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PubMed1998

Intracellular storage and regulated plasma membrane expression of human complement receptor type 1 in rat basophil leukemia cell transfectants.

Polymorphonuclear neutrophils (PMN) contain multiple distinct secretory compartments that are sequentially mobilized during cell activation. Complement receptor type 1 (CR1) is a marker for a readily mobilizable secretory vesicle compartment, which can undergo exocytic fusion with the plasma membrane independently of secretion of traditional granule contents. The basis for the formation of these distinct compartments is incompletely understood. Primary and secondary granules are generated directly from the Golgi complex during different stages of development of the cell, obviating the need for sorting signals for proper packaging of their constituents. To determine whether the secretory vesicles are formed in a similar manner, we studied a stable rat basophilic leukemia cell line (RBL-CR1) transfected with a plasmid containing the cDNA of human CR1 driven by a viral promoter. The CR1 was present primarily intracellularly in small vesicles resembling the CR1 storage pools in resting PMN. Activation of RBL-CR1 resulted in translocation of intracellular CR1 to the plasma membrane, with mobilization requirements different from those of the classical RBL granules. Thus, in RBL-CR1, continuously synthesized CR1 is stored and upregulated in much the same way as in PMN. This suggests that differential timing of gene expression is not essential for proper storage of CR1 and that other sorting mechanisms are involved, which can be studied in RBL-transfectants.

Animals↗
PubMed1983

A human leukocyte differentiation antigen family with distinct alpha-subunits and a common beta-subunit: the lymphocyte function-associated antigen (LFA-1), the C3bi complement receptor (OKM1/Mac-1), and the p150,95 molecule.

The human lymphocyte function-associated antigen-1 (LFA-1), the complement receptor-associated OKM1 molecule, and a previously undescribed molecule termed p150,95, have been found to be structurally and antigenically related. Each antigen contains an alpha- and beta-subunit noncovalently associated in an alpha 1 beta 1-structure as shown by cross-linking experiments. LFA-1, OKM1, and p150,95 alpha-subunit designations and their molecular weights are alpha L = 177,000 Mr, alpha M = 165,000 Mr, and alpha X = 150,000 Mr, respectively. The beta-subunits are all = 95,000 Mr. Some MAb precipitated only LFA-1, others only OKM1, and another precipitates all three antigens. The specificity of these MAb for particular subunits was examined after subunit dissociation by high pH. MAb specific for LFA-1 or OKM1 bind to the alpha L- or alpha M-subunits, respectively, while the cross-reactive MAb binds to the beta-subunits. Coprecipitation experiments with intact alpha 1 beta 1-complexes showed anti-alpha and anti-beta MAb can precipitate the same molecules. In two-dimensional (2D) isoelectric focusing-SDS-PAGE, the alpha subunits of the three antigens are distinct, while the beta-subunits are identical. Biosynthesis experiments showed alpha L, alpha M, and alpha X are synthesized from distinct precursors, as is beta. The three antigens differ in expression on lymphocytes, granulocytes, and monocytes. During maturation of the monoblast-like U937 line, alpha M and alpha X are upregulated and alpha L is downregulated. Some MAb to the alpha subunit of OKM1 inhibited the complement receptor type three. LFA-1, OKM1, and p150,95 constitute a novel family of functionally important human leukocyte antigens that share a common beta-subunit.

Antibodies, Monoclonal↗
PubMed1995

Functional analysis of complement receptor 1 using a new monoclonal antibody, KuN241.

A monoclonal antibody (MAb), KuN241, recognized an antigen present on all monocytes, polymorphonuclear leukocytes (PMNs), B cells, and a subpopulation of T cells. Cell surface expression pattern and immunoprecipitation studies indicated the molecule recognized by KuN241 to be complement receptor 1 (CR1). This was confirmed by sequential immunoprecipitation using E11, a CR1-specific monoclonal, and by immunoprecipitation analysis of a truncated transfection product of CR1. In vivo activation of PBLs for 7 days with pokeweed mitogen (PWM) abrogated surface expression of CR1 on B cells. Overnight culture with phorbol 12-myristate 13-acetate (PMA) downregulated the expression of CR1 detected by KuN241 both on PMNs and monocytes. Addition of MAb KuN241 to purified PMN and monocytes resulted in a transient increase in intracellular calcium ([Ca2+]i). This was blocked by the Fab fragment of MAb KuFc79 directed against the Fc gamma receptor. Further, Fab fragment of KuN241 cross-linked with F(ab')2 goat anti-mouse Ig failed to increase [Ca2+]i levels. Taken together, these results suggested a novel mechanism for transmembrane signaling events by dual binding of KuN241, the Fab region to CR1 and the Fc region of Fc gamma RII.

Animals↗
PubMed1995

Comparison of the binding of C3S and C3F to complement receptors types 1, 2, and 3.

The two common polymorphic variants of C3 are C3S/HAV4.1- and C3F/HAV4.1+. It was reported previously that erythrocytes coated with C3F rosetted more strongly with mononuclear cells than erythrocytes coated with C3S. We examined the binding of C3S/HAV4.1- and C3F/HAV4.1+ to complement receptors CR1, CR2, and CR3. The binding of 125I-labeled C3b dimers to erythrocyte CR1 was measured. Scatchard analysis showed a two-binding constant model with very similar binding constants for dimers prepared with C3S and C3F: for C3S Kd1 = 18.3 +/- 2 nM; Kd2 = 6.2 +/- 1 nM; for C3F Kd1 = 21.5 +/- 4 nM; Kd2 = 7.2 +/- 3 nM (mean +/- SEM). One-third of the binding sites were of the higher affinity. The rosetting of erythrocytes with different densities of iC3b, prepared from C3S or C3F, to CR2 on Raji cells was analyzed. The percentage of Raji cells rosetted was related to the coating dose of EC3bi: 400 molecules/cell = 9% rosettes; 5000 molecules/cell = 75%. The dose-response curves were very similar for C3S- and C3F-coated erythrocytes. CR3-dependent rosetting was studied in a similar manner by using neutrophils activated with f-met-leu-phe. CR3-dependent rosette formation with the indicator erythrocytes (600 to 6000 iC3b/cell) increased from 10% to 60% in a dose-dependent manner and was closely similar for C3S and C3F. Inhibition of CR2 and CR3 rosetting by fluid phase ligand was also studied. iC3b dimers (0.4 to 50 micrograms/ml) inhibited CR2-dependent rosetting in a dose-dependent manner but had no inhibitory effect on CR3-dependent rosetting. When the dimers were absorbed to fluorescent microspheres, they mediated phagocytic uptake of the microspheres in a CR3-dependent manner by neutrophils. CR3-dependent binding by activated neutrophils required surface-bound ligand.

Complement C3↗
PubMed1993

Presence of serum modulates expression of complement receptor type 1 (CR1) on human granulocytes after quartz exposure.

We have investigated the interaction between granulocytes and quartz with respect to the expression of complement receptor type 1 (CR1) and the presence of normal human serum (NHS). Quartz down-regulates selectively CR1 on activated granulocytes. This down-regulation is abolished in the presence of both NHS and heat-inactivated NHS (NHS56) but not human albumin. When quartz was preincubated with NHS (quartz-NHS) before exposure to activated granulocytes, a down-regulating effect was observed in contrast to preincubation with NHS56, which did not induce a down-regulation. Preincubation with cytochalasin B reduced the down-regulation of quartz-NHS, indicating a cytoskeleton-dependent internalization of the receptor. The serine protease inhibitor PMSF partly reduced this down-regulation. Our results indicate that the presence of NHS in the alveolar space influences the interaction between quartz and recruited granulocytes with respect to CR1 expression. Since CR1 is an important opsonin receptor and soluble CR1 can modulate the inflammatory response, this may be of importance in the inflammation and fibrosing process induced by quartz in the alveolar space and lung interstitium.

Blood Physiological Phenomena↗
PubMed1997

Monoclonal antibody-mediated, complement-independent binding of human tumor necrosis factor-alpha to primate erythrocytes via complement receptor 1.

Monoclonal antibody (MAb)-based heteropolymers (HP) were used to simulate immune adherence. The HP is constructed by cross-linking MAbs that recognize complement receptor 1 (CR1) and tumor necrosis factor-alpha (TNF-alpha). 125I-labeled TNF-alpha was cocultured with either sheep, monkey, or human erythrocytes in the presence or absence of HP. Human erythrocytes demonstrated 63% +/- 0 (mean +/- SD) binding of 125I-labeled TNF-alpha, while binding of 125I-labeled TNF-alpha in the absence of HP was 4% +/- 1% (P < .001). Monkey erythrocytes showed similar results, while sheep erythrocytes (which lack CR1) demonstrated low binding. The effect of HP binding on biologic activity of TNF-alpha was examined in an assay of stimulated human neutrophils. The HP completely inhibited the ability of TNF-alpha to prime neutrophils, occurring regardless of the presence or absence of erythrocytes but solely dependent on the addition of HP. Thus, the HP facilitated specific, saturable, and significant binding of 125I-labeled TNF-alpha to primate erythrocytes in vitro.

Animals↗
PubMed2004

Quantitative polymorphism of complement receptor type 1 (CR1) in patients undergoing haemodialysis.

BACKGROUND: The level of complement receptor type 1 (CR1) on erythrocytes (E-CR1) is determined by the presence of high (H) or low (L) expression alleles. We investigated whether acquired loss of E-CR1 occurs in haemodialysis patients and, if so, which factors may contribute to acquired loss of E-CR1 in these patients. METHODS: The E-CR1 level was determined in 195 Japanese haemodialysis patients, and we selected patients with a high or low E-CR1 level. In patients with low E-CR1 expression, sequence analysis of polymorphic sites (A3650G and C5507G) in the CR1 gene was performed. To assess the effect of the type of dialysis membrane used in the patients with low E-CR1 expression, the dialysis membrane was changed from a cellulose membrane to a biocompatible membrane (to a polyacrylonitrile membrane and then to a polysulfone membrane). To evaluate the susceptibility of E-CR1 to proteolysis, erythrocytes were incubated with various concentrations of trypsin, and the level of remaining CR1 on the erythrocytes was determined. RESULTS: Among patients with high E-CR1 expression (n = 30), 87% had HH alleles and 13% had HL alleles. Among patients with low E-CR1 expression (n = 29), 24% had LL alleles, 45% had HL alleles and 31% had HH alleles. Nucleotides 3650G and 5507G in the CR1 gene were associated with the L allele. Nucleotides 3650A and 5507C were associated with the H allele. Only one patient with HH alleles had nucleotides 3650G and 5507C. Three months after changing the haemodialysis membrane, the E-CR1 level significantly increased (P<0.02). The proteolysis curves of E-CR1 of patients with low or high E-CR1 expression and normal controls were similar. CONCLUSION: Use of a non-biocompatible dialysis membrane may contribute to acquired loss of E-CR1 in haemodialysis patients.

Aged↗
PubMed1979

A simple method to detect complement receptors using baker's yeast: Y C rosettes.

A technique is described to identify complement-receptor-bearing cells, using serum-treated baker's yeast as a ligand. The method consists of incubation of heat-killed baker's yeasts with fresh AB normal serum, freezing, thawing, and washing of the particles, followed by mixing with the cells. Serum is required to coat the yeasts for the rosette formation. Experiments designed to establish the serum factors responsible for the attachment of the particles to cells show that heat inactivation, chelating agents, or anti-C3 treatment prevent rosette formation. This is taken as evidence that yeasts (Y) are coated with complement (C) to compose the reagent for the YC rosette technique. The application of this technique to twenty-five normal individuals demonstrated that a mean of 11.6 per 100 lymphocytes (+/- 4.3) form rosettes; absolute number: 275 (+/- 160) rosette-forming lymphocytes per mm3. Either AB or autologous fresh serum can be used to coat the yeasts. A combined technique for YC plus E rosettes can be performed allowing the identification and enumeration of four populations of lymphocytes: (a) those having receptors for sheep erythrocytes, (b) complement-receptor-bearing lymphocytes, (c) those having both receptors (D lymphocytes), and (d) non-rosette-forming non-phagocytic cells.

Adult↗
PubMed1981

IgG and complement receptors on purified mouse eosinophils and neutrophils.

Mouse eosinophil and neutrophil receptors for IgG and complement have been examined by means of rosette formation, phagocytosis and 51Cr release assays, using mouse monoclonal antibodies and complement-coated sheep erythrocytes. Mouse eosinophils and neutrophils form a high number of rosettes in the presence of mouse complement but eosinophils show a higher requirement for complement molecules. Both types of granulocyte phagocytose complement-coated sheep erythrocytes very actively, although low levels of 51Cr release are obtained. Eosinophils and neutrophils show higher activity in the presence of IgG2b than in the presence of IgG1, and while both cell types are similarly active when the former antibody is used, neutrophils are the more active when IgG1 is used. However, it remains uncertain whether this is a result of the higher binding obtained with the IgG2b monoclonal antibody. Both cell types behave similarly at high antibody concentrations but neutrophils are the more active at high antibody dilutions. The 51Cr release assay is shown to be superior to the rosette assay at it allows comparisons between eosinophils and neutrophils at high antibody concentrations. A time course study indicates that highest values of phagocytosis of opsonized red cells are obtained after 5 minutes rather than the half to one hour incubation periods normally used.

Animals↗
PubMed2001

Validation of an ELISA for the quantitation of human complement receptor 1.

An ELISA was developed and validated for the quantitation of Complement Receptor 1 (CR1) in human plasma. The ELISA employed a monoclonal anti-CR1 antibody adsorbed onto microtiter plates to capture CR1 in human plasma. The captured CR1 was treated with a detecting antibody which had a different epitopic specificity for CR1. HRP conjugated anti IgG (secondary antibody) was used for quantitation. The standard curve covered a wide range from 10 pg to 800 pg. The inter- and intra-assay variation were found to be low and within the acceptable limits. Specificity and accuracy for the assay was established by ensuring negligible cross reactivity with other proteins and an excellent parallelism between the sample and standard curve. The samples were checked for loss of sCR1 levels through freeze/thaw cycles at different intervals of time stored at -70 degrees C.

Complement C1↗
PubMed1982

Purification and structural characterization of LFA-1, a lymphocyte function-associated antigen, and Mac-1, a related macrophage differentiation antigen associated with the type three complement receptor.

LFA-1, an antigen associated with antigen-specific T lymphocyte-mediated killing, and Mac-1, a macrophage differentiation antigen associated with type three complement receptor function, contain alpha chains of Mr = 180,000 and 170,000, respectively, and beta chains of Mr = 95,000. The monoclonal antibodies defining these antigens do not cross-react. The LFA-1 and Mac-1 beta chains are highly homologous or identical, whereas the alpha chains are highly different by tyrosyl tryptic peptide mapping (Kürzinger, K., Ho, M. K., and Springer, T. A. (1982) Nature (Lond.) 296, 668-670). T lymphoma cell lines express LFA-1 but not Mac-1 as shown by immunofluorescence and immunoprecipitation. Conversely, some macrophage-like lines express Mac-1 but not LFA-1. Other macrophage-like lines co-express Mac-1 and small amounts of LFA-1. Mac-1 and LFA-1 are present as separate molecules in these cells. [35S]Methionine and [[3H]glucosamine are incorporated into both alpha and beta chains of Mac-1 and LFA-1, showing both chains are endogenously synthesized and are glycoproteins. Cross-linking and two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis experiments show that in both Mac-1 and LFA-1 the alpha and beta chains are noncovalently associated in alpha 1 beta 1 quaternary structures. By quantitative immunofluorescence flow cytometry, the EL-4 T lymphoma and P388D1 macrophage-like lines were estimated to express 10(5) LFA-1 and 1.6 x 10(5) Mac-1 molecules/cell, respectively. From these sources the antigens have been purified to homogeneity in 200-400-micrograms quantities by monoclonal antibody affinity chromatography. The purified antigens contain only the alpha and beta subunits.

Animals↗
PubMed1995

Regulation of the complement cascade by soluble complement receptor type 1. Protective effect in experimental liver ischemia and reperfusion.

The complement cascade was inactivated in a model of rat liver ischemia with the purpose of studying the role of complement in tissue injury after ischemia and reperfusion. Soluble human complement receptor type 1 (sCR1) was administered either in a single dose of 25 mg/kg or in 2 doses of 50 mg/kg i.v. over 24 hr after vascular occlusion. Sham-operated rats, nontreated rats submitted to liver ischemia, and rats pretreated with cobra venom factor and submitted to liver ischemia were used as controls. This experiment consists of the temporary interruption of arterial and portal blood flow to the left lateral and medial lobes of the liver for 45 min, followed by a 24-hr period of follow-up after reperfusion. Liver blood flow and hemoglobin saturation were recorded for 1 hr after declamping, with statistically significant differences between the experimental groups and the untreated control group, which received liver ischemia (P < 0.001). At 24 hr, galactose elimination was assayed as a liver function test; it was significantly better in the sCR1-treated rats when compared with control rats submitted to ischemia (P < 0.01). Alanine aminotransferase levels were also significantly lower in the sCR1-treated rats at 6 and 24 hr (P < 0.05). Complement activity was reduced to 25% and 12.5% of normal rats with the respective doses of sCR1. Immunoperoxidase stainings for C3 and C9 were performed on liver sections; they showed endothelial deposits of C3 and C9 in the control group subjected to ischemia. Few C3 deposits were present in the sCR1 (25 mg/kg)-treated rats, but not in the cobra venom factor or sCR1 (50 mg/kg) groups. These results confirm that complement is inactivated by sCR1 with amelioration of reperfusion injury in the rat liver.

Animals↗
PubMed1992

Mutagenesis of the Arg-Gly-Asp triplet in human complement component C3 does not abolish binding of iC3b to the leukocyte integrin complement receptor type III (CR3, CD11b/CD18).

The leukocyte integrin complement receptor type III (CR3, CD11b/CD18) binds the C3 cleavage product iC3b. Many other integrins bind their ligands via an Arg-Gly-Asp (RGD) triplet. Both the RGD-containing C3 peptide 1390TRYRGDQDATMS1401 (pro-C3 numbering) and the RGD-like fibrinogen peptide GGAKQAGDV, which binds to the platelet integrin glycoprotein IIb-IIIa, were shown to inhibit the iC3b-CR3 interaction, suggesting that this binding is also RGD-mediated (Wright, S.D., Weitz, J.I., Huang, A. J., Levin, S.M., Silverstein, S.C., and Loike, J.D. (1988) Proc. Natl. Acad. Sci. U.S.A. 85, 7734-7738). However, unlike other integrin-ligand interactions, that of CR3 and iC3b is unaffected by the hexapeptide GRGDSP, and substitutions in the RGD triplet of C3 from other species appear to be tolerated. It was, therefore, proposed (Grossberger, D., Marcuz, A., du Pasquier, L., and Lambris, J.D. (1989) Proc. Natl. Acad. Sci. U.S.A. 86, 1323-1327) that the highly conserved DATMS portion of the inhibitory C3 peptide may have been responsible for its binding. To address these inconsistencies and directly assess the role of the 1390-1401 segment within the complete iC3b molecule in mediating binding to CR3, a human C3 cDNA was altered by site-directed mutagenesis and the expressed recombinant proteins were examined in a CR3-specific assay. Replacement of RGD by AAA did not abolish rosetting of the corresponding iC3b-coated erythrocytes to human CR3-bearing leukocytes. In addition, mutant iC3b molecules in which the positively charged R1391 (corresponding to K in the fibrinogen peptide) and the highly conserved 1397DATMS sequence were replaced by Q and NAAMA respectively, were still bound by CR3. We conclude that the iC3b-CR3 interaction is not mediated by the RGD triplet or its neighboring residues.

Amino Acid Sequence↗
PubMed2002

Mucosal type mast cells express complement receptor type 2 (CD21).

Fragments of complement component C3 generated upon activation of the cascade play an important role in the induction and regulation of immune responses. Receptors interacting with various fragments of this versatile complement protein are expressed on a wide variety of cell types, including lymphocytes, macrophages, dendritic cells, follicular dendritic cells, granulocytes, erythrocytes and consequently, C3-products may influence several biological functions at different sites of the body, where complement activation occurs. Regarding the expression of various C3-receptors on mast cells, mainly rodent serosal type mastocytes have been investigated so far. It has been known for a long time that C3a triggers the release of mediators of immediate type hypersensitivity via binding to serosal-type cells. Complement receptor type 1 (CR1/CD35) and type 2 (CR2/CD21) interacting with the larger activation products, such as C3b and C3d, have so far been shown on serosal type mast cells only. In this study, the expression of CR1/2 on mucosal type mast cells is demonstrated. Using mouse CR1/2 specific single chain antibodies and the natural ligand C3d in cytofluorimetric measurements, we show that the rat mucosal mast cell line RBL-2H3 and mouse bone marrow-derived mast cells (BMMC) express CD21. RT-PCR experiments carried out with mouse CR1 and CR2 specific primers show CD21, but not CD35 specific products in BMMC. It is also demonstrated that, in contrast to serosal type mast cells, mucosal mastocytes do not express CD19. In an attempt to reveal the possible function of CR2 on mucosal type mast cells, the effect of receptor-clustering was tested regarding degranulation, Ca-response and IL-6 production, but no CR2-mediated change was detected in any of these processes.

Animals↗
PubMedDate not supplied

How are immune complexes bound to the primate erythrocyte complement receptor transferred to acceptor phagocytic cells?

Immune complexes (IC) bound to the primate erythrocyte (E) complement receptor (CR1) are cleared from the circulation of primates and localized to phagocytic cells in the liver and spleen without E destruction. IC can be bound to E CRI either via C3b opsonization or with cross-linked mAb complexes (heteropolymers, HP) which contain a mAb specific for CRI and a mAb specific for an antigen. The long-term goal of our work is to apply the HP system to the treatment of human diseases associated with blood-borne pathogens. This review discusses the mechanism by which the E-bound IC are transferred to acceptor cells. Our studies in animal models as well as our in vitro investigations indicate that IC transfer is rapid (usually >90% in 10 min) and does not lead to lysis or phagocytosis of the E. Experiments with specific inhibitors and the use of IC prepared with Fab' fragments suggest that transfer depends mainly upon recognition by Fc receptors on the acceptor cell. Moreover, we find that IC release from the E is associated with a concerted loss of CR1, and is followed by uptake and internalization of the IC by the acceptor cell. We suggest that recognition and binding of the E-bound IC substrates by Fc receptors allows close contact between the E and acceptor cells, which in turn facilitates proteolysis of E CR1, presumably by a macrophage-associated protease. After proteolysis, the released IC are internalized by the macrophages.

Animals↗
PubMed2003

Complement receptor 1 inhibitors for prevention of immune-mediated red cell destruction: potential use in transfusion therapy.

Activation of complement cascade via the antibody-mediated classical pathway can initiate red blood cell (RBC) destruction, causing transfusion reactions and hemolytic anemia. In the present study, we have assessed the ability of a human recombinant soluble form of complement receptor 1 (sCR1) to inhibit complement-mediated RBC destruction in vitro and in vivo. Using an in vitro alloimmune incompatibility model, sCR1 inhibited complement activation and prevented hemolysis. Following transfusion of human group O RBCs into mice lacking detectable pre-existing antibodies against the transfused RBCs, systemic coadministration of 10 mg/kg sCR1, a dose well tolerated in human subjects for prevention of tissue injury, completely inhibited the in vivo clearance of the transfused RBCs and surface C3 deposition in the first hour after transfusion, correlating with the half-life of sCR1 in the circulation. Treatment with sCR1 increased the survival of transfused human group A RBCs in the circulation of mice with pre-existing anti-A for 2 hours after transfusion by 50%, reduced intravascular hemolysis, and lowered the levels of complement deposition (C3 and C4), but not immunoglobulin G (IgG) or IgM, on the transfused cells by 100-fold. We further identified potential functional domains in CR1 that can act to limit complement-mediated RBC destruction in vitro and in vivo. Collectively, our data highlight a potential use of CR1-based inhibitors for prevention of complement-dependent immune hemolysis.

ABO Blood-Group System↗
PubMed2003

Prevention of collagen-induced arthritis in mice transgenic for the complement inhibitor complement receptor 1-related gene/protein y.

The objective of these studies was to examine collagen-induced arthritis (CIA) in C57BL/6 mice transgenic for the rodent complement regulatory protein complement receptor 1-related gene/protein y (Crry) (Crry-Tg), a C3 convertase inhibitor. The scores for clinical disease activity and for histological damage in the joints were both significantly decreased in Crry-Tg mice in comparison to wild-type (WT) littermates. The production of both IgG1 and IgG2a anti-collagen Abs was reduced in the Crry-Tg mice, although spleen cell proliferation in response to collagen type II was not altered. The production of IFN-gamma, TNF-alpha, and IL-1beta by LPS-stimulated spleen cells was decreased, and IL-10 was increased, in cells from Crry-Tg mice in comparison to WT. The steady-state mRNA levels for IFN-gamma, TNF-alpha, and IL-1beta were all decreased in the joints of Crry-Tg mice in comparison to WT. The synovium from Crry-Tg mice without CIA contained the mRNA for the Crry transgene, by RT-PCR, and the synovium from transgenic mice with CIA exhibited little deposition of C3 protein by immunohistological analysis. These results suggest that suppression of CIA in Crry-Tg mice may be due to enhanced synthesis of Crry locally in the joint with decreased production of proinflammatory cytokines.

Animals↗
PubMed2003

A human complement receptor 1 polymorphism that reduces Plasmodium falciparum rosetting confers protection against severe malaria.

Parasitized red blood cells (RBCs) from children suffering from severe malaria often adhere to complement receptor 1 (CR1) on uninfected RBCs to form clumps of cells known as "rosettes." Despite a well documented association between rosetting and severe malaria, it is controversial whether rosetting is a cause or a correlate of parasite virulence. CR1-deficient RBC show greatly reduced rosetting; therefore, we hypothesized that, if rosetting is a direct cause of malaria pathology, CR1-deficient individuals should be protected against severe disease. In this study, we show that RBC CR1 deficiency occurs in up to 80% of healthy individuals from the malaria-endemic regions of Papua New Guinea. This RBC CR1 deficiency is associated with polymorphisms in the CR1 gene and, unexpectedly, with alpha-thalassemia, a common genetic disorder in Melanesian populations. Analysis of a case-control study demonstrated that the CR1 polymorphisms and alpha-thalassemia independently confer protection against severe malaria. We have therefore identified CR1 as a new malaria resistance gene and provided compelling evidence that rosetting is an important parasite virulence phenotype that should be a target for drug and vaccine development.

Adult↗