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PubMed1987

Inherited deficiency of erythrocyte complement receptor type 1 does not cause susceptibility to systemic lupus erythematosus.

There is a deficiency of complement receptor type 1 (CR1) on the erythrocytes of patients with systemic lupus erythematosus (SLE). This receptor is involved in the processing of immune complexes. Whether the deficiency is inherited or acquired has been the subject of controversy. A restriction fragment length polymorphism (RFLP), identified using a complementary DNA probe for CR1, has been correlated with the numeric expression of CR1 on normal erythrocytes. The gene frequency for the 2 alleles defined by this RFLP was compared in 44 patients with SLE (from 42 families), 43 of their consanguineous relatives, and 50 nonrelated normal subjects. The gene frequency for the alleles correlating with high and low expression of CR1 was 0.73 and 0.27, respectively, in the normal subjects. The gene frequency was not significantly different in the SLE patients. However, the SLE patients expressed fewer CR1 molecules per erythrocyte within each genotype, compared with normal subjects and compared with their consanguineous relatives. The low allele for numeric expression of CR1 on erythrocytes is not a disease susceptibility gene for SLE.

Alleles↗
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↗
PubMed1997

Mouse complement receptors type 1 (CR1;CD35) and type 2 (CR2;CD21): expression on normal B cell subpopulations and decreased levels during the development of autoimmunity in MRL/lpr mice.

Human complement receptors type 1 (hCR1;CD35) and type 2 (hCR2;CD21) are expressed on B lymphocytes at specific stages during differentiation and activation. These receptors play critical roles in the immune response to T-dependent Ags in addition to germinal center formation. Expression of both hCR2 and hCR1 is decreased on B lymphocytes of patients with systemic lupus erythematosus (SLE). We have studied the expression of mouse CR2 and CR1 on normal populations of mouse B lymphocytes in BALB/c mice. Our results demonstrate that expression of these receptors in the normal state closely parallels that of hCR2. During bone marrow development, expression is first detected on low B220/high IgM cells, demonstrating that complement receptors appear after central tolerance mechanisms are completed. In the splenic microenvironment the highest levels of receptor expression are found on marginal zone B lymphocytes. Mouse CR2 and CR1 are also found on peritoneal B1a and B1b cells in addition to IgA+ Peyer's patch B cells. Activation of splenic B cells under Th2 conditions results in a marked decrease in receptor expression. To determine whether the patterns of receptor expression also parallel those found in human disease, we studied the MRL lpr/lpr (MRL/lpr) model of SLE. Interestingly, we found an early decrease in complement receptor expression that is progressive and first detectable before major clinical manifestations of nephritis. We hypothesize that the early decrease in complement receptor expression such as that demonstrated by MRL/lpr mice plays an important role in the pathogenesis of murine and perhaps human SLE.

Animals↗
PubMed1995

Complement receptors in neutrophils.

Human neutrophils contain numerous intracellular granules and vesicles that are exocytosed in a hierarchic manner on stimulation of the neutrophil with inflammatory mediators. Secretory vesicles are mobilized completely to the plasma membrane when neutrophils are stimulated with inflammatory mediators in nanomolar concentrations. There is evidence that secretory vesicles contain at least four different complement receptors, namely, C1qR, CR1, CR3, and CR4. These complement receptors are all transported to the neutrophil surface in parallel by the mobilization of secretory vesicles. A fifth complement receptor, C5aR, is constitutively present on the neutrophil plasma membrane. Because secretory vesicles are mobilized by virtually all inflammatory mediators known to stimulate neutrophils, a prompt upregulation of complement receptors is ensured early in neutrophil activation. The integrins CR3 and CR4 are located both in secretory vesicles and granules, and this diverse subcellular localization may reflect their functional versatility. The residence of complement receptors in several intracellular compartments ensures a graded upregulation of these receptors in response to stimulation.

Humans↗
PubMed1974

Ontogeny of B lymphocytes. 3. H-2 linkage of a gene controlling the rate of appearance of complement receptor lymphocytes.

The frequency of lymphocytes bearing complement receptors in the spleens of 2-wk old mice appears to be controlled by two independent genes. The presence of a "high" allele at either locus leads to intermediate or high frequency of CRL at 2 wk of age. One of the genes controlling complement receptor lymphocyte (CRL) frequency (CRL-1) is linked to the H-2 complex. Thus, in progeny of (AKR x DBA/2)F(1) x DBA/2, all mice with a low frequency of CRL at 2 wk of age are homozygous for the H-2 type of the low CRL parent (DBA/2). Furthermore, in the B10 series of congenic mice, CRL frequency at 2 wk of age is similar to the frequency in the donor of the H-2 region. Thus, C57BL/10, B10.BR, and B10-D2 mice are all of the low CRL type while B10.A mice are intermediate in CRL frequency at 2 wk. C57BR and DBA/2, the donors of the H-2 complex of the B10.BR and B10.D2, respectively, are of low CRL type while the A/WySn, the donor of the H-2 complex in the B10.A, is an intermediate CRL strain. Similarly in the A/WySn series of congenic mice, A.CA, A.SW, and A.BY are all low CRL strains while the A/WySn is intermediate. Studies of CRL frequency in mice with recombinant H-2 chromosomes (B10.A(2R), (4R), and (5R); B6/TL(+); and A/TL(-)) indicate that CRL-1 is to the right of the Ss-Slp genes and to the left of Tla.

Age Factors↗
PubMed1990

The role of the type 3 complement receptor in the induced recruitment of myelomonocytic cells to inflammatory sites in the mouse.

The type 3 complement receptor (CR3), initially identified as the leukocyte cell surface receptor for iC3b, is now known to form part of the extended integrin family of cell adhesion molecules that mediate both cell-cell and cell-extracellular matrix interactions. The identification of a heritable deficiency of human leukocyte adhesion together with the advent of monoclonal antibodies has shed some light on the central role of CR3 in the transendothelial migration of macrophages and neutrophils to sites of inflammation. We review the general structural features of CR3 and then examine our understanding of its role in both nonspecific and T cell-dependent inflammatory processes based on our murine in vivo experiments. CR3-dependent inflammation seems to contribute to the pulmonary response to some stimuli (lipopolysaccharide) but not to others (bacillus Calmette-Guerin). These studies highlight the potential therapeutic benefits, as well as the significant risks of potentiating acute bacterial infections, of CR3 blockade in vivo.

Animals↗
PubMed1995

Decreased levels of complement receptor 1 (CD35) on B lymphocytes in persons with HIV infection.

Previous studies have shown that complement receptor 1 (CR1) expression on erythrocytes is decreased under several conditions including HIV infection and autoimmune diseases. The goal of this study was to determine whether expression of CR1 on peripheral blood B cells, where this receptor plays a role during immune responses, is altered in persons with HIV infection. The B cells from rheumatoid arthritis (RA) patients were also assessed since this represents a group with known complement and B cell abnormalities. The CD19+ B cells from persons with either HIV infection or RA had significantly reduced levels of CR1 when compared with control donors (75 and 72% CR1+ versus 94% CR1+ for control donors). The reduction of B cell CR1 occurred in both the percentage of B cells positive for CR1 and the levels of CR1 found on positive cells. In contrast, CR1 on monocytes was not reduced. As shown in previous studies, CR2 was also found to be reduced on B cells from the HIV-infected persons and there was extensive overlap between the B cell subsets which lacked expression of CR1 and CR2. The complement receptor-negative B cells found in HIV-infected persons were not immature or activated as defined by their lack of expression of CD10 or B7, respectively. Elevated levels of C4d, a classical complement pathway-activation product, were detected in plasma from both HIV-infected and RA patients. These studies suggest that chronic complement activation occurring in persons with HIV infection or RA can affect the complement receptor phenotype of peripheral blood B cells. Since complement receptors are involved in activation of B cells, the subset that lacks CR1 may represent cells that have encountered immune complexes and may therefore be stimulated. Additionally, the downregulation of complement receptors may have significant effects on the ability of B cells to capture and present opsonized antigens.

Antigen-Antibody Complex↗
PubMed1994

Tissue-specific Fc gamma and complement receptor expression by alveolar macrophages determines relative importance of IgG and complement in promoting phagocytosis of Pseudomonas aeruginosa.

Because the expression of IgG Fc receptors and complement receptors on macrophages may vary in a tissue-specific manner, we used monoclonal antibodies and flow cytometry to define the expression and function of opsonin receptors on fresh normal and cystic fibrosis (CF) bronchoalveolar lavage (BAL) macrophages. Using flow cytometry to separately analyze individual types of cells, we then determined the relative contributions of IgG and complement to phagocytosis of Pseudomonas aeruginosa by fresh BAL cells, avoiding alterations in receptor expression due to in vitro purification or culturing techniques. Neither normal nor CF BAL macrophages express appreciable amounts of the complement receptors CR1, CR2, or CR3. These results were confirmed by immunohistochemical staining of fixed lung sections. BAL macrophages express a high-affinity IgG receptor, Fc gamma RI, that is not found on neutrophils (PMN). In contrast, chemoattractant-stimulated blood PMN express large amounts of CR1 and CR3 but do not express Fc gamma RI. These results correlate with phagocytosis assays, which show that phagocytosis by macrophages is enhanced by relatively low concentrations of IgG but that the addition of complement does not further increase their phagocytosis. In contrast, low concentrations of IgG alone do not promote phagocytosis by PMN, whereas addition of complement markedly enhances phagocytosis by PMN. These results may explain the previously reported sensitivity of macrophages rather than PMN to the "blocking" effects of anti-Pseudomonas antibodies from CF patients, and emphasize the pathologic significance of interference with IgG and complement mediated opsonization in the lung in CF.

Adolescent↗
PubMed1990

Complement-mediated antibody-dependent enhancement of HIV-1 infection requires CD4 and complement receptors.

In this study it is demonstrated that complement-mediated antibody-dependent enhancement (C'-ADE) of HIV-1 infection in vitro is blocked by murine monoclonal antibodies to CD4 and complement receptor type 2 (CR2) while HIV-1 infection in the absence of C'-ADE is blocked by anti-CD4 but not anti-CR2 monoclonal antibodies. The anti-CR2 murine monoclonal antibody, OKB7, blocked C'-ADE of HIV-1 infection at concentrations greater than 1 microgram/ml. The anti-CD4 monoclonal antibody, OKT4a, but not OKT4f blocked C'-ADE at concentrations greater than 0.06 microgram/ml. HIV-1 infections were quantitated by cytopathic effect, indirect immunofluorescence, and reverse transcriptase release. It appears from these in vitro studies that C'-ADE of HIV-1 infection requires both CD4 and complement receptors while HIV-1 infection in the absence of antibody and complement requires only CD4.

Antibodies, Monoclonal↗
PubMed2006

The complement receptor 1, CR1 (CD35), mediates inhibitory signals in human T-lymphocytes.

The modulation the specific, adaptive immune response by complement, particularly of by complement C3, is mainly attributed to its interaction with complement receptors on B-lymphocytes. The function of complement receptors on T-lymphocytes, in contrast, is less well understood, although expression of the complement receptor (CR)1 and CR3 on T-cells has been described years ago. In the present study we investigated the effect of antibodies to CR1 on T-cell lines and peripheral T-cells of healthy donors, respectively. Antibodies to CR1 profoundly inhibited the proliferation of the T-cells; of note is, that exogenously added interleukin 2, though enhancing proliferation, did not overcome the inhibitory effect mediated by anti-CR1. While anti-CR1 had no effect on the activation of the immediate early genes c-jun or c-fos nor on the early increase of gamma interferon- or interleukin 2-specific RNA, the protein synthesis of those cytokines was inhibited. Moreover, synthesis of the proliferating cell nuclear antigen (PCNA) was reduced as was the expression of cyclins, particularly of cyclin A and cyclin D3. Taken together, the data indicate that triggering CR1 inhibits proliferation of T-lymphocytes by a mechanism operating downstream of the initial signalling events.

Cell Cycle↗
PubMed1996

Effects of inhibition of complement activation using recombinant soluble complement receptor 1 on neutrophil CD11b/CD18 and L-selectin expression and release of interleukin-8 and elastase in simulated cardiopulmonary bypass.

The inflammatory response to cardiopulmonary bypass includes activation of complement and induction of several neutrophil activation pathways. A recombinant soluble form of complement receptor 1 was used as a specific inhibitor of complement activation in simulated cardiopulmonary bypass circuits. Substantial complement activation was observed in these circuits with progressive accumulation of both plasma C3a and terminal complement complex. Soluble complement receptor 1 resulted in a significant reduction in C3a levels (p < 0.01) but did not inhibit terminal complement complex generation. A marked rise in neutrophil CD11b/CD18 expression, simultaneous loss of L-selectin expression, and a progressive accumulation of plasma elastase-alpha 1-antitrypsin occurred and were not affected by soluble complement receptor. However, generation of interleukin-8 in the circuits was inhibited (p < 0.05) by pretreatment with soluble complement receptor. These data suggest that changes in neutrophil activation seen during cardiopulmonary bypass may not be induced directly by anaphylatoxin generation.

CD11 Antigens↗
PubMed2000

Complement receptor 1/CD35 is a receptor for mannan-binding lectin.

Mannan-binding lectin (MBL), a member of the collectin family, is known to have opsonic function, although identification of its cellular receptor has been elusive. Complement C1q, which is homologous to MBL, binds to complement receptor 1 (CR1/CD35), and thus we investigated whether CR1 also functions as the MBL receptor. Radioiodinated MBL bound to recombinant soluble CR1 (sCR1) that had been immobilized on plastic with an apparent equilibrium dissociation constant of 5 nM. N-acetyl-d-glucosamine did not inhibit sCR1-MBL binding, indicating that the carbohydrate binding site of MBL is not involved in binding CR1. C1q inhibited MBL binding to immobilized sCR1, suggesting that MBL and C1q might bind to the same or adjacent sites on CR1. MBL binding to polymorphonuclear leukocytes (PMNs) was associated positively with changes in CR1 expression induced by phorbol myristate acetate. Finally, CR1 mediated the adhesion of human erythrocytes to immobilized MBL and functioned as a phagocytic receptor on PMNs for MBL-immunoglobulin G opsonized bacteria. Thus, MBL binds to both recombinant sCR1 and cellular CR1, which supports the role of CR1 as a cellular receptor for the collectin MBL.

Binding Sites↗
PubMed1987

Studies on human blood lymphocytes with iC3b (type 3) complement receptors. II. Characterization of subsets which regulate pokeweed mitogen-induced lymphocyte proliferation and immunoglobulin synthesis.

Human blood lymphocytes that express Type 3 complement receptors (CR3) can be divided into a major subset with high density Fc receptors for IgG (FcR) identified with the monoclonal antibody Leu 11 and two minor subsets which display either CD8 (Leu 2) or CD4 (Leu 3) markers. We isolated CR3+ lymphocyte subsets and examined them for regulatory effects on pokeweed mitogen (PWM) stimulated cells. The FCR CR3+ cell suppressed PWM-induced proliferation and Ig production. Pretreatment of these lymphocytes with immune complexes was required to suppress proliferation, but not IgG production. The CR3+ Leu 2+ FCR- subset also had suppressive activity, but this effect was not observed unless the CR3+ Leu 3+ enriched subset was removed. In fact, the CR3+ Leu 3+ enriched subset enhanced IgG synthesis. Brief exposure of CR3+ lymphocytes to recombinant interleukin 2, recombinant alpha-interferon, but not gamma-interferon, markedly enhanced the inhibitory effect. Time course studies and a comparison of inhibition of Ig synthesis with natural killer cell activity suggested that CR3+ lymphocytes act shortly after lymphocytes are exposed to PWM and that Ig production was regulated by suppression rather than cytotoxicity. These CR3+ lymphocyte subsets may have broad antigen non-specific effects on immunoglobulin synthesis.

Antigen-Antibody Complex↗
PubMed1996

LPS induces CD14 association with complement receptor type 3, which is reversed by neutrophil adhesion.

CD14, a glycosylphosphatidyl inositol (GPI)-linked membrane protein, is a key membrane binding site for LPS (endotoxin). Although CD14 lacks transmembrane and cytoplasmic sequences, it activates CR3-mediated leukocyte adhesion and cytokine release. Since CR3 has been shown to interact with other GPI-linked membrane proteins, we tested the hypothesis that CD14 can physically associate with CR3. Using qualitative and quantitative resonance energy transfer microscopy, we show that LPS in the presence of serum or LPS binding protein triggers formation of CD14-CR3 complexes. Kinetic studies show that CD14-CR3 complexes dissociate as neutrophils attach to substrates. We speculate that LPS-charged CD14 enhances CR3-mediated adhesion by directly binding to CR3.

Adult↗
PubMed2006

Expression of human soluble complement receptor 1 by a pig endothelial cell line inhibits lysis by human serum.

The importance of complement activation and naturally occurring anti-pig antibodies in the hyperacute rejection (HAR) observed in models of pig-to-human xenotransplantation is well established. To overcome this, much effort has been dedicated to preparing transgenic pigs by knocking out Galalpha(1-3)Gal expression in these animals, or knocking in the expression of human complement regulatory proteins (CRPs), such as CD59 or decay accelerating factor. A soluble form of another membrane CRP, complement receptor type 1 (CR1), has also been shown to inhibit complement activation. Here, we show that transfection of a pig endothelial cell line with a truncated form of human soluble complement receptor 1 (sCR1) almost completely protected these cells from complement-mediated lysis by human AB serum. Pigs genetically manipulated to express human sCR1 may represent an additional strategy to inhibit HAR of pig-to-human transplanted organs.

Animals↗
PubMed1991

Selective up-regulation of human granulocyte integrins and complement receptor 1 by cytokines.

The percentage of human granulocytes expressing the integrins CD11b and CD11c as well as complement receptor 1 (CD35) was increased by short-term incubation of whole blood with interleukin-2 (IL-2), interleukin-4 (IL-4) and tumour necrosis factors alpha and beta (TNF-alpha and TNF-beta). The mean fluorescence intensity of granulocyte CD18 was also increased by the above cytokines, whilst that of CD11b was only increased by TNF-alpha. Up-regulation of granulocyte CD18 expression was seen with 1 U/ml of IL-2, TNF-alpha or TNF-beta, in contrast to the effect of IL-4 which was only observed with 100 U/ml. Similarly, enhanced expression of CD35 was induced by 1 U/ml of IL-2 or TNF-alpha but not by concentrations of IL-4 or TNF-beta lower than 100 U/ml. Cytokine effects on the CD11/CD18 complex and CD35 molecules were not modified by cycloheximide, suggesting that their increased expression was not due simply to synthesis de novo. None of the granulocyte surface determinants investigated was altered upon short-term incubation of blood with either IL-1, IL-6 or interferon-gamma (IFN-gamma). The demonstration in vitro that cytokines selectively up-regulate granulocyte integrins and complement receptor 1, suggests that similar mechanisms may be operating during the control of granulocyte-mediated inflammatory processes.

Antigens, CD↗
PubMed2003

Complement receptor 1 gene polymorphisms are associated with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, fibrotic disorder underlain by aberrant wound healing of repeated lung injury. Environmental triggers and genetic background are likely to act as modifiers of the fibrotic response. Erythrocyte complement receptor 1 is a membrane protein mediating the transport of immune complexes to phagocytes. Three gene polymorphisms are related to the erythrocyte surface density of complement receptor 1 molecules, which in turn are related to the rate of immune complexes' clearance. There is evidence of association between sarcoidosis and the complement receptor 1 gene. We wondered whether IPF is associated with the complement receptor 1 gene alleles coding for a reduced molecule/erythrocyte ratio. We studied 74 patients and 166 control subjects. Three polymorphic sites of the gene, A3650G exon 22, HindIII RFLP intron 27, and C5507G exon 33, were analyzed and found to be in linkage disequilibrium. The GG genotype for the C5507G exon 33 polymorphism was significantly more common in patients with IPF than in control subjects (odds ratio = 6.232, 95% confidence interval = 2.198-18.419, p = 0.00023). The significant difference was found in both sexes. These findings agree with speculations on the role of the complement receptor 1 gene in idiopathic pulmonary fibrosis.

Aged↗
PubMed1999

Contribution of the innate immune system to autoimmune diabetes: a role for the CR1/CR2 complement receptors.

B lymphocytes are required for diabetogenesis in nonobese diabetic (NOD) mice. The complement component of the innate immune system regulates B cell activation and tolerance through complement receptors CR1/CR2. Thus, it is important to assess the contribution of complement receptors to autoimmune diabetes in NOD mice. Examination of the lymphoid compartments of NOD mice revealed striking expansion of a splenic B cell subset with high cell surface expression of CR1/CR2. This subset of B cells exhibited an enhanced C3 binding ability. Importantly, long-term in vivo blockade of C3 binding to CR1/CR2 prevented the emergence of the CR1/CR2(hi) B cells and afforded resistance to autoimmune diabetes in NOD mice. These findings implicate complement as an important regulatory element in controlling the T cell-mediated attack on islet beta cells of NOD mice.

Animals↗