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PubMed1978

[Immunologic study of pleural neoplastic effusions: Detection of immune complexes and complement activation].

Occurrence of immune complexes in malignant pleural effusions has been investigated by the 125I-c1q binding test. 55% of the pleural effusions had C1q binding activity levels higher than those found in transudates used as controls. The levels of C1q binding activity in effusions were significantly higher than those found in the serum of the same cancer patients. High levels of C1q binding activity were found in malignant effusion independently of type or differentiation of the tumors involved. The C1q binding material had properties of immune complexes. The levels of CH50 and C3d, i.e. the degradation product of C3, in malignant effusion were similar to those of transudates. These observations show a high incidence of immune complexes in malignant effusions and a slight activation of complement inadequate for its local consumption. The persistence in major quantity of immune complexes in malignant effusion suggests local formation or decreased clearance.

Antigen-Antibody Complex↗
PubMed1990

Immunohistologic study of epiretinal membranes in proliferative vitreoretinopathy.

We performed an immunohistologic study on 11 specimens of epiretinal membranes surgically obtained from patients who had rhegmatogenous retinal detachment with proliferative vitreoretinopathy. Immunostaining procedures were used to identify immunoglobulin and complement deposits, to visualize class II antigen expression by proliferating cells, and to determine eventual infiltration by cells of the immune system. Diffuse deposits of IgG, IgA, IgE, C1q, C3c, and C3d were found in epiretinal membranes, whereas numerous cells, including glial or pigmented epithelial cells, expressed HLA-DR and HLA-DQ antigens. Some macrophages and B or T8 lymphocytes were identified. These results suggest activation of the immune system during the course of proliferative vitreoretinopathy. Class II antigen expression could be dependent upon growth-promoting factors and interferon gamma and could play a crucial role in this immune reaction, which resulted in immunoglobulin deposition and activation of complement. However, the eventual role of immune phenomena in the extension of proliferative processes remains to be determined.

Adult↗
PubMed1982

Unique role of the complement receptor CR1 in the degradation of C3b associated with immune complexes.

The main finding of this paper is that CR1, the membrane receptor for C3b and C4b, together with C3b/C4b-inactivator (I), degrades C3b bound to immune complexes (C3b*). Two fragments are generated: C3c, which is released from the immune complexes, and C3d*. The C3c fragment released from the cell intermediate EAC1423b prepared with 125I-C3 was analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and radioautography. It has a 135,000 mol wt and contains disulfide bonded labeled polypeptide chains of 75,000 and 31,000 mol wt, which presumably represent the beta and a fragment of the alpha-chain of C3b*. Silver staining of the SDS-PAGE gels revealed other C3-derived bands with 39-42,000 mol wt. Human erythrocytes + I also cleave C3b* into C3c and C3d*. The activity of the erythrocytes is CR1 mediated because it can be totally inhibited by monoclonal antibodies to CR1. In contrast with these results, I together with the serum protein beta 1H (H) transform EAC1423b into hemolytically inactive EAC1423bi and cleave the alpha' chain of C3b* into fragments of 70,000 and 40,000 mol wt. Small amounts of C3c are also released at relatively high concentrations of H. On a molar basis, the efficiency of CR1 in the generation of C3c and C3d is 10(4)-10(5) greater than H. An additional observation was that C3c could be released by treating EAC1423bi with CR1 + I and that this reaction was also inhibited by monoclonal antibodies to CR1. Therefore, it is likely that CR1 has binding affinity for iC3b and that the degradation of C3b* proceeds as follows: C3b (formula, see text) C3c + C3d*. Taken together, our findings argue that the processing of C3b* in vivo occurs in solid phase, that is, on the surface of cells bearing CR1.

Antigen-Antibody Complex↗
PubMed1991

Complement activation during bypass in acquired C1 esterase inhibitor deficiency.

Serial complement estimations during cardiopulmonary bypass are reported in a patient with acquired C1 esterase inhibitor deficiency. Although the extent of classic and alternative pathway activation appeared appropriate, exaggerated common pathway activation with massive increase in the C3d:C3 ratio occurred. A fatal hemostatic disorder, pulmonary edema, and circulatory collapse ensued despite prophylaxis and therapy.

Aged↗
PubMed1983

Inhibition of phagocytosis of complement C3- or immunoglobulin G-coated particles and of C3bi binding by monoclonal antibodies to a monocyte-granulocyte membrane glycoprotein (Mol).

Events that lead to phagocytosis of complement (C3)- or IgG-coated particles after their interaction with specific cell surface receptors are poorly understood. Two mouse monoclonal antibodies (an IgM and an IgG2a) to a human granulocyte-monocyte surface membrane differentiation antigen (Mol) inhibited ingestion by granulocytes both of oil Red O particles opsonized with normal human serum or with IgG and of sheep erythrocytes sensitized with IgG. In addition, they specifically inhibited rosetting between phagocytes and sheep erythrocytes coated with C3bi, a fragment of the complement component C3, generated by cleaving C3b with C3b inactivator and beta IH protein. These monoclonal anti-Mol antibodies did not inhibit IgG Fc, C3b or C3d receptor-mediated binding of erythrocytes coated with the respective proteins. The Fab fragment of the IgG2a monoclonal antibody inhibited noncytotoxic enzyme release from granulocytes when these cells were stimulated with zymosan coated with C3bi. Electrophoretic transfer of polymorphonuclear leukocyte detergent lysates to nitrocellulose, followed by immunofixation with monoclonal antibody, showed that these antibodies were directed to a 155,000-mol wt glycoprotein. This surface membrane structure appears to be involved in Fc and C3 receptor-dependent phagocytosis and closely associated with the C3bi receptor.

Antibodies, Monoclonal↗
PubMedDate not supplied

Binding of fluid phase C3b to nonsensitized bystander human red cells. A model for in vivo effects of complement activation on blood cells.

There is evidence that activated complement fragments (C3b) can bind to human red cells (RBCs) serving as adsorbing surfaces, but not as antigens. This evidence prompted the present in vitro experiments. Using the standard antiglobulin test (AGT), the radioimmune antiglobulin test (RIAT), and the immune adherence test, we found that C3 can indeed be attached to "bystander" human RBCs if complement is activated either through the classical pathway (anti-A hemolysins plus blood group A1 RBCs) or the alternative pathway (activator surfaces, i.e., Escherichia coli bacteria, rabbit RBCs, or inulin). On Scatchard plot analysis, between 24,000 and 44,000 radiolabeled anti-C3d molecules were bound per one adjacent "bystander" RBC, while untreated control RBCs, or RBCs preincubated with fresh compatible serum, bound only 200 to 300, and 600 to 800 molecules, respectively. Despite strong coating with C3 fragments, only "bystander" paroxysmal nocturnal hemoglobinuria, but not normal, RBCs were hemolyzed by complement activation, i.e., through E. coli at pH 8.0. RBCs were not coated with C3 when complement was activated in the fluid phase by heat-aggregated IgG or a staphylococcal "decomplementation antigen." We conclude that the findings of our in vitro experiments accurately mimic some old, but as yet insufficiently understood, in vivo effects of complement activation on circulating blood cells.

Binding Sites, Antibody↗
PubMed2001

Cr2, a candidate gene in the murine Sle1c lupus susceptibility locus, encodes a dysfunctional protein.

The major murine systemic lupus erythematosus (SLE) susceptibility locus, Sle1, corresponds to three loci independently affecting loss of tolerance to chromatin in the NZM2410 mouse. The congenic interval corresponding to Sle1c contains Cr2, which encodes complement receptors 1 and 2 (CR1/CR2, CD35/CD21). NZM2410/NZW Cr2 exhibits a single nucleotide polymorphism that introduces a novel glycosylation site, resulting in higher molecular weight proteins. This polymorphism, located in the C3d binding domain, reduces ligand binding and receptor-mediated cell signaling. Molecular modeling based on the recently solved CR2 structure in complex with C3d reveals that this glycosylation interferes with receptor dimerization. These data demonstrate a functionally significant phenotype for the NZM2410 Cr2 allele and strongly support its role as a lupus susceptibility gene.

Alleles↗
PubMed1995

A novel bifunctional chimeric complement inhibitor that regulates C3 convertase and formation of the membrane attack complex.

Human cells express cell surface complement regulatory molecules that inhibit the activity of the C3/C5 convertases (DAF, MCP, CR1) or inhibit the membrane attack complex (CD59). A single molecule that inhibits both the convertase activity and formation of the membrane attack complex has never been characterized. To this end, we have developed two reciprocal chimeric complement inhibitors (CD, NH2-CD59-DAF-GPI; and DC, NH2-DAF-CD59-GPI) that contain the functional domains of decay accelerating factor (DAF; CD55) and CD59. Cell surface expression of the CD and DC chimeric proteins was detected with DAF- and CD59-specific antisera. Cell surface C3d deposition was inhibited on cells expressing the chimeric molecules, thereby indicating that the DAF moiety was functional in both molecules. Conversely, Ab-blocking experiments demonstrated that only the DC molecule retained CD59 function. Therefore, the DC molecule represents a novel potent chimeric bifunctional complement inhibitor that retains the functional domains of two distinct complement regulatory molecules.

Animals↗
PubMed1992

Factors influencing the interaction of herpes simplex virus glycoprotein C with the third component of complement.

The factors influencing the interaction of herpes simplex virus (HSV) glycoprotein C (gC) with the third component of complement (C3) were investigated in this study. The ability of gC of HSV type 1 (gC-1) to bind to the C3b fragment of C3 was found to be influenced by cell specific processing of gC-1 in a different manner, binding being remarkably enhanced in some cell lines following removal of sialic acid residues. Testing several intertypic recombinants of HSV we found that only strains expressing gC-1 exhibited binding to C3b, even though their genome consisted mainly of HSV-2 sequences in some recombinants. Expression of type-2 glycoproteins gB, gD, gE, gG, gH, and gI did not alter the ability of gC-1 to bind to C3b. Rosetting of HSV-1 infected Vero cells with C3b-coated red blood cells (EAC) was found to be temperature dependent and could be inhibited with purified C3b and anti-C3 antibodies. Polyanions like heparin or dextran sulfate were also inhibitory in a dose dependent manner, whereas C3d, neomycin and other aminoglycoside antibiotics failed to block. As the tested polyanions are also known to inhibit the infectivity of HSV, it could be speculated, that the complement binding function and the heparin-binding/attachment function of gC might be related.

Amino Acid Sequence↗
PubMed1979

Studies on the preservation of red blood cells. Attachment of the third component of human complement to erythrocytes during storage at 4 degrees C.

Utilizing an automated antiglobulin test, we have investigated the presence of the third and fourth components of human complement on normal red blood cells (RBCs). Only negligible amounts of the fourth component, C4, could be detected on either freshly collected or stored RBCs. The fragment C3d of the third component, C3, was detectable on both freshly collected and stored normal RBCs. A product derived from C3 and reacting with anti-C3c antibody was only barely detectable on freshly collected normal RBCs. During storage of blood at 4 degrees C, increasing quantities of this material were detected on the RBC membrane. Bromelin treatment rendered stored RBCs completely nonreactive with anit-C3c antibody, whereas only partial loss of reactivity was observed following incubation with heated plasma. In contrast, incubation of EC43 with heated plasma completely abolished their ability to react with anti-C3c antibody. We suggest that the presence of this C3 fragment on stored RBCs may contribute to the development of "preservation injury".

Agglutinins↗
PubMed1990

C3 activation products correlate with antibodies to lipid A in pauciarticular juvenile arthritis.

IgM antibodies to monophosphoryl-lipid A were found to be elevated in sera from children with all forms of juvenile arthritis (JA) and systemic lupus erythematosus. Of more interest, in patients with pauciarticular JA, IgG antibody titers to monophosphoryl-lipid A were found to be correlated with the C3a concentration and the C3d:C3 ratio. Although the full specificity of these antibodies is unknown, they are the first that have been found to be correlated with complement activation products in any form of JA.

Arthritis, Juvenile↗
PubMed1987

Modulation of neutrophil expression of C3b receptors (CR1) by soluble monomeric human C3b.

Upon incubation at 37 degrees C with purified human C3b (500 micrograms/ml), polymorphonuclear neutrophils (PMN) were found to express up to 50% more C3b receptors (CR1) than PMN incubated with buffer alone. This up-regulation of CR1, assessed by the binding of radiolabeled CR1-specific monoclonal antibody, was dependent on the dose of C3b, occurred within 10-20 min and was stable for at least 90 min. PMN incubated with C3b also demonstrated enhanced CR1-dependent binding functions, such as EC3b rosette formation and phagocytosis of EIgGC3b particles. C3b at a concentration of 500 micrograms/ml induced up to 90% increase in the attachment or the phagocytic index. However, CR1 remained unable to promote phagocytosis of EC3b intermediates. Fc receptor-mediated functions were unaffected by the treatment with C3b. The active factor was characterized as monomeric C3b and, in particular, shown to be distinct from C5a. C3b purified by anion-exchange fast protein liquid chromatography on a Mono Q column or eluted from a monoclonal anti-C3b-Sepharose retained its modulating activity, while native C3 or C3 fragments such as iC3b, C3c or C3d,g were ineffective.

Antibodies, Monoclonal↗
PubMed1983

Differential characteristics of immune-bound antibodies in diffuse proliferative and membranous forms of lupus glomerulonephritis.

Diffuse proliferative (PGN) and membranous (MGN) glomerulonephritis represent contrasting histologic lesions in systemic lupus erythematosus (SLE). Serum, cryoglobulins, and renal biopsies in 8 SLE patients with PGN and 8 with MGN were studied in order to determine whether variations in the properties of immune-bound antibodies correlate with the pattern of glomerular involvement. Several immunologic parameters suggested differences in complement activation between the two groups. PGN cryoglobulins demonstrated immunoglobulin G (IgG) anti-native DNA (nDNA) subclass heterogeneity with highest titers of IgG3. These findings contrasted with the observation that MGN was characterized by a predominance of IgG4 in cryoglobulins. The major glomerular IgG subclasses in PGN were IgG3 and IgG1, while MGN biopsies demonstrated IgG4 in largest amount. Serum C1q was lower in PGN than in MGN. Serum anti-nDNA antibodies, solid-phase C1q-binding IgG immune complexes, and cryoglobulin protein concentrations were higher in PGN sera. Cryoglobulin complement component and control protein concentrations were greater in PGN than in MGN, while cryoglobulin Ig and immune-bound anti-nDNA were not different. In vitro C3 fixation by cryoglobulin anti-nDNA was greater in PGN than in MGN. Glomerular C1q, C4-binding protein (C4bp), and C3c were present in comparable amounts to IgG deposits in PGN biopsies, while in MGN IgG was demonstrable in greater quantities than C1q, C4bp, and C3c. In contrast, glomerular C3d (alpha 2d), C5, C6, P, and H were comparable in the two groups. It was concluded that immune-bound antibodies in cryoglobulins and in glomerular immune deposits in SLE PGN appear to activate complement via the classical and alternative pathways, while complement activation in MGN appears to occur predominantly via the alternative pathway. These differences in IgG subclass composition may account for the differential complement activation and may explain the contrasting histologic expression of immune aggregate localization in glomerular capillaries in these variants of lupus nephritis.

Antibodies, Antinuclear↗
PubMed1980

Relation of putative thioester bond in C3 to activation of the alternative pathway and the binding of C3b to biological targets of complement.

The reaction of [14C]methylamine with native human C3 led to the stoichiometric incorporation of methylamine, loss of hemolytic activity, and the concomitant exposure of a sulfhydryl group that could be labeled with [14C]iodoacetamide. Both labeled sites were located in the C3d portion of the alpha-chain, which is known to contain the metastable binding of C3b. The methylamine-modified C3 [C3(CH3NH2)] was shown to exhibit many of the functional properties of C3b, although the C3a portion of the molecule remained covalently attached. C3(CH3NH2) bound Factor B and beta 1H, and could be cleaved by C3b inactivator in the presence of beta 1H. C3(CH3NH2) added to human serum caused activation of the alternative pathway and consumption of C3. In presence of Factors B and D and Mg++, C3(CH2NH2) formed a C3 convertase. The convertase-forming material could be removed from solution by anti-C3a Sepharose and the preformed convertase was completely inhibited by purified antibody to C3a. This antibody did not affect the function of the C3 convertase that contained C3b. Similar functional properties were exhibited by C3 exposed for short periods of time to relatively low concentrations of chaotropic reagents, such as KSCN or guanidine. These results suggest that the initial C3 convertase of the alternative pathway may be formed from native C3, without proteolysis, by the attack of a variety of nucleophiles including water. The C3 convertase formed from this altered C3 then generates by proteolytic cleavage the initial metastable C3b that is capable of attaching to receptive surfaces. Conversion of C3 to C3b exposes one sulfhydryl residue as does modification of C3 with methylamine. When the C3d portion of C3b bound to zymosan particles via the metastable binding site was treated with radiolabeled methylamine, the fragment was released from the particles in radiolabeled form. These findings are consistent with the concept that native C3 contains an active carbonyl group, probably in the form of a thioester, which can either react with water to form functionally C3b-l;ike C3 or, upon enzymatic conversion of C3 to C3b, allows C3b to form an ester bond with hydroxyl groups on the target surface.

Complement Activation↗
PubMed1996

[Mixed warm and cold antibody type autoimmune hemolytic anemia associated with systemic lupus erythematosus].

A 56-year-old woman developed mixed warm and cold antibody type autoimmune hemolytic anemia (mixed AIHA) associated with systemic lupus erythematosus. The patient was admitted to our hospital for acrocyanosis and shortness of breath. High fever and jaundice were observed. Urinalysis revealed protein and hemoglobin, and the sediment contained granular and hyaline casts. Her erythrocytes agglutinated markedly at room temperature. Her hemoglobin was 5.6 g/dl and reticulocyts were 19.3%. Total bilirubin, GOT and LDH were elevated, while haptoglobin and complements were abnormally reduced. Polyclonal increase of immunoglobulin, ANA and anti-Sm antibody were detected. The direct antiglobulin test was positive; IgG1, IgG3 and C3d were detected on the red cell surface. The cold agglutinin (CA) titer was 4096, showing anti-I blood group specificity, and was still active at 30 degrees C. Upon administration of prednisolone gradual increase of hemoglobin and decrease of reticulocytes were observed, indicating the healing of hemolysis. CA disappeared but the direct antiglobulin test remained positive. Mixed AIHA has been defined as the presence of both warm and cold antibodies. In addition, the presence of symptoms of cold agglutinin disease, or low-titer and high thermal amplitude CA might be necessary for the diagnosis of mixed AIHA.

Anemia, Hemolytic, Autoimmune↗
PubMed1978

Requirements for beta1H globulin and C3b inactivator in the control of the alternative complement pathway in human serum.

Using beta1H-depleted and C3b inactivator (C3b1NA)-deficient sera we have investigated the regulatory roles of beta1H and C3bINA in the turnover of the alternative pathway. Spontaneous turnover of C3 and factor B occurred in both beta1H-depleted and C3bINA-deficient sera. In neither case was C3d generated. Prevention of activation could be achieved by the addition of the missing protein, but not by increasing the concentration of the remaining protein. Thus both beta1H and C3bINA must be present simultaneously to prevent spontaneous activation of the alternative pathway.

Beta-Globulins↗
PubMed1990

Genomic organization of human complement component C3.

Six overlapping clones, spanning the entire C3 gene and the 5' flanking region, were isolated from two genomic lambda libraries. Thirty exons, covering the complete beta chain and part of the alpha chain as far as the C3d region, were analyzed. The full exon-intron organization of the gene was deduced by combining our data with the reported organization of the alpha' chain (Barnum et al., 1989, J. Biol. Chem. 264: 8471-8474). The complete gene is 41 kb and consists of 41 exons. The C3 beta chain spans 13 kb from exon 1 to exon 16. Exon 16 encodes both alpha and beta chains. The alpha chain is 28 kb and contains 26 exons, including exon 16. The 5' flanking region was sequenced up to 514 bases upstream from the ATG start site. The major transcription initiation site was mapped to an adenine residue 61 bases upstream from the signal peptide by primer extension analysis of poly(A)+ mRNA from hepatocytes and U937 cells. The TATA box motif was assigned at position -85. Several putative binding sites for transcription factors were found in the 5' flanking region, suggesting possible pathways for the regulation of the C3 gene.

Base Sequence↗