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PubMed1988

Platelet activating factor increases expression of complement receptors on human neutrophils.

The phospholipid inflammatory mediator platelet activating factor (PAF) has been shown to stimulate certain functions of polymorphonuclear leukocytes (PMN). However, the effect of PAF on surface complement receptors of PMN has not been described. Using monoclonal antibodies and flow cytometry, we have assessed the effects of PAF on surface expression of membrane receptors for C3bi (CR3) and C3b (CR1) in human PMN. PAF (optimal concentration of 1 x 10(-8) M) increased CR3 190% and CR1 174% compared with unstimulated cells at 37 degrees C, while the PAF analogue lyso-PAF had no stimulatory effect. Both CR3 and CR1 responses to PAF reached maximum levels at 15-30 min. PAF effects were comparable to peak effects induced by LTB4 but less than induced by FMLP. A PAF receptor antagonist, SRI 63-441, blocked the increased complement receptor expression in a dose-dependent manner with maximal inhibition of 80-95% at 5 x 10(-6) M. Extracellular calcium had no effect on CR1 expression but slightly enhanced and EGTA partially inhibited the PAF-induced increase in CR3 expression. Simultaneous incubation with PAF and LTB4 enhanced CR3 and CR1 expression more than either agent alone. These findings indicate that PAF, alone and in combination with LTB4, can induce altered expression of complement receptors on the surface of PMN. This effect may enhance adhesion and phagocytosis by PMN at inflammatory reaction sites.

Calcium↗
PubMed1990

Stimulus-specific effects of pentoxifylline on neutrophil CR3 expression, degranulation, and superoxide production.

The effects of pentoxifylline (Trental) on human neutrophil CR3 up-modulation, degranulation, and superoxide production were studied. We used the chemotactic peptide fMLP and the phorbol ester PMA as soluble stimuli, and beta-glucan particles as a CR3-specific solid phase stimulus of neutrophil superoxide production. Since neutrophils have adenosine A2 receptors, we compared effects of pentoxifylline to effects of adenosine, and we also looked at the effect of cytochalasin B, which breaks up actin filaments. Pentoxifylline inhibited both CR3 up-modulation and degranulation of myeloperoxidase and lysozyme. Pentoxifylline is a more potent inhibitor of fMLP- compared to PMA-induced degranulation, and is especially potent against superoxide production. While pentoxifylline is less potent than adenosine in its inhibition of fMLP-induced superoxide production, it is more potent in its inhibition of PMA- and beta-glucan particle-stimulated superoxide production. Cytochalasin B, which enhances degranulation and fMLP-stimulated superoxide production, was found to inhibit beta-glucan particle-stimulated superoxide production. These findings are consistent with the hypothesis that pentoxifylline can affect both the cytoskeletal architecture of unstimulated neutrophils and the activation and responses of neutrophils which involve actin polymerization and receptor-cytoskeletal interactions.

Adenosine↗
PubMed1992

Macrophage cytoskeleton association with CR3 and CR4 regulates receptor mobility and phagocytosis of iC3b-opsonized erythrocytes.

Alveolar macrophages (AM phi) were examined for CR1 (C3b receptor, CD35), CR3 (iC3b receptor; CD11b/CD18), and CR4 (iC3b receptor; CD11c/CD18) by assays for binding of C3-opsonized sheep erythrocytes (EC3b or EC3bi) and uptake of specific monoclonal antibodies (mAbs). In AM phi isolates from nine normal volunteers, 49% of cells bound EC3b and 71% bound EC3bi. Quantitation of receptors per cell with [125I]mAbs showed 8.5 x 10(4) CR4, 5.1 x 10(4) CR3, and 2.6 x 10(4) CR1. With most AM phi preparations, CR3 was the major receptor mediating attachment of EC3bi, despite the predominance of CR4 antigens. Anti-CR3 inhibited EC3bi rosettes by > or = 50%, whereas anti-CR4 blocked rosettes by < or = 18%. U937 cells differentiated with phorbol myristate acetate resembled AM phi in receptor expression but exhibited almost no CR4-dependent rosetting. Despite the relative inability of CR4 to mediate EC3bi attachment, AM phi ingestion of [51Cr]EC3bi was blocked by either anti-CR3 or anti-CR4. Two lines of evidence indicated that CR3 were more mobile within the membrane than were CR4. Immunofluorescence staining demonstrated patching and occasional capping of CR3, whereas CR4 remained uniformly distributed. This patching and capping of CR3 required the actin cytoskeleton, as it was inhibited by cytochalasin D. Modulation experiments using surfaces coated with anti-CR3 or anti-CR4 also showed that CR3 was more mobile than was CR4. However, there was some variation among AM phi isolates from different donors. In seven isolates, no CR4 modulation was produced with anti-CR4, whereas in six other isolates, CR4 was modulated by 66%. Incubation of cells in cytochalasin D increased modulation of both CR3 and CR4 on mAb-coated surfaces. Cells exhibiting increased mobility of CR4 showed an increased ability to form CR4-dependent EC3bi rosettes. The data are consistent with the hypothesis that CR3 and CR4 exhibit a variable association with the cytoskeleton that regulates their mobility and function. A relatively mobile subset of CR3 and/or CR4 mediates EC3bi attachment, whereas a relatively immobile subset of CR3 and/or CR4 fails to mediate EC3bi attachment but functions to promote ingestion of EC3bi.

Antigens, CD↗
PubMed1993

Quartz selectively down-regulates CR1 on activated human granulocytes.

We have investigated the interaction between quartz and granulocytes with respect to complement receptor expression. When N-formylmethionyl-leucyl-phenylalanine (fMLP)-stimulated leukocytes were exposed to quartz at 37 degrees C, CR1 was down-regulated but CR3 was not affected. This was a direct effect on granulocytes because it occurred in a similar fashion when mixed leukocyte suspensions and isolated granulocyte populations were used as targets for quartz. The observed down-regulation by quartz was not affected by the microfilament-disrupting agent cytochalasin B and the total detectable pool of CR1 was reduced after quartz exposure. When protease inhibitors, such as aprotinin or phenylmethanesulfonyl fluoride, were present during quartz exposure, the down-regulation of CR1 was less pronounced, but this was not the case not when protease inhibitors such as EDTA-Na2 and pepstatin were present. Exposure to quartz was not accompanied by a pronounced release of beta-glucuronidase (marker for the primary granules) or vitamin B12 binding protein (marker for the secondary granules). In contrast to quartz, exposure to alumina did not affect the expression of CR1 and CR3. The spontaneous mobilization of CR1 at 37 degrees C was reduced when quartz was present but the CR3 mobilization was unaffected. Our results indicate that quartz induces a granule protease-dependent selective shedding of CR1 but not CR3 despite a low degree of degranulation.

Aprotinin↗
PubMed1996

Cooperation between CR1 (CD35) and CR3 (CD 11b/CD18) in the binding of complement-opsonized particles.

We analyzed the binding of sheep erythrocytes bearing C3b (EC3b) to cells transfected with human complement receptors. EC3b bound avidly to cells expressing CR1 but failed to bind to cells expressing CR3. In the presence of factor I, the binding of EC3b, to CR1 was transient. Primary monocytes and cotransfected cells expressing both CR1 and CR3 mediated a stable resetting of EC3b, even in the prolonged presence of factor I. This stable adhesion was dependent on the presence of CR3, because blocking CR3 with mAb resulted in the factor I-dependent release of erythrocytes from these cells. A model is proposed in which these two complement receptors cooperate in a unique manner. These results suggest that the stable adhesion of complement-opsonized particles to cells expressing CR1 and CR3 is actually a dynamic molecular process in which an important function of leukocyte CR1 is to generate the ligands for CR3.

Animals↗
PubMed1996

Effects of released products from platelets on neutrophilic adhesion to endothelial cells and nylon fibers.

In this study, the effects of platelet release products (PRPr), ATP, and ADP on the adhesion of human neutrophils to human umbilical vein endothelial cells (HUVEC) and nylon fibers (NF) are described and the implications of various adhesion molecules are considered. Adhesion of neutrophils to HUVEC and NF was increased by PRPr, ATP, and ADP, while their adhesion-increasing actions were cancelled or considerably repressed by apyrase treatment. When anti-CD11a or anti-CD11b was added to neutrophils with PRPr, ATP, or ADP, the adhesion-increasing action was cancelled or considerably repressed. On the other hand, anti-ICAM-1 and anti-CD35 had no significant effects on this action. The above results indicated that platelets, through ATP and ADP in PRPr, increased the adhesion of neutrophils to endothelial cells and foreign bodies. Although it was suggested that the adhesion-increasing action was at least partially based on CD11a and CD11b, ICAM-1 and CD35 had no part in the enhancement of the adhesion.

Adenosine Diphosphate↗
PubMed1997

Neutrophils from burn patients are unable to increase the expression of CD11b/CD18 in response to inflammatory stimuli.

Neutrophils (PMNs) from patients with thermal injury are dysfunctional for the CD11b/CD18-dependent functions of diapedesis, chemotaxis, and phagocytosis. The expression of CD11b/CD18 on normal PMNs is increased after an inflammatory stimulus. We proposed that CD11b/CD18 expression on burn patient PMNs would respond abnormally to inflammatory stimuli. PMNs were obtained from nonseptic burn patients during the second week after thermal injury. PMNs from burn patients incubated with lipopolysaccharide (LPS), N-formyl-methionyl-leucyl-phenylalanine, phorbol myristate acetate, or A23187 did not increase the expression of CD11b/CD18 to the same degree exhibited by normal PMNs. This inability to increase CD11b/CD18 was not due to differences in CD14 receptor expression, LPS binding, or factors present in the serum of burn patients. The upregulation of CD35 also was decreased on burn patient PMNs. Western blot analysis revealed decreased quantities of CD11b protein in burn patient PMNs compared with normal control PMNs. The deficiency in CD11b/CD18 expression after inflammatory stimuli may explain some of the abnormalities observed in burn PMN function.

Burns↗
PubMed1999

Soluble complement receptor 1 is increased in patients with leukemia and after administration of granulocyte colony-stimulating factor.

Complement receptor type 1 is expressed by erythrocytes and most leukocytes. A soluble form is shed from the leukocytes and found in plasma (sCR1). sCR1 is a powerful inhibitor of complement. We report an increased sCR1 in the plasma of leukemia patients, up to levels producing measurable complement inhibition. Half of the 180 patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CLL) had sCR1 levels above the normal range. The highest levels were observed in T-ALL (17 patients). The complement function of a T-ALL serum was improved by blocking sCR1 with a specific mAb (3D9). Measurements in 16 peripheral stein cell donors before and after granulocyte colony-stimulating factor (G-CSF) administration showed an increase in sCR1 (before, 43.8+/-15.4; at day 5, 118.3+/-44.7 ng/mL; P < 0.0001). This increase paralleled the increase in total leukocyte counts and was concomitant with de novo leukocyte mRNA CR1 expression in all three individuals tested. Whether pharmacological intervention may be used to up-regulate sCR1 so as to inhibit complement in vivo should be further investigated.

Animals↗
PubMedDate not supplied

Targeting with scFv: immune modulation by complement receptor specific constructs.

The fate of a microbe in the host is determined by various molecules of the innate immune system, which recognize the microbe and enhance its interaction with antigen presenting cells. This 'natural targeting' phenomenon, however, does not function when antigens with limited immunogenicity enter the host. Peptide vaccines, for instance, require adjuvants to induce immune responses. As a surrogate for the natural targeting mechanisms, antibodies against selected receptors of antigen presenting cells, conjugated with the peptides, could be used as targeting devices. Here we review various antibody-mediated antigen-targeting strategies, paying special attention to complement receptor-mediated targeting. We also describe and summarize our method of single-chain antibody-mediated targeting of viral epitopes to complement receptor type two and discuss the perspectives of single-chain antibody-mediated antigen targeting.

Adjuvants, Immunologic↗
PubMed1994

Molecular cloning of the rat complement regulatory protein, 5I2 antigen.

We have cloned a cDNA which encoded for rat complement regulatory protein, 5I2 antigen. The deduced amino acid sequence of 497 residues predicted essentially the same domain structure as the mouse complement regulatory protein, Crry/p65, composed of five short consensus repeat (SCR) domains, a transmembrane domain and a cytoplasmic domain. 5I2 antigen, however, had an additional SCR which showed a close similarity to the sixth SCR of mouse complement receptor 1 (CR1) or to the sixth, thirteenth, twentieth and twenty seventh SCR of human CR1. Corresponding domains of 5I2 antigen and mouse Crry/p65 showed 70%-86% amino acid identity, indicating that 5I2 antigen is the rat counterpart of mouse Crry/p65.

Amino Acid Sequence↗
PubMedDate not supplied

The mechanism of loss of CR1 during maturation of erythrocytes is different between factor I deficient patients and healthy donors.

During the in vivo maturation of erythrocytes, the number of CR1 per cell decreases by approximately two-thirds in 30 days. The CR1 loss is enhanced in several diseases such as SLE, AIDS, and particularly in factor I deficiency. Microvesicles enriched in CR1 and DAF are released from erythrocytes matured in vitro, leading to the same loss of both molecules. When comparing reticulocytes and erythrocytes, CR1 and DAF were lost similarly in 15 normal individuals, suggesting that vesiculation may be at the origin of CR1 loss in vivo. However, the enhanced loss of CR1 in 3 patients with factor I deficiency was contrasted with a normal loss of DAF, raising the possibility that, in this pathological condition, CR1 might be proteolytically cleaved, leaving small CR1 fragments on the erythrocytes. To answer this question, a rabbit polyclonal antibody was raised against the cytoplasmic (tail) domain of CR1, which recognised specifically CR1 of erythrocytes and urinary vesicles on Western blots. However, no CR1 fragments could be detected on erythrocytes of the factor I deficient patients although this antibody was able to recognise CR1 fragments after treatment of normal erythrocytes or urinary vesicles with elastase. These data suggest that cell surface domains rich in CR1, but not in DAF, are specifically lost in factor I deficiency.

Afibrinogenemia↗
PubMed1995

Expression of the CR1 receptor on human leukemia-derived CD4+ T cell lines.

The complement receptor type 1 (CR1) is a membrane glycoprotein expressed on a variety of cells including some, but not all, human T lymphocytes. The present study was designed to investigate CR1 expression on human leukemia-derived CD4+ T cell lines. The expression of CR1, as well as the complement receptor type 2 (CR2) and membrane cofactor protein (MCP), were analyzed on cells from the SUP-T1, CEM-SS, HUT-78, and MOLT-3 cell lines by flow cytometry. All four cell lines expressed CR2 and MCP, but only the SUP-T1 cell line contained CR1+ cells. Within the SUP-T1 cell line, a mean of 8.5% of the cells were CR1+. Scatchard analysis indicated that approximately 2700 CR1 molecules were expressed per CR1+ SUP-T1 cell, a value that corresponds to the quantitative expression of CR1 on normal peripheral blood T lymphocytes. Separation of CR1+ and CR1- cells within the SUP-T1 cell line by flow cytometry and subsequent reculture of the sorted cells showed that both the enriched CR1+ and the enriched CR1- cell populations returned to a mixed CR1 phenotype over time. These data suggest that SUP-T1 cells can express CR1, but only transiently. Two-color flow cytometric analysis indicated that the expression of CR1 by SUP-T1 cells did not fluctuate with the cell cycle. SUP-T1 cells were also cultured in the presence of agents known to activate T cells. Phytohemagglutinin and phorbol 12-myristate 13-acetate induced a transient increase in the percentage of SUP-T1 cells expressing CR1, compared to cells cultured in media alone. These results suggest that CR1 expression is up-regulated during T cell activation. The CR1+ SUP-T1 cell line, as well as the CR1- cell lines, may provide useful models for investigating how CR1 expression is regulated and for exploring a possible role for CR1 in the pathogenesis of AIDS.

CD4-Positive T-Lymphocytes↗
PubMed1999

Antiinflammatory effects of soluble complement receptor type 1 promote rapid recovery of ischemia/reperfusion injury in rat small intestine.

We examined the effect of soluble complement receptor type 1 (sCR1) on mucosal injury and inflammation in a rat model of ischemia/reperfusion. Groups of vehicle- and sCR1-treated rats underwent 30 min of mesenteric ischemia followed by 60 or 120 min of reperfusion. When compared to vehicle-treated rats, treatment with sCR1 (12 mg/kg) prior to 120 min of reperfusion significantly reduced mucosal injury, neutrophil infiltration, leukotriene B4 production, and restored villus height to control levels. The protective effect of sCR1 evident at 120 min of reperfusion was not observed at 60 min of reperfusion despite rapid inactivation of complement. These data suggest that complement inhibition minimized mucosal disruption by facilitating mucosal restitution or interrupting the inflammatory process. Delayed administration of sCR1 for 30 or 60 min into the reperfusion period progressively reduced the protection. sCR1-mediated rapid recovery of rat intestine after ischemia/reperfusion underscores the fundamental role of complement activation in neutrophil-mediated tissue injury.

Animals↗
PubMed1999

Infusion of bispecific monoclonal antibody complexes into monkeys provides immunologic protection against later challenge with a model pathogen.

Heteropolymers (HP), bispecific mAbs which bind target pathogens to primate erythrocytes via complement receptor 1, facilitate clearance of pathogens from the bloodstream by targeting them for destruction in the liver without causing lysis or clearance of the erythrocytes. We show that when HP prepared with mouse IgG are intravenously infused into monkeys one or more times prior to exposure to a prototype pathogen, they bind to erythrocytes and remain in the circulation long enough to act as "sentinels," preventing pathogen invasion of the bloodstream. The effectiveness of HP as sentinels is limited both by the monkey's immune response to the HP and, prior to the immune response, by a gradual loss of the HP from monkey erythrocytes over a period of 1 week, and we have investigated possible causes of this HP loss. In overview, our results suggest that HP prepared with mouse IgG are able to effectively function as sentinels for a minimum of 4 days and, after repeat infusion, possibly for up to 2 weeks.

Animals↗
PubMed2002

Evaluation of antigen-based heteropolymer for treatment of systemic lupus erythematosus in a nonhuman primate model.

Autoantibodies that react with double-stranded DNA (dsDNA) are a hallmark for diagnosis of systemic lupus erythematosus (SLE) and are also considered the pathogenic subset that is most associated with lupus nephritis. As an agent to remove the pathogenic dsDNA antibodies from the circulation of SLE patients, we are developing an antigen-based heteropolymer (AHP). The AHP consists of a monoclonal antibody to the complement receptor (CR1) cross-linked to salmon testis dsDNA to effect clearance of anti-DNA antibodies by binding them to erythrocyte CR1. Utilizing a cynomolgus monkey model for SLE in which we infused plasma from SLE patients containing a high titer of high-avidity anti-dsDNA antibody, we have evaluated the safety and efficacy of AHP infusion. The results demonstrate that AHP rapidly (within 2 min of infusion) binds to monkey erythrocytes without causing any toxicological effects. We also demonstrate that human Ig (G+M) antibodies are rapidly bound to the AHP-erythrocyte complex. These events are mirrored in their kinetics by a substantial drop in the level of high-avidity dsDNA antibody in the plasma.

Animals↗
PubMed1993

Implication of membrane factors other than DAF and CD59 in complement-mediated lysis of paroxysmal nocturnal hemoglobinuria erythrocytes.

Erythrocytes from two patients (F.K. and A.M.) with paroxysmal nocturnal hemoglobinuria, which were almost completely deficient in decay-accelerating factor and CD59, were found to differ in their susceptibility to homologous complement. Whereas 50-70% of F.K. erythrocytes were lysed, almost 100% of the erythrocytes from A.M. were lysed. These observations were seen under both acidified and nonacidified conditions, and regardless of whether or not the normal human serum was adsorbed with normal erythrocytes to remove natural antibodies. Erythrocytes from two other patients, J.S. and Y.K., about 85% of which did not express CD59, showed lytic profiles similar to those of patient F.K. The differences between patients were not related to levels of natural antibody or other membrane regulatory proteins such as complement receptor type I or membrane cofactor protein. Erythrocytes from F.K. and A.M. differed in their reconstitution with decay accelerating factor and CD59. While erythrocytes from F.K. were reconstituted with CD59 in a unimodal pattern, erythrocytes from A.M. showed a bimodal pattern of reconstitution assessed by flow cytometry. After reconstitution with CD59, erythrocytes from F.K. and A.M. differed in their protection against homologous complement. It is concluded that erythrocyte membrane constituents other than the known inhibitors differ in these patients.

Antigens, CD↗
PubMed1994

Selective, prolonged alteration of complement-mediated immune clearance after acute exposure of mice to ethanol.

A selective and prolonged alteration in complement-mediated immune clearance was found in mice given a single intraperitoneal injection of ethanol. Rate constants for the separate components of complement- and IgG Fc gamma-mediated clearance were determined using a branched series, first-order reaction sequence model and measurements of the disappearance of radiolabeled IgG-opsonized murine erythrocytes from the circulation of BALB/c mice. The rate constant governing immune clearance mediated by IgG Fc gamma receptors (k3) decreased to 16% of control at 1 hr after ethanol injection but returned to normal in 72 hr. A > 50% decrease in complement-mediated clearance occurred, with a nadir of complement-mediated sequestration (k1) and complement-dependent phagocytosis (k4) at 1 hr (P < 0.001). In this case, however, k1 and k4 rate constant values did not return to control levels until 6 weeks after the injection of ethanol. The rate constant governing C3b deactivation and release of deactivated, sensitized cells back to the circulation before they undergo phagocytosis (k2) was initially normal, but decreased in Week 6 and remained low to the end of the observation period at 22 weeks (P < 0.0001). These changes resulted in a major reduction in overall complement-mediated immune clearance up to 4 weeks after the ethanol injection. The change to normal rates for sequestration and phagocytosis coupled with decreased deactivation and release at 6 weeks postinjection resulted in a small increase in overall complement-mediated clearance that persisted through Week 22.

Alcohol Dehydrogenase↗
PubMed1994

Relationship between immune complex binding and release and the quantitative expression of the complement receptor, type 1 (CR1, CD35) on human erythrocytes.

Primate erythrocytes (E) play a central role in clearing potentially pathogenic immune complexes (IC) from the circulation. E capture circulating IC via interaction between C3b and C4b sites, generated on the IC during activation of the complement cascade, and the complement receptor, type 1 (CR1), expressed on E. IC are released from E when C3b and C4b sites on the IC are cleaved by Factor I. The goal of this study was to examine the interactions between human E and model IC in the context of quantitative variations in CR1 expression. IC were prepared by combining murine monoclonal IgG1, IgG2b, or IgG3 anti-dinitrophenyl (DNP) antibodies with DNP-bovine serum albumin. The expression of CR1 on E, obtained from eight healthy donors, was quantified by radioimmunoassay and Scatchard analysis. On the basis of quantitative CR1 expression, preparations of E obtained from different donors at various times were categorized into phenotypic groups expressing high, intermediate, or low numbers of CR1. While there was some variation in the expression of CR1 of individual donors, five of the eight donors remained within the same phenotypic group upon repeated sampling. Surprisingly, when interactions between IC and E were examined in vitro, there was no direct relationship between the number of CR1 per E and the peak magnitude of IC binding to E. When peak binding and release rates were calculated, there was a direct correlation between the number of CR1 per E and the peak binding rate of IC constructed with IgG3 antibodies (IgG3 IC). In addition, there was an inverse correlation between the number of CR1 per E and the peak release rate of IgG2b IC. There was no direct correlation between the quantitative expression of CR1 on E and the peak binding or release rates of IgG1 IC. These data indicate that the quantitative expression of CR1 can affect the interactions between IC and E, but that these interactions are also dependent upon the immunochemical properties of the IC. These findings may be relevant to the pathogenesis of diseases, including systemic lupus erythematosus and AIDS, in which E express reduced numbers of CR1.

Antigen-Antibody Complex↗