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PubMed1990

Immune complex binding to erythrocyte-CR1 (CD 35), CR1 expression and levels of erythrocyte-fixed C3 fragments in SLE outpatients.

Erythrocytes (E) from a cross-sectional group of 22 outpatients with systemic lupus erythematosus (SLE) and/or mixed connective tissue disease (MCTD), the majority without active disease (n = 14), were analyzed for CR1 antigen expression and capacity to bind complement opsonized, radiolabelled immune complexes (IC). Furthermore, E-bound C3 fragments and the plasma C3d concentration were determined. E-bound C3b/iC3b fragments were not elevated in patients with SLE, whereas E from 11 out of 22 SLE patients had increased C3d levels which correlated with the plasma C3d concentration (Rs 0.73, p less than 0.001). E-fixed C3d fragments did not affect the binding of Mab or preopsonized IC to E-CR1 and were not correlated with disease activity or medical treatment. Antigen expression of E-CR1 measured by ELISA or agglutination showed positive correlation with the IC binding capacity of E-CR1 (Rs 0.92 and 0.72 respectively, p less than 001). The IC binding capacity of E-CR1 from SLE patients was significantly reduced (p less than 0.005), whereas the antigen expression of CR1 (ELISA) on E from the patients did not differ from that of E from healthy donors (p greater than 0.1). E-CR1 antigen was measured by Mab reacting with an epitope outside the IC-binding site of E-CR1. E-CR1 antigen expression or IC binding showed no correlation either with disease activity or prednisolone treatment. However, 4 og 5 patients with MCTD and 4 of 5 patients receiving Imurel were found to have low E-CR1 expression and capacity to bind IC. Thus, measurement of antigenic E-CR1 in a cross-sectional group of SLE outpatients by use of Mab reacting with an epitope outside the ligand-binding region of CR1 did not reveal a significantly reduced CR1 expression. However, an assay for CR1-mediated IC binding showed a clearly reduced E-CR1 function.

Antigen-Antibody Complex↗
PubMed2006

Erythrocyte complement receptor 1 (CR1) expression level is not associated with polymorphisms in the promoter or 3' untranslated regions of the CR1 gene.

Complement receptor 1 (CR1) expression level on erythrocytes is genetically determined and is associated with high (H) and low (L) expression alleles identified by a HindIII restriction fragment-length polymorphism (RFLP) in intron 27 of the CR1 gene. The L allele confers protection against severe malaria in Papua New Guinea, probably because erythrocytes with low CR1 expression, are less able to form pathogenic rosettes with Plasmodium falciparum-infected erythrocytes. Despite the biological importance of erythrocyte CR1, the genetic mutation controlling CR1 expression level remains unknown. We investigated the possibility that mutations in the upstream or 3' untranslated regions of the CR1 gene could control erythrocyte CR1 level. We identified several novel polymorphisms; however, the mutations did not segregate with erythrocyte CR1 expression level or the H and L alleles. Therefore, high and low erythrocyte CR1 levels cannot be explained by polymorphisms in transcriptional control elements in the upstream or 3' untranslated regions of the CR1 gene.

3' Untranslated Regions↗
PubMed2001

Mucin-like molecules as modulators of the survival and proliferation of primitive hematopoietic cells.

Current data suggest that interplay between two classes of molecules contributes to the regulation of hematopoiesis: hematopoietic growth factors, which regulate the survival, proliferation, and development of primitive hematopoietic cells and cell adhesion molecules (CAMs), which are responsible for the localization of hematopoiesis to the bone marrow (BM) and for mediating physical association between developing hematopoietic cells and marrow stromal tissue. A range of cell surface molecules representing several CAM superfamilies including integrins, selectins, the immunoglobulin gene superfamily and an emerging family of mucin-like molecules (the sialomucins) are involved in supporting cell-cell and cell-extracellular matrix (ECM) interactions between primitive hematopoietic cells and the stromal cell-mediated hematopoietic microenvironment (HM) of the bone marrow. There is abundant evidence in non-hematopoietic tissues that CAMs are signalling molecules which participate in a range of signal transduction events important not only for regulating cell adhesion and motility, but also for cell growth and survival. Although the signalling functions of CAMs have not been studied extensively in primitive hematopoietic progenitors (HPCs), extrapolation from burgeoning data in other systems is consistent with the hypothesis that hematopoiesis within the BM is regulated by interaction between signals generated locally by CAMs and those elicited by cytokines. Evidence in support of this notion was initially provided by studies on normal HPCs demonstrating cross-talk between members of the integrin superfamily and cytokine receptors. In this article we review recent reports that mucin-like molecules are also signalling molecules on primitive hematopoietic cells and that the signals they deliver potently inhibit hematopoiesis.

Animals↗
PubMed1993

A study of erythrocyte C3b receptors (E-CR1) in patients with acute viral hepatitis.

Erythrocyte C3b receptors (E-CR1) were assayed by ELISA in 16 patients with acute viral hepatitis. In 13 patients with hepatitis type A, type B, or type non-A non-B, the E-CR1 level was significantly lower in the acute phase than in healthy controls, and recovered in the convalescent phase. The E-CR1 levels in 3 patients with non-A, non-B hepatitis remained below the mean level of the healthy controls. These findings suggest that the E-CR1 level fluctuates in acute viral hepatitis, and that it continues to be reduced in some patients with non-A non-B acute hepatitis.

Acute Disease↗
PubMed2005

Formation, distribution, and elimination of infliximab and anti-infliximab immune complexes in cynomolgus monkeys.

Infliximab (IFX) is a chimeric IgG1 monoclonal antibody specific for human tumor necrosis factor-alpha that is approved in the United States and Europe for the treatment of rheumatoid arthritis (RA) and Crohn's disease (CD). Approximately 10% of RA and CD patients receiving maintenance treatment with IFX will develop antibodies to IFX. The objective of this study was to develop a model to assess the in vivo formation, distribution, and elimination of immune complexes resulting from a low-level immune response in the presence of the excess concentration of a therapeutic antigen. In this model, cynomolgus monkeys were treated with a single intravenous injection of IFX, followed by injection of either radiolabeled, purified monkey anti-IFX IgG antibody (n = 3, test group) or radiolabeled monkey, nonimmune IgG (n = 3, control group). High-performance liquid chromatography analysis of collected sera revealed a rapid formation of immune complexes comprised of IFX and radiolabeled anti-IFX IgG antibody immune complexes. The terminal half-life of the anti-IFX IgG antibody immune complex was approximately 38 h compared with 86 h for the nonimmune antibody. However, the pharmacokinetic profile of IFX, although slightly lower in concentration over time for the test group, was not notably different relative to the control group. There were no macroscopic or microscopic histological findings in either treatment group. These data confirm that immune complexes between IFX and anti-IFX IgG antibodies can form in vivo and that these immune complexes are eliminated more rapidly than nonimmune antibodies in the presence of excess IFX.

Animals↗
PubMed2000

A critical role for murine complement regulator crry in fetomaternal tolerance.

Complement is a component of natural immunity. Its regulation is needed to protect tissues from inflammation, but mice with a disrupted gene for the complement regulator decay accelerating factor were normal. Mice that were deficient in another murine complement regulator, Crry, were generated to investigate its role in vivo. Survival of Crry-/- embryos was compromised because of complement deposition and concomitant placenta inflammation. Complement activation at the fetomaternal interface caused the fetal loss because breeding to C3-/- mice rescued Crry-/- mice from lethality. Thus, the regulation of complement is critical in fetal control of maternal processes that mediate tissue damage.

Animals↗
PubMed1983

Differential activation of resident macrophage subsets with two sources of lymphokine preparations.

Resident murine macrophages were separated into subsets by Percoll density gradient centrifugation before treatment with lipopolysaccharide-stimulated lymphocytes or different lymphokine preparations. The lymphokines used were culture supernatants from lymphocytes obtained from lipopolysaccharide-injected mice or from purified protein derivative-treated lymphocytes from mice bearing an active BCG infection. The macrophage subsets were activated by the stimulated lymphocytes or lymphokine preparations to express C3b receptor-mediated ingestion or to inhibit the intracellular replication of Toxoplasma gondii or both. The results showed that the macrophage subsets were heterogeneous with respect to ingestion and T. gondii inhibition when activated with lipopolysaccharide-stimulated lymphocytes or lipopolysaccharide-derived lymphokines but were all homogeneous when activated with lymphokines from purified protein derivative-stimulated lymphocytes. When the macrophage subsets were allowed to remain in vitro for various times before lymphokine treatment, the relative pattern of subset activation changed when treated with lipopolysaccharide-derived lymphokines. In contrast, the macrophage subsets remained equally activated throughout the in vitro period when treated with the lymphokines from purified protein derivative-stimulated lymphocytes. The results suggested that functional macrophage heterogeneity depends not only on the nature of the activating signal but also on a state of receptivity of that signal by the macrophage population.

Animals↗
PubMed1983

Inhibition of neutrophil function by fluid phase C3b of complement.

A high-molecular-weight fragment of C3 was isolated from normal human serum by column chromatography, was generated by incubation of serum at 37 degrees C with inulin, and was produced from highly purified C3 by limited digestion with trypsin. This product was shown to inhibit the antibacterial function of neutrophils by using Escherichia coli O75 as the main test organism. The inhibitor reacted with anti-C3b and anti-C3c, but not with anti-C3B (anti-native C3) or anti-C3a. The manner of preparation of the inhibitor, the sodium dodecyl sulfate-polyacrylamide gel electrophoresis pattern, and the amino acid composition of the inhibitor indicated that it was fluid phase C3b. The inhibitor of neutrophil function (fluid phase C3b) was shown to bind to C3b receptors or acceptors on sheep erythrocytes in a model system.

Amino Acids↗
PubMed1988

Cutaneous host defense in leishmaniasis: interaction of isolated dermal macrophages and epidermal Langerhans cells with the insect-stage promastigote.

Leishmania species are obligate intracellular pathogens of mononuclear phagocytes. Successful infection depends on sequestration of the promastigote (insect form) within host cells, allowing transformation into the relatively hardy amastigote stage. Promastigotes are killed readily by circulating phagocytes and nonimmune serum, suggesting that cutaneous infection is initiated within a permissive cell in the epidermis or dermis. From large sections of primate skin dermal macrophages and epidermal Langerhans cells were isolated, and their interaction with promastigotes of Leishmania major was investigated in vitro. Dermal macrophages were readily infected with promastigotes, and successful transformation to and replication of amastigotes was observed. Ingestion of promastigotes by dermal macrophages was not associated with a significant respiratory burst, in contrast to that by other macrophage populations, and was associated with significantly greater survival of parasites. Stimulation of these cells with phorbol myristate acetate or opsonized zymosan revealed that those cells were generally oxidatively deficient. Langerhans cells could not be successfully infected by promastigotes under similar conditions. Examination of these cells for expression of CR3, which has been identified as a potential Leishmania receptor, revealed that Langerhans cells did not express the alpha M subunit of CR3, whereas dermal macrophages were CR3 positive. These data support the concept that dermal macrophages are the site of initiation of Leishmania infection.

Animals↗
PubMed1989

C3bi-binding protein on Candida albicans: temperature-dependent expression and relationship to human complement receptor type 3.

We investigated in detail the previously described capacity of pseudohyphae of Candida albicans to bind C3-coated particles. We show that the expression of the C3bi receptor of C. albicans was dependent upon the growth temperature of the fungi. C. albicans grown at 30 degrees C bound strongly to EAC1423bi, whereas those cells grown at 38.5 degrees C were completely devoid of this capacity. The molecule responsible for the attachment of EAC1423bi was heat labile and trypsin sensitive. Several, but not all, monoclonal antibodies to the alpha-chain of human complement receptor type 3 (CR3) stained C. albicans, and this reactivity was expressed in parallel with the capacity of C. albicans to bind EAC1423bi, i.e., both were dependent on the growth temperature of the fungi and were trypsin sensitive. In contrast to CR3, the binding of EAC1423bi to C. albicans did not require the presence of divalent cations. Rabbit immunoglobulin G antibodies directed against C. albicans inhibited the binding of EAC1423bi to C. albicans but not to human CR3. These inhibiting IgG antibodies recognized antigens expressed on the surface of pseudohyphae but not those of yeast cells. OKM-1, a monoclonal antibody to human CR3 inhibited the attachment of EAC1423bi to CR3 and also to C. albicans. OKM-1 precipitated a 130-kilodalton band from solubilized 125I-labeled C. albicans. We conclude that the complement receptors on C. albicans and human CR3 were antigenically related but not identical and that they differed in their functional characteristics.

Animals↗
PubMed1993

Isolation and biochemical characterization of the iC3b receptor of Candida albicans.

In an effort to identify the protein structure on Candida albicans, pseudohyphal forms which had been shown earlier to bind human iC3b, a protein of about 42 kDa (p42), were obtained from lysates of pseudohyphal forms by absorption with C3(H2O)-Sepharose. An antiserum raised in rabbits against this protein effectively inhibited adherence of sheep erythrocytes carrying iC3b (EAC3bi) to pseudohyphal forms. p42 cross-reacted with OKM-1, a monoclonal antibody directed against the human complement receptor type 3 (CR3, CD11b). This protein, p42, was designated p42-CR3. The antiserum against p42-CR3 was used for further purification of lysates by affinity chromatography. Three proteins of 66, 55, and 42 kDa were isolated. All were recognized by OKM-1 in immunoblots (p66-, p55-, and p42-CR3). The different proteins were separated and treated with neuraminidase and endoglycosidase F. Almost complete deglycosylation of the p66-CR3 protein was obtained after treatment with neuraminidase, indicating a high degree of glycosylation. Neuraminidase also had an effect on p55-CR3, but not on p42-CR3. Endoglycosidase F did not alter any of the three proteins. In ligand blots, p42-CR3 bound C3(H2O), C3b, and iC3b but not C3d; p55-CR3 clearly reacted with C3(H2O) and weakly reacted with C3b and iC3b. p66-CR3 never showed reactivity. It is suggested that p55 and p66 represent glycosylated forms of p42-CR3. Although C. albicans CR3 and human CR3 cross-react and bind identical ligands, the two receptors differ in structure.

Candida albicans↗
PubMed1993

Inhibition of human neutrophil migration in vitro by low-molecular-mass products of nontypeable Haemophilus influenzae.

Nontypeable Haemophilus influenzae commonly causes infections in the lower and upper respiratory tract, although the mechanisms of its colonization and persistence in the airways are unclear. Culture filtrates from six clinical isolates of this bacterium were assessed for their abilities to influence neutrophil function in vitro. Each culture filtrate was assessed on six separate occasions with neutrophils obtained from six different donors. During the log and early stationary phases of growth (0 to 18 h), culture filtrates contained primarily neutrophil chemokinetic activity but no activity affecting neutrophil migration toward the chemotactic factors N-formyl-L-methionyl-L-leucyl-L-phenylalanine and leukotriene B4. In contrast, filtrates obtained after 24 h of culture contained factors which inhibited neutrophil migration toward both of these chemotactic factors. This chemotaxis-inhibitory activity persisted between 24 and 72 h of bacterial culture, and it was not associated with the presence of either chemotactic or chemokinetic activity as assessed by checkerboard analysis. Gel filtration of pooled 72-h filtrates yielded three major peaks of chemotaxis-inhibitory activity. Endotoxin was present together with two other low-molecular-mass hydrophobic factors of approximately 8 and 2 kDa. These low-molecular-mass factors are chloroform insoluble and heat stable, and they are inactivated by protease, periodate, and diborane reduction. Activity was completely retained on a wheat germ agglutinin column, and it could be eluted with N-acetyl-D-glucosamine. These data suggest that inhibitory activity is associated with N-acetyl-D-glucosamine-containing glycopeptides, possibly derived from the bacterial cell wall. The production of these compounds may contribute to the persistence of this bacterium in vivo by inhibiting neutrophil chemotaxis in the microenvironment of the respiratory mucosa.

Biological Factors↗
PubMed1993

Capsular polysaccharide regulates neutrophil complement receptor interactions with type III group B streptococci.

The capsular polysaccharide of type III group B streptococci contributes substantially to the virulence of this organism. We explored the extent to which capsular polysaccharide influences neutrophil complement receptor interactions by using a poorly encapsulated strain (COH 31r/s), two well-encapsulated strains (M732 and M912), and strains produced from COH 31r/s by transposon mutagenesis that lacked capsule (COH 31-15) or had capsular polysaccharide lacking terminal sialic acid residues (COH 31-21). When tested with normal human serum, each strain had initially high bactericidal indices (85 to 96%). Monoclonal antibody blockade of neutrophil complement receptor 3 (CD11b/CD18) inhibited opsonophagocytosis to a significantly greater extent for the well-encapsulated strain than for the poorly encapsulated, asialo, or unencapsulated mutant strain. The addition of antibody with specificity for capsular polysaccharide reduced the inhibitory effect significantly for the encapsulated but not for the mutant strains. Blockade of neutrophil complement receptor 1 (CD35) effected only low-level inhibition. However, simultaneous blockade of complement receptors 1 and 3 augmented the inhibitory effect. When hypogammaglobulinemic serum was used as an antibody-free complement source, the initial bactericidal index was low (30% +/- 15%) for an encapsulated strain and was not affected for the mutant strains. Blockade of either neutrophil complement receptor 1 or 3 or the combination fully inhibited killing of the encapsulated strain. These results demonstrate that the type III group B streptococcal capsular polysaccharide regulates interactions with neutrophil complement receptors. We conclude that efficient phagocytic killing of encapsulated group streptococci in nonimmune serum requires ligation of complement receptors 1 and 3.

Adult↗
PubMed1993

The intracellular bacterium Rhodococcus equi requires Mac-1 to bind to mammalian cells.

Rhodococcus equi is a facultative intracellular bacterium of macrophages that causes disease in immunocompromised individuals, particularly those with AIDS. In this report, we demonstrate that R. equi binding to mammalian cells requires complement and is mediated primarily by the leukocyte complement receptor, Mac-1. Bacteria bind to macrophages poorly unless exogenous complement is added to the incubation medium. The addition of fresh nonimmune serum, which contains no detectable antibodies to R. equi, greatly enhances bacterial binding to macrophages, whereas heat inactivation of this serum or immunological depletion of C3 from the serum reduces binding to levels only slightly higher than those of binding under serum-free conditions. Human serum depleted of C2 or C4 is fully opsonic, indicating that complement activation and fixation occur by the alternative pathway. The serum-dependent binding of rhodococci to macrophages is mediated primarily by the macrophage complement receptor type 3, Mac-1 (CD11b/CD18). Bacteria do not bind to fibroblastoid or epithelial cells that lack this receptor. Most of the bacterial binding to macrophages is inhibited by a monoclonal antibody to Mac-1 but is unaffected by a monoclonal antibody to complement receptor type 1. Furthermore, opsonized, but not unopsonized, bacteria bind to purified Mac-1 immobilized on plastic. In addition, in the presence of opsonic complement, rhodococci bind efficiently to fibroblastoid cells transfected with cloned Mac-1 but relatively poorly to cells transfected with the complement receptor type 1. Hence, R. equi fixes complement by activating the alternative complement pathway, and this fixation is a requirement for bacterial adhesion and invasion. Furthermore, complement fixation defines rhodococcal host cell tropism, since R. equi binds specifically and exclusively to cells expressing Mac-1.

Animals↗
PubMed1995

Complement-independent binding of microorganisms to primate erythrocytes in vitro by cross-linked monoclonal antibodies via complement receptor 1.

Under certain circumstances, soluble antigens, particulate antigens, and/or microorganisms have been shown to bind to primate erythrocytes via complement receptor 1 (CR1) in the presence of specific antibodies and complement. This immune adherence reaction, specific for CR1, can lead to neutralization of antigens in the circulation and their subsequent clearance from the blood. The present experiments utilized cross-linked monoclonal antibody complexes (heteropolymers) with specificity for both CR1 and either 35S-labeled herpes simplex virus capsid or Haemophilus influenzae as prototype viral and bacterial particulate antigens, respectively. In each case, the respective specific heteropolymers facilitated binding of the target antigens (> or = 70 to 90%) in vitro to erythrocytes in the absence of complement. Several experimental protocols were employed to demonstrate that heteropolymers mediate specific, rapid (> or = 30 s), and quantitative binding of prototypical particulate pathogens to human and monkey erythrocytes but not to sheep erythrocytes, which lack CR1. These results extend the potential use of the erythrocyte-heteropolymer system to the neutralization and clearance of particulate viral and bacterial pathogens from the blood.

Animals↗
PubMed1996

Leishmania major-human macrophage interactions: cooperation between Mac-1 (CD11b/CD18) and complement receptor type 1 (CD35) in promastigote adhesion.

It has been suggested that the developmental maturation of Leishmania major promastigotes can affect their interaction with human complement receptors. To study this, we measured the adhesion of metacyclic and logarithmic-phase L. major promastigotes to complement receptors expressed on primary macrophages, to recombinant receptors expressed on transfected cells, or to purified complement receptors in a cell-free system. We demonstrate that complement-opsonized promastigotes can bind to both Mac-1 and complement receptor type 1 (CR1) and that the transition of promastigotes from the noninfectious logarithmic phase of growth to the infectious metacyclic stage does not affect this interaction. Furthermore, we show that Mac-1 and CR1 can cooperate to mediate the efficient adhesion of complement-opsonized metacyclic promastigotes to cells expressing both receptors. On human monocyte-derived macrophages, Mac-1 appears to make a quantitatively greater contribution to this adhesion than does CR1, since blocking macrophage Mac-1 diminishes metacyclic promastigote adhesion to a greater extent than does blocking CR1. In addition, bovine monocytes lacking Mac-1 exhibit a dramatic decrease in complement-dependent promastigote adhesion, relative to normal monocytes. The predominance of Mac-1 in these interactions is due, at least in part, to the factor I cofactor activity of CR1, which facilitates the conversion of C3b to iC3b. The stable adhesion of complement-opsonized metacyclic promastigotes to Mac-1 is a prerequisite for phagocytosis by human monocyte-derived macrophages. Blocking Mac-1 on macrophages abrogates the majority of the complement-dependent phagocytosis of promastigotes, whereas blocking CR1 has no detectable effect on phagocytosis. In addition, bovine monocytes lacking Mac-1 exhibit a dramatic reduction in promastigote phagocytosis relative to normal bovine monocytes. We conclude, therefore, that the two complement receptors, Mac-1 and CR1, can cooperate to mediate the initial complement-dependent adhesion of metacyclic promastigotes to human monocyte-derived macrophages and that Mac-1 is the predominant complement receptor responsible for the phagocytosis of complement-opsonized metacyclic promastigotes.

Adhesiveness↗
PubMed2000

Intracellular trafficking and killing of Streptococcus pneumoniae by human alveolar macrophages are influenced by opsonins.

Human alveolar macrophages (HAM) are the major resident phagocytic cells of the gas-exchanging areas of the lung. Following contact with macrophages, bacteria enter phagosomes, which gradually acquire the characteristics of terminal phagolysosomes, with incorporation of lysosome-associated membrane protein (LAMP). We measured the binding of type 1 Streptococcus pneumoniae to the surface of HAM and then measured subsequent internalization and phagosomal incorporation of LAMP-1 under various opsonic conditions. Opsonization with serum containing immunoglobulin resulted in significantly greater binding of pneumococci to HAM compared with opsonization with immunoglobulin G (IgG)-depleted serum containing complement, which in turn resulted in marginally increased binding over that observed in the absence of opsonization. Internalization of opsonized S. pneumoniae gradually increased to a maximum of 20% of bound bacteria by 120 min of warm incubation, with 20% of internalized pneumococci being localized within LAMP-containing compartments by 80 min. Internalization of opsonized S. pneumoniae by HAM correlated with a reduction of bacterial viability. When inocula were adjusted so that pneumococcal binding under different conditions was equalized, subsequent internalization, trafficking to LAMP-containing compartments, and reduction of bacterial viability were less efficient in the absence of opsonization than that observed following opsonization with adsorbed or IgG-replete adsorbed serum. Once bound to the surface of HAM, pneumococci opsonized with adsorbed serum with or without IgG were internalized, processed, and killed equally well. In conclusion, binding, intracellular trafficking, and killing of S. pneumoniae by HAM are each significantly increased by opsonization with serum containing immunogloblin and/or complement.

Antigens, CD↗