the virulence factors filamentous hemagglutinin (FHA), pertactin, and the minor fimbrial subunit FimD. Receptors on monocytes that mediate binding of B. pertussis to these cells include complement receptor type 3 (CR3), which binds to FHA of B. pertussis, and very late antigen-5 (VLA-5), which binds to an, as yet, unknown ligand on these bacteria. In the present study, the possibility that FimD acts as a ligand for VLA-5 was investigated. Soluble fibronectin, which is the natural ligand for VLA-5, or mAbs against VLA-5 inhibited binding to monocytes of B. pertussis strains that express FimD but not of mutant strains that lack FimD. Beads that were coated with the fusion protein maltose-binding protein-FimD bound to adherent monocytes, and this binding was inhibited by soluble fibronectin or mAb against the alpha- or beta-chain of VLA-5, while soluble collagen or mAb against VLA-4, VLA-6, CR3, or HLA class II had no effect. Down-modulation of VLA-5 on the apical surface of monocytes by plating the cells onto surfaces precoated with anti-VLA-5 mAb also inhibited binding of beads coated with maltose-binding protein-FimD to monocytes, while precoating of the surfaces with mAb against VLA-6 or CR3 had no effect. These results indicate that VLA-5 on monocytes serves as a receptor for FimD on B. pertussis. Binding of C3bi-coated erythrocytes to monocytes, which is a measure of the binding activity of CR3, was enhanced when monocytes were adhered onto plates precoated with purified fimbriae of B. pertussis, while precoating with fimbriae lacking FimD had no effect. Precoating of the plates with FimD-containing fimbriae also enhanced binding of B. pertussis, which express FHA, but not of strains that lack FHA, to monocytes. The enhanced binding of C3bi-coated erythrocytes and B. pertussis to monocytes could be markedly inhibited by tyrphostin-47, a protein tyrosine kinase inhibitor. These results demonstrate that interaction of FimD of B. pertussis with VLA-5 on monocytes activates CR3, which requires protein tyrosine kinases and results in enhanced binding of B. pertussis to the latter receptor via FHA.
BACKGROUND: In pig-to-nonhuman primate solid organ xenotransplantation using organs from donors transgenic for human decay-accelerating factor (hDAF), the main type of rejection is antibody-mediated (acute humoral xenograft rejection, AHXR). This occurs despite the complement-regulatory function of the transgene, neutralization of natural antibodies to Galalpha1-3Gal (Gal) using soluble glycoconjugates, and chronic immunosuppression. As complement components play a major role in graft destruction after antibody binding, we evaluated the efficacy of chronic complement inhibition by soluble complement receptor type 1 (TP10). METHODS: Life-supporting hDAF-transgenic kidney transplantation was performed in cynomolgus monkeys, using cyclophosphamide induction, and maintenance immunosuppression with cyclosporin A, mycophenolate sodium, and tapering steroids. Rejection was treated with bolus steroid injections: if not successful animals were terminated. Three groups were studied: in group 1 (n=4) GAS914 (a soluble glycoconjugate comprising Gal on a poly-L-lysine backbone) was added before and after transplantation; group 2 (n=2) received GAS914 as in group 1 and in addition TP10 before and after transplantation; in group 3 (n=4) GAS914 was only given before transplantation and TP10 as in group 2. Monitoring included the regular assessment of anti-porcine antibodies, complement activity (soluble C5b-9), therapeutic drug monitoring, and graft histology. RESULTS: Survival in group 1 was 6, 12, 31 and 37 days, respectively, and in all four cases graft histology showed AHXR. The two animals in groups 2 survived 3 and 15 days, respectively, and similarly showed AHXR in graft histology. In group 3 two animals showed AHXR (10 and 37 days survival, respectively), and two others did not show AHXR (20 and 32 days survival, respectively). The diagnosis AHXR included the deposition of complement activation products in the graft, which were present at lower intensity in animals treated with TP10. In all animals GAS914 effectively neutralized circulating anti-Gal antibody. Antibodies were detectable in the circulation of all animals using porcine erythrocytes in a hemolytic assay, although at lower levels than before transplantation. Soluble C5b-9 was not detectable in the circulation of animals receiving TP10, and circulating TP10 concentrations in these animals were in a presumed pharmacologically active range. CONCLUSIONS: The inclusion of TP10 in the immunosuppressive protocol does not clearly lead to improved xenograft survival. Despite effective neutralization of anti-Gal antibodies and effective inhibition of systemic complement activity, AHXR was apparent in four of six animals under chronic TP10 treatment, including deposits of complement activation products in the graft. Apparently, effective systemic complement inhibition by TP10 in combination with local complement regulation by the hDAF transgene product does not necessarily result in effective inhibition of complement activation at locations in the xenograft upon binding of anti-porcine antibodies to the grafted endothelium.
Immune complexes of BSA-anti BSA (IgG F(ab')2) will activate human complement by the alternate pathway. The C3 bound to these complexes binds to human peripheral blood mononuclear cells which bear complement receptors. This interaction is visualized by fluoresceinated antigen (BSA-FITC) or fluorescein conjugated antisera directed at the C3 component of complement. The assay appears to be more sensitive than the usual IgMEAC rosette technique and correlates well with the rosette method.
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Pseudohyphae of Candida albicans bear surface receptors for iC3b and C3d. In order to determine a possible role for these receptors in the pathogenesis of candidiasis, a spontaneous C. albicans mutant, m-10, which exhibits reduced ability to adhere in vitro to fibrin platelet clots and epithelial cells or to cause endocarditis in a rabbit model, and its parent wild-type (wt) strain were compared for receptor expression in rosetting assays with sheep erythrocytes carrying iC3b (EAC1423bi) or C3d (EAC1423d). An equally high attachment to wt and m-10 was seen with EAC1423d, whereas rosetting with EAC1423bi was reduced by 53% in m-10 compared with wt. In inhibition studies, rosetting of wt with EAC1423bi was markedly inhibited by culture filtrate, hyphal-cell extract, and DEAE-fractionated material prepared from wt (54, 87, and 70% decreases in rosetting, respectively), thus suggesting the presence of the soluble, functionally active iC3b receptor of C. albicans in each of these preparations. Minimal inhibition of iC3b rosetting, however, was seen with the identical materials from m-10 (21, 5, and 12%, respectively). All of the preparations from the two strains were equally effective in their inhibitory activities against rosetting of C3d. A human serum specimen obtained from a patient with chronic mucocutaneous candidiasis blocked iC3b rosetting of the wt strain almost completely. When used in an immunoblot, this serum recognized proteins of 68 to 71, 55, and 50 kilodaltons (kDa) in hyphal-cell extracts of the wt. With the same preparation of the avirulent mutant, only weak reactions with the 68- to 71-kDa and 55-kDa proteins occurred, while the 50-kDa protein was not detectable. Taken together, these results indicate that the expression of the functionally active iC3b receptor on C. albicans may be involved in the virulence of the organism, possibly by mediating adherence to mammalian cells.
Factor H, a regulatory protein of the alternative pathway of complement (APC), is present in amyloid-beta (Abeta) plaques in Alzheimer's disease (AD). Abeta plaques also contain significant amounts of heparan sulfate proteoglycans (HSPGs), such as agrin, as well as numerous activated microglia expressing increased levels complement receptor 3 (CR3). Here, we show the colocalization of each of these molecules in the AD brain and the functional capacity for these molecules to bind to one another in vitro. We propose that CR3 receptors expressed by microglia are used for ligand binding to factor H bound to HSPGs and Abeta in plaques in the AD brain.