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Results for “Receptors, Complement”

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PubMed1981

Isolation of lymphocyte membrane complement receptor type two (the C3d receptor) and preparation of receptor-specific antibody.

A glycoprotein binding complement component C3d was isolated from media used for culture of Raji human lymphoblastoid cells. Analysis by sodium dodecyl sulfate/polyacrylamide gel electrophoresis and gas/liquid chromatography indicated that the C3d-binding glycoprotein consisted of a single polypeptide chain with extensive intrachain disulfide bonds, a molecular weight of 72,000, and several different bound carbohydrates. Several lines of evidence indicated that this medium-derived C3d-binding protein originated from membrane complement receptor type two (CR2, the C3d receptor), presumably shed during membrane turnover. The C3d-binding protein bound to sheep erythrocytes coated with C3d (EC3d) but not to sheep erythrocytes coated with C3b (EC3b). Antisera, prepared by immunization with the purified C3d-binding glycoprotein, inhibited lymphocyte rosette formation with EC3d but not with EC3b. Analysis by sodium dodecyl sulfate gel electrophoresis of the radiolabeled and solubilized lymphocyte antigens reactive with the anti-C3d-binding protein sera revealed a single-chain cell-surface protein of molecular weight 72,000 that was apparently identical to the isolated C3d-binding protein. Parallel assay of lymphocytes for Cr2 by direct immunofluorescence with F(ab')2 anti-C3d-binding protein (anti-CR2) and rosette formation with EC3d indicated that both assays had the same specificity and nearly the same sensitivity. With both systems CR2 expression was limited to B cells, and was undetectable on T cells, monocytes, or neutrophils.

Animals↗

PubMed2003

Availability of complement bound to Staphylococcus aureus to interact with membrane complement receptors influences efficiency of phagocytosis.

Complement-mediated opsonization of encapsulated Staphylococcus aureus (CP+) of the predominant capsule types, 5 and 8, remains poorly understood. Our previous work showed that complement is important for mouse survival of CP+ type 5 bacteremia and that the type 5 capsule inhibits the binding of opsonic C3 fragments to the organism. The importance of complement-mediated opsonization of CP+ was tested by neutrophil phagocytosis assays. Complement-mediated opsonization of CP+ increased phagocytosis by 57% compared to opsonization in complement-inhibited serum. Agar-grown CP+, enhancing capsule expression, was phagocytosed only one-tenth as well as the capsule-negative organisms (CP-), supporting the belief that staphylococcal polysaccharide capsules impair phagocytosis. Despite relatively poor phagocytosis of CP+ compared to CP-, complement activation increased the phagocytosis of CP+ by 103%. Thus, complement in normal human serum may have an important role in opsonizing CP+, even when capsule expression is strong. The ability of bound C3 fragments to interact with complement receptor 1 (CD35) on the membrane of human erythrocytes was tested in an immune adherence assay. S. aureus capsule was able to mask C3 fragments on the organism from binding to complement receptor 1. The inhibition of C3 binding to CP+ and the masking of deposited C3 fragments caused by the presence of capsule was associated with markedly decreased phagocytosis. The addition of anti-capsule antibodies to normal human serum was found to markedly improve the recognition of deposited C3 fragments by complement receptor 1 even when the absolute number of C3 molecules bound to S. aureus was not increased.

Antibodies, Bacterial↗

PubMed1986

Kupffer cell complement receptor clearance function and host defense.

Kupffer cells are well known to be important for normal host defense function. The development of methods to evaluate the in vivo function of specific receptors on Kupffer cells has made it possible to assess the role of these receptors in host defense. The rationale for studying complement receptors is based on the proposed important role of these receptors in host defense and on the observation that the hereditary deficiency of a complement receptor is associated with recurrent severe bacterial infections. The studies reviewed here demonstrate that forms of injury that are associated with depressed host defense including thermal injury, hemorrhagic shock, trauma, and surgery also cause a decrease in complement receptor clearance function. This decrease in Kupffer cell receptor clearance function was shown not to be the result of depressed hepatic blood flow or depletion of complement components. Complement receptor function was also depressed following the phagocytosis of particulates that are known to depress Kupffer cell host defense function. Endotoxemia and bacteremia also were associated with a depression of complement receptor function. Complement receptor function was experimentally depressed in uninjured animals by the phagocytosis of IgG-coated erythrocytes. There was a close association between the depression of complement receptor clearance function and increased susceptibility to the lethal effects of endotoxin and bacterial infection. These studies support the hypotheses that complement receptors on Kupffer cells are important for normal host defense and that depression of the function of these receptors impairs host defense.

Animals↗

PubMed2005

Characterization of complement receptor 1 domains for prevention of complement-mediated red cell destruction.

BACKGROUND: Complement activation resulting in intravascular hemolysis can cause transfusion-associated mortality. We recently showed that a recombinant soluble form of complement receptor 1 (CR1) effectively reduces complement-mediated red blood cell (RBC) destruction in vitro and more importantly prolongs the survival of transfused human RBCs in mice. To determine CR1-active sites that prevent RBC destruction, structure-function analysis of its extracellular 1930-amino-acid domain has been performed. STUDY DESIGN AND METHODS: Several CR1-truncated soluble proteins were prepared and tested for their ability to prevent complement-mediated RBC destruction in vitro and in mice. RESULTS: A 250-amino-acid region in CR1 that possesses antihemolytic activity and is effective in prolonging survival of transfused RBCs in vivo was identified. Mutation of two critical residues (D109N and E116K) in this 250-amino-acid domain, previously shown to improve complement-inhibitory functions of CR1 derivatives, resulted in a more potent inhibition of complement activation in vitro. In vivo, however, the activity of mutant proteins was comparable to the wild-type molecules. CONCLUSION: Our structure-function studies have characterized smaller CR1-based complement inhibitors for future development of structure-derived transfusion therapeutics. Our studies underscore the importance of testing CR1 inhibitors in vivo.

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 receptor enhancement as evidence of neutrophil activation after exercise-induced asthma.

To determine whether neutrophils are activated after exercise-induced asthma, increases in neutrophil complement receptor numbers (complement receptor enhancement) were measured by the rosette technique. In twelve asthmatic patients there was a time-dependent rise in complement receptor numbers for up to 60 min after treadmill exercise. This enhancement of complement receptors was preceded by a rise in plasma neutrophil chemotactic activity and a reduction in the peak expiratory flow rate. These changes could be inhibited by prior administration of disodium cromoglycate. The changes were not observed in seven asthmatic patients in whom asthma was not induced by an identical exercise task. Complement receptor enhancement was also observed in vitro when partially purified neutrophil chemotactic activity from a patient with exercise-induced asthma was incubated with normal neutrophils. These findings suggest that inflammatory cells are activated after exercise-induced asthma, possibly as a result of the release of neutrophil chemotactic activity and other mast-cell-associated mediators.

Asthma↗

PubMed1976

A simple rosette assay for demonstration of complement receptor sites using complement-coated zymosan beads.

In the present article we describe a simple rosette assay for detection of C3 receptor-bearing B lymphocytes with complement (C)-coated zymosan (Zy) beads. Zy coated with murine or human C bound to a distinct population of human and mouse lymphocytes as well as to the majority of lymphoblastoid cells of several human established cell lines. Rosette formation was also observed with human red blood cells, with human monocytes and neutrophils. Experiments with anti-immunoglobulin sera, with other B and T cell markers and with mouse thymocytes proved that the capacity to bind C-coated Zy is primarily a feature of B lymphocytes. The following findings suggested that C-coated Zy is bound via receptor sites for the activated components of C3: (a) Zy coated with C3-deficient serum failed to bind, (b) comparable percentages of various lymphoid and nonlymphoid cells formed rosettes with C-coated Zy as well as with antibody and C-coated sheep red blood cells, and (c) antibodies against human or murine C3 inhibited the binding of C-coated Zy.

B-Lymphocytes↗

PubMed2002

Complement receptors CD21/35 link innate and protective immunity during Streptococcus pneumoniae infection by regulating IgG3 antibody responses.

The CD21/35 receptor provides an important link between innate and adaptive immunity. Its importance during protective immune responses to encapsulated extracellular bacteria was assessed using a new line of mice completely deficient in CD21/35 expression (CD21/35(-/-)). CD21/35 expression was essential for the rapid trapping of C3dg-antigen complexes by B cells in vivo, especially in splenic marginal zones. Despite normal B cell development in CD21/35(-/-) mice, T cell-independent and -dependent antibody responses to low-dose antigens were significantly decreased, with a striking impairment in IgG3 responses. Accordingly, CD21/35(-/-) mice were more susceptible to acute lethal Streptococcus pneumoniae infection. Thus, CD21/35 expression is critical for early protective antibody responses to lethal pathogens that rapidly multiply and quickly overwhelm the immune system.

Animals↗

PubMed2000

Antibody production in mice deficient for complement receptors 1 and 2 can be induced by IgG/Ag and IgE/Ag, but not IgM/Ag complexes.

Deficiencies in C factors C2, C3, or C4 as well as lack of C receptors 1 and 2 (CR1/2) lead to impaired Ab production. Classical pathway activation plays a major role, as mice deficient in factor B, a key factor in the alternative pathway, have normal Ab production. Abs in complex with their specific Ag are known to feedback regulate the Ab response, and enhanced responses are initiated by IgM, IgE, and IgG. IgM acts via the C system, whereas IgE and IgG can operate independently of C via Fc receptors. Here we have investigated whether these isotypes are able to enhance Ab responses in mice lacking CR1/2. SRBC-specific IgM, administered with SRBC, does not enhance Ab responses in these animals. In contrast, 2,4, 6-trinitrophenyl-specific IgE and IgG2a, administered with BSA-2,4, 6-trinitrophenyl, induce potent Ab responses in CR1/2-deficient mice. Additionally, BSA administered with CFA or alum induced strong Ab responses in the absence of CR1/2. These results indicate that CR1/2 is needed to promote IgM-mediated induction of primary Ab responses. The data also show that the need for CR1/2 can be circumvented by Abs typical of a secondary immune response forming complexes with Ag or by conventional adjuvants, presumably mimicking physiological inflammatory reactions.

Adjuvants, Immunologic↗

PubMed2003

B cell complement receptor 2 transfer reaction.

The B cell C receptor specific for C3dg (CR2) shares a number of features with the primate E C receptor (CR1). Previously, we have demonstrated, both in vitro and in animal models, that immune complexes (IC) bound to primate E CR1, either via C opsonization or by means of bispecific mAb complexes, can be transferred to acceptor macrophages in a process that also removes CR1 from the E. We have now extended this paradigm, the transfer reaction, to include B cell CR2. We used both flow cytometry and fluorescence microscopy to demonstrate that IC bound to Raji cell CR2, either via C opsonization or through the use of an anti-CR2 mAb, are transferred to acceptor THP-1 cells. This reaction, which appears to require Fc recognition of IgG bound to Raji cell CR2, also leads to transfer of CR2. Additional support for the B cell transfer reaction is provided in a prototype study in a monkey model in which IC bound to B cell CR2 are localized to the spleen. These findings may have important implications with respect to defining the role of C in IC handling during the normal immune response.

Animals↗

PubMed1995

Antibodies to murine complement receptor 1 and 2 can inhibit the antibody response in vivo without inhibiting T helper cell induction.

Administration to mice of mAb against CR1/CR2 inhibits the primary and secondary in vivo Ab response. We have addressed the question of whether induction of T helper cells, in addition to B cells, is inhibited by this treatment. A hapten-carrier system was used, where one group of mice was immunized with a monoclonal CR1/CR2-specific Ab and Ag (SRBC or keyhole limpet hemocyanin (KLH)), another with Ag alone, and a third group left nonimmunized. After 2 to 15 wk, spleen cells from these mice were transferred to irradiated syngeneic recipients, together with Ag coupled to the hapten 4-hydroxy-5-iodo-3-nitro-phenacetyl (NIP). The number of NIP-specific, IgG-producing B cells, which in this system is an indication of T cell priming, was determined in an ELISPOT assay. Although the primary SRBC- or KLH-specific IgG response was inhibited markedly (74-98%) by CR1/CR2-specific Ab, no decrease in the number of NIP-specific IgG-producing B cells was detected after secondary immunization. In sharp contrast, the SRBC- or KLH-specific secondary IgG responses were low or undetectable. These findings suggest that CR1/CR2-specific Ab can inhibit the primary Ab response without affecting T helper cells and that the induction of B cell memory is decreased markedly by this treatment.

Animals↗

PubMed1989

Human liver Kupffer cells express CR1, CR3, and CR4 complement receptor antigens. An immunohistochemical study.

The expression of complement receptor antigens by human Kupffer cells (KC) was investigated by immunohistochemical techniques in seven normal human liver biopsies. Polyclonal and monoclonal antibodies were revealed by double labeling of cells using indirect immunofluorescence and immunoenzymatic techniques or by using double immunoenzymatic techniques. In most experiments, one antigen was revealed by streptavidin-biotin-peroxidase complexes whose reaction product was examined by light microscopy and the second antigen stained using the alkaline phosphatase antialkaline phosphatase method visualized by fluorescence microscopy using fluorescein isothiocyanate or tetramethylrhodamine isothiocyanate filters. KC were identified using monoclonal antibody EBM11 that recognizes 100% of KC in hepatic lobules and was paired with each antibody directed against complement receptors. CR1 and CR3 (alpha- and beta-chains) were found to be the predominant receptor antigens expressed by human KC. CR4 (p150,95) was expressed on all KC, but staining with anti-CR4 monoclonal antibodies was consistently weaker than that observed with anti-CR3 antibodies. No staining of KC was observed with anti-CR2 (CD 21) antibodies. Expression of CR1, CR3, and CR4 complement receptors on KC provides the cells with an optimal capacity to bind and phagocytize particles or immune complexes coated with any type of ligands for C3 receptors.

Antibodies, Monoclonal↗

PubMed1983

Fc and complement receptor lymphocytes in the ocular tissues of rabbits immunized intravitreally with ovalbumin.

The numbers of antibody producing cells (PFC) and the percentages of Fc receptor cells (FcR) and complement receptor cells (CRL) in the ocular and lymphoid tissues of rabbits immunized intravitreally with ovalbumin were determined. Antibody-producing cells were detected first in the lymph nodes and then in the uveas and corneas. The uveal tracts contained more than 50% FcR early in the antibody response, but the percentages returned to normal levels during the second postinjection week. An apparent inverse relationship between the numbers of ocular PFC and the percentages of ocular FcR was noted. The percentages of CRL in the spleens and lymph nodes were similar to those reported by other investigators. No obvious correlation between CRL percentages in the ocular tissues and the numbers of PFC was seen. The "T-" or "B-" cell nature of the ocular FcR and their possible functions in regulating ocular immune responses are yet to be determined.

Animals↗

PubMed2001

Structure-function relationships of complement receptor type 1.

Human complement receptor type 1 (CR1) is a large, multifunctional glycoprotein which is a member of the regulators of complement activation family. Like other members of this family, it is composed mainly of tandemly arranged modules, each about 60-70 amino acids long, known as complement control protein repeats (CCPs). Each domain folds independently and contains a hydrophobic core wrapped in beta sheets. These domains mediate interactions with C3/C4-derived fragments. CR1 is the most versatile inhibitor of both classical and alternative pathway C3 and C5 convertases due to its decay-accelerating activity and co-factor activity for C3b/C4b cleavage. Moreover, CR1 plays a major role in immune complex clearance due to its high affinity for C3b and C4b. CR1 is an excellent model to study structure-function relationships because its functions are mediated by two distinct but highly homologous sites, each composed of three CCPs. CR1 derivatives carrying just one active site were used to define critical sequences/amino acids. This was achieved by testing functional profiles of the proteins carrying a mutated active site produced by substituting peptides/amino acids with their counterparts from the other site. These mutated proteins, of which we analyzed over 100, permitted the fine mapping of the functional sites. CR1 on primate erythrocytes varies in size. In most cases it is smaller and has fewer active sites than does human CR1. This variation was used to determine that increased copy number (3,000 to 20,000 versus 300 for human CR1) compensates for a smaller size. Moreover, studies of primate CR1 led to the finding that subtle differences in the critical areas, as compared to human sites, produce active sites with a broader functional repertoire. These alterations ensure that short CR1 forms possess similar biologic activities to the large CR1 forms. There is much interest in producing therapeutic agents to inhibit unwanted complement activation. Based on these structure-function analyses, smaller and more potent complement inhibitors derived from CR1 can be produced.

Amino Acid Sequence↗

PubMed2003

Regulation of B-cell activation by complement receptors CD21 and CD35.

The role of complement in the development and regulation of antibody responses under both healthy and pathological conditions is known for long. Unraveling the elements involved and the molecular mechanisms underlying the events however is still in progress. This review focuses on the role of complement receptors CR1 (CD35) and CR2 (CD21) expressed on B lymphocytes, which interact with ligands generated upon activation of component C3, the major protein of the complement cascade. The binding and possible effects of immune complexes comprising antigen, antibody and complement on B-cell activation are discussed. Results of clinical studies of autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis and conclusions drawn from animal models used to investigate various aspects of human diseases are also debated. We discuss similarities regarding the overall structure and certain functions of complement and complement receptors in mice and men however, call the attention to major differences regarding tissue distribution and their role in B-cell functions.

Animals↗

PubMed2006

CRIg: a macrophage complement receptor required for phagocytosis of circulating pathogens.

The complement system serves an important role in clearance of pathogens, immune complexes, and apoptotic cells present in the circulation. Complement fragments deposited on the particle surface serve as targets for complement receptors present on phagocytic cells. Although Kupffer cells, the liver resident macrophages, play a dominant role in clearing particles in circulation, complement receptors involved in this process have yet to be identified. Here we report the identification and characterization of a Complement Receptor of the Immunoglobulin superfamily, CRIg, that binds complement fragments C3b and iC3b. CRIg expression on Kupffer cells is required for efficient binding and phagocytosis of complement C3-opsonized particles. In turn, Kupffer cells from CRIg-deficient mice are unable to efficiently clear C3-opsonized pathogens in the circulation, resulting in increased infection and mortality of the host. CRIg therefore represents a dominant component of the phagocytic system responsible for rapid clearance of C3-opsonized particles from the circulation.

Animals↗

PubMed1982

Complement receptors of rat macrophages.

Some species, including rabbits, guinea pigs, and humans, have complement receptors on resident alveolar macrophages, whereas Swiss mice lack detectable receptors on these macrophages. Using complement-coated sheep erythrocytes or bacteria, we were unable to detect complement receptors (CR1, CR2, or CR3) on resident alveolar macrophages of male Sprague-Dawley rats. Nonelicited peritoneal macrophages from Sprague-Dawley rats had CR1 and CR3 receptors and were able to bind bacteria opsonized with complement. Resident alveolar macrophages of Long-Evans and Fisher rats lacked detectable complement receptors, but CR1 and CR3 receptors were detected on the alveolar macrophages of Lewis-Wistar rats. The reason for the lack of complement receptors on murine macrophages is not known, but studies of this phenomenon may prove useful in elucidating the role of macrophage complement receptors in the pulmonary inflammatory response.

Animals↗

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↗