[The receptor for the C3b fragment of complement, CR1, in pathology].
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Acquired Immunodeficiency Syndrome↗
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Epithelial deposits of immunoglobulin G1 and activated complement colocalise with the M(r) 40 kD putative autoantigen in ulcerative colitis.
The intestinal expression pattern and general tissue distribution of the M(r) 40 kD putative epithelial autoantigen in ulcerative colitis were re-examined by in situ two and three colour immunofluorescence staining including the murine monoclonal antibody 7E12H12. The intestinal distribution was also compared with the epithelial codeposition of IgG1 and activated complement (C3b and terminal complement complex) seen selectively in ulcerative colitis. The M(r) 40 kD antigen was found for the first time in goblet cells of normal terminal ileum and proximal colon but not in rectal goblet cells. By contrast, colonic enterocytes expressed this antigen apically with increasing intensity in a distal direction, expanding to intense cytoplasmic expression in rectal enterocytes. The antigen was also expressed by the epithelium of the fallopian tubes, major bile ducts, gall bladder, and epidermis but not by proximal gastrointestinal tract epithelium or 13 other extra-gastrointestinal organs. Activated complement and IgG1 often colocalised with the M, 40 kD antigen apically on the surface epithelium in active ulcerative colitis but not in Crohn's disease. Our results support the idea that an autoimmune response to this antigen, leading to complement activation mediated by IgG1, is a possible pathogenetic mechanism for epithelial damage and persistent inflammation in ulcerative colitis.
Adolescent↗
Local complement activation in inflammatory bowel disease.
To trace sites for local complement activation in inflammatory bowel disease, an indirect two-colour immunofluorescence method was applied on prewashed and directly ethanol-fixed mucosal specimens from patients with ulcerative colitis, Crohn's colitis, or terminal ileitis. Monoclonal antibodies to the IgG subclasses and to neoepitopes of activated complement C3b and the terminal complement complex (TCC) were used in combination with rabbit antiserum to immunoglobulins and various complement components. Deposits of activated C3b were found on the luminal face of the surface epithelium in the most affected ulcerative colitis specimens from 91% of 23 studied patients, together with cytolytic TCC in 81%. Furthermore, there was a selective deposition of the immunoglobulin G subclass 1 (IgG1) within the epithelial immune complexes in 63% of 11 studied patients. These results suggested that IgG1 autoantibodies to brush-border antigen(s) induce a complement-mediated attack on the epithelium in ulcerative colitis. The epithelial complement deposition seen in Crohn's disease tended to be more granular and was observed in 5 of 10 patients with colitis and in 4 of 10 with ileitis. No co-localization of IgG was observed, suggesting that complement activation had been induced by the alternative pathway. Type III immune reaction may, in addition, take place in both diseases since there was evidence of continuous vascular complement activation in submucosal blood vessels.
Blood Vessels↗
Heparin prevents formation of the human C3 amplification convertase by inhibiting the binding site for B on C3b.
Fluid-phase heparin prevents generation of the C3 amplification convertase of human complement, C3b, Bb most likely by inhibiting the formation of the bimolecular complex between cell-bound C3b and B. The effect of heparin on the binding of B to C3b was examined using 125I-labelled B and C3b-bearing sheep erythrocytes (EsC3b). In the absence of heparin, B bound to EsC3b with an affinity of 0.5-1 X 10(6) M-1 in the presence of 5 mM Mg2+. Incremental amounts of heparin (100-700 micrograms/10(7) EsC3b) inhibited the binding of 125I-B to C3b in a dose-dependent manner. Scatchard analysis of the binding data in the presence of four inhibitory concns of heparin revealed that heparin did not affect the binding affinity of B for C3b but decreased the number of C3b sites recognized by B on the cells. No inhibition of binding occurred in the presence of totally (N- and O-) desulfated heparin which has no anticomplementary activity. These results demonstrate that heparin prevents generation of the C3 amplification convertase by binding to cell-bound C3b and masking the binding site for B on C3b.
Animals↗
Membrane receptors for IgG and complement (C4, C3b and C3d) on human eosinophils and neutrophils and their relation to eosinophilia.
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Animals↗
[Erythrocyte complement receptor (C3b) expression in multiple sclerosis].
The study was carried out in 121 patients with multiple sclerosis and a control group of 519 healthy individuals. In 13 cases of multiple sclerosis and 12 controls family studies were carried out. Complement receptors (C3bR) on the erythrocytes were demonstrated by the haemagglutination test using human IgG heat-aggregated and guinea pig serum which served as a source of complement. On the basis of haemagglutination intensity and results of radioimmunoassay three phenotypes of complement receptor were isolated: high HH(C3bRh/C3bRh) producing strong agglutination, medium HL (C3bRh/Cbl) producing weak agglutination, and low phenotype LL (C3bR1/Cbl) in which no visible agglutination of erythrocytes was noted. Considerable differences were observed in the distribution of these phenotypes between controls and multiple sclerosis patients in whom the low phenotype (C3bR1/C3bR1) was more frequent. Family studies of controls suggested presence of two codominant alleles C3bRh and C3bR1 with Mendelian inheritance while similar studies of multiple sclerosis patients it was found that e.g. a child with multiple sclerosis whose parents had high C3bR phenotypes, that it were homozygotes for the C3bRh gene, had low phenotype. On the other hand, the high phenotype was found in a child of a female multiple sclerosis patient with the low phenotype (C3bR1/C3bR1). These observations suggest that reduced expression of the complement receptor on the erythrocytes depends in multiple sclerosis on the disease process in the first place, and not on genetic factors.
Adult↗
Circulating immune complexes and peripheral B lymphocytes in non insulin dependent diabetic patients.
Serum circulating immune complexes (CIC) were measured in 27 patients with non insulin dependent diabetes (NIDD). This was done by measuring the degree of binding to human red blood cells by the C3b complement fraction. At the same time, the percentage of B lymphocytes in peripheral blood was evaluated by means of the direct immunofluorescence technique for surface IgG and EAC rosettes for cells with receptors to C3b complement fraction. Twenty normal control subjects were simultaneously studied by the same methodology. An increase in serum CIC was observed in NIDD patients, as compared to healthy subjects. Values were 35.8 +/- 3.2 and 25.6 +/- 2.1 micrograms/ml, respectively. The percentage of cells with surface IgG was 10.2 +/- 0.8 in diabetic patients; this value was significantly higher than that found in the control group (6.0 +/- 0.8). No significant quantitative difference in the percentage of EAC binding cells was found between NIDD patients and the control group. When NIDD patients were divided into two groups, those with and those without microvascular complications, neither differences in CIC levels nor in the percentage of B lymphocytes were found. Nor any correlation could be found between the highest individual CIC levels and the highest percentage of lymphocytes with surface IgG. These data show an increase of CIC levels and of cells with surface IgG in NIDD patients who had not received insulin at least not in a constant or prolonged therapy. This could allow us to suspect the existence of antigen-antibody complexes different to insulin-antiinsulin CIC found in insulin dependent diabetes.
Adult↗
Complement-opsonized IgG antibody/dsDNA immune complexes bind to CR1 clusters on isolated human erythrocytes.
We used fluorescence microscopy, quantitative FACS analyses, and radioimmunoassays to examine the distribution of complement (C3b)-opsonized antibody/dsDNA immune complexes (IC) bound to normal human erythrocytes (RBCs) via immune adherence (IA). IC were detected with fluorescent anti-human IgG, and the RBC IA-receptor (CR1) was revealed with monoclonal antibodies (Mabs) to CR1 and fluorescent anti-mouse IgG. Under saturating conditions RBCs exhibit a large heterogeneity in binding; a significant fraction binds no IC. The positions of bound IC coincide with CR1 clusters on RBCs, as predicted by several investigators. FACS experiments indicate an excellent correlation between CR1 number and IC binding within an RBC population. The number of CR1 clusters able to bind IC is proportional to the number of CR1 per RBC. However, IC (fluorescent spots) detected per RBC (on average less than 10) are less than the average number of IC bound (20-30). This suggests that each fluorescent spot represents a small number of aggregated IC bound to a CR1 cluster. These "patches" of aggregated complexes may facilitate transfer of RBC-bound IC to cells of the mononuclear phagocytic system. Finally, not all the CR1 clusters bind IC, suggesting that proper geometric alignment of multiple C3b per IC with several CR1 in the cluster is required for IA.
Antigen-Antibody Complex↗
Immune complexes in preeclampsia and normal pregnancy.
We determined in normal nonpregnant (group I) and normal pregnant (group II) women and in patients with preeclampsia (group III): (1) immunoglobulins and complement C3b associated with polymorphonuclear leukocytes and platelet surfaces in an attempt to evaluate the interaction in vivo of immune complexes with the membranes of these cells; (2) the occurrence of circulating immune complexes; (3) the serum levels of immunoglobulins, C3, and C4; and (4) the plasma levels of complement C3d. In patients with preeclampsia (group III), the percentages of polymorphonuclear leukocytes and platelets positive for membrane-bound IgG, IgM, IgA, and C3 were significantly higher than the percentages in groups I and II. In group III, there also was a significant increase in circulating immune complexes, as compared to groups I and II. However, circulating immune complexes were also present in significant amounts in normal pregnancy (group II). The plasma levels of complement C3d were markedly increased in the most severe cases of preeclampsia.
Adult↗
Effect of disodium cromoglycate on activation of human eosinophils and neutrophils following reversed (anti-IgE) anaphylaxis.
Immunological release of histamine and lipid mediators is known to occur when basophils, contained in whole blood human leucocytes, are incubated with anti-IgE (reversed anaphylaxis). In the present study we show that IgE-dependent stimulation of basophils was associated with activation of bystander eosinophils and neutrophils, as assessed by enhanced complement (C3b) and IgG (Fc) rosettes, and increased cytotoxicity for complement-coated schistosomula of Schistosoma mansoni. These changes in eosinophil and neutrophil function were totally inhibited in a dose-dependent fashion by prior incubation with disodium cromoglycate (DSCG). In all in vitro systems examined, complete inhibition of enhancement was observed with concentrations as low as 10(-7) moles/l. In contrast, DSCG had no effect on histamine release, or the percentage of rosettes or cytotoxicity prior to anti-IgE stimulation. These results suggest that DSCG inhibits activation of inflammatory cells consequent to an IgE-dependent stimulus.
Anaphylaxis↗
Endothelial cells of bovine pulmonary artery lack receptors for C3b and for the Fc portion of immunoglobulin G.
Bovine pulmonary endothelial cells do not possess receptors for the 3b component of complement (C3b) or for the Fc portion of immunoglobulin G. The lack of these receptors may help explain the nonthrombogenic function of endothelial cells. Our findings rule out the possibility that endothelial cells participate in pulmonary immune complex disease through the binding of C3b or Fc fragments.
Animals↗
Activation of complement C3 by different calcium phosphate powders.
The ability of different calcium phosphate to activate the complement system is studied by crossed immunoelectrophoresis demonstrating conversion of C3 to C3b. Complement consumption is determined by a haemolytic assay CH50. Hydroxyapatite powders after sintering induce a significant conversion of C3 and reduction of CH50 value. However the complement system is not activated by sintered tricalciumphosphate (beta-whitlockite). This is not related to the adsorption behaviour; it depends neither on chemical composition nor on crystal lattice. It is argued that C3 conversion is not triggered by the convertase of the classical pathway.
Calcium Phosphates↗
Complement receptors and regulatory proteins in human atherosclerotic lesions.
Complement activation in human atherosclerotic lesions is indicated by the presence of C5b-9 terminal complexes. By using monoclonal antibodies to the complement C3b receptor (CR1) and the iC3b receptor (CR3), it was observed that approximately 20% of the cells in complicated human carotid lesions express CR1 and CR3 antigens. One to five percent of complement receptor-positive cells stained for smooth muscle cell-specific myosin, and the remainder were determined to be predominantly macrophages, based on their reactivity to anti-LeuM3 (CD14) monoclonal antibody. No C3dg receptor (CR2)-positive cells were observed in any of the eight lesions examined. The complement regulatory glycoprotein decay accelerating factor (DAF) was widely distributed extracellularly, in addition to being present on 20% to 60% of the total cell population. Factor H, a plasma protein that regulates alternative pathway C3 convertase formation, was observed extracellularly in 70% of the lesions examined. C1 inhibitor was present in a few plaque specimens, was relatively sparse, and appeared largely cell associated. Terminal C5b-9 complement complexes were pervasive in all lesions. Both the complement regulatory proteins and the activation products were limited to the area of lesion involvement and were absent from normal arterial wall. The results demonstrate that molecules involved in complement regulation and complement ligand binding are present in atherosclerotic lesions, where they may function to modulate the activities of complement.
Arteriosclerosis↗
The glomerular complement receptor in immunologically mediated renal glomerular injury.
We examined 25 renal-biopsy specimens to determine whether there is a relation between immunologically mediated renal diseases and the activity of complement receptors that selectively bind antigen-antibody complexes containing activated third component of complement (C3b). These receptors have been termed glomerular complement receptors. Renal lesions associated with in vivo deposition were associated with a loss of receptor sites as demonstrated by reduced or absent in vitro binding of C3b-coated test reagents by glomerular complement receptor. These findings suggest that binding of complement containing immune complexes to glomerular complement receptors in human subjects may participate in the immunopathologic processes of certain immune-complex-mediated renal diseases.
Antibody Specificity↗
Covalent binding of [35S]cysteine to the labile binding site of the third component of complement: a physiological approach.
The alternative pathway of complement was activated physiologically by agarose beads to which [35S]cysteine had been bound by a disulfide link. The activated form of the third component of complement, C3b, which had bound to the radioactive cysteine was then released from the agarose bead with dithiothreitol. The [35S]cysteine was shown to be covalently bound to the alpha' chain of C3b, and to its known major breakdown product, the 66,000-Da polypeptide. This is highly suggestive that complement activation has led to formation of a peptide bond between the radioactive cysteine and the labile binding site on the alpha' chain of C3b. This radioactive marker will enable the amino acid sequence of the labile binding site to be determined, with the knowledge that the labeling of the amino acid(s) has occurred during physiological activation.
Complement Activation↗
Blocking immune evasion as a novel approach for prevention and treatment of herpes simplex virus infection.
Many microorganisms encode immune evasion molecules to escape host defenses. Herpes simplex virus type 1 glycoprotein gC is an immunoevasin that inhibits complement activation by binding complement C3b. gC is expressed on the virus envelope and infected cell surface, which makes gC potentially accessible to blocking antibodies. Mice passively immunized with gC monoclonal antibodies prior to infection were protected against herpes simplex virus challenge only if the gC antibodies blocked C3b binding. Mice treated 1 or 2 days postinfection with gC monoclonal antibodies that block C3b binding had less severe disease than control mice treated with nonimmune immunoglobulin G (IgG). Mice immunized with gC protein produced antibodies that blocked C3b binding to gC. Immunized mice were significantly protected against challenge by wild-type virus, but not against a gC mutant virus lacking the C3b binding domain, suggesting that protection was mediated by antibodies that target the gC immune evasion domain. IgG and complement from subjects immunized with an experimental herpes simplex virus glycoprotein gD vaccine neutralized far more mutant virus defective in immune evasion than wild-type virus, supporting the importance of immune evasion molecules in reducing vaccine potency. These results suggest that it is possible to block immune evasion domains on herpes simplex virus and that this approach has therapeutic potential and may enhance vaccine efficacy.
Animals↗
Expression of Ia antigens on macrophages is reduced after stimulation with homologous C3b.
The complement cleavage product C3b was examined for its ability to influence the expression of Ia antigens on macrophages. Monoclonal anti-Ia antibodies were applied for quantitation of Ia antigens by using FACS analysis. Albumin-elicited guinea pig peritoneal macrophages were cultured for 48 hr in the presence of C3b. C3b at final concentrations varying from 10 to 80 micrograms/ml reduced the proportion of Ia-positive macrophages from 87 to 25%. The C3b-stimulated loss of Ia antigens from the macrophage surface was mediated by metabolites of the cyclooxygenase pathway as shown by the inhibitory effect of indomethacin. Exposure of macrophages to C3b for 5 min was sufficient to induce Ia reduction, seen after subsequent 48-hr incubation. C3b generated in vivo in the course of inflammatory reactions might therefore influence the interaction of immunocompetent cells by modulating macrophage Ia expression.
Animals↗
Mode of inheritance of decreased C3b receptors on erythrocytes of patients with systemic lupus erythematosus.
The erythrocytes of patients with systemic lupus erythematosus have been shown to have a decreased number of receptors for the major cleavage fragment of the third component of complement (C3b). We studied the basis for this decreased number of C3b receptors by measuring the uptake of anti-C3b-receptor antibody on cells from 113 normal subjects, 38 patients with systemic lupus erythematosus, 14 of their spouses, and 47 of their relatives. The normal subjects had 5014 +/- (mean +/- S.E.M.) receptor sites per cell, but the patients and their relatives had significantly fewer sites--2809 +/- 241 and 3167 +/- 196, respectively (P less than 0.0005). The number of sites in the patients' spouses did not differ from normal (P greater than 0.3). Three phenotypes, indicated by the numbers of receptors, occurred in the normal population; a high phenotype (HH, with 5500 to 8500 sites per cell), an intermediate phenotype (HL, with 3000 to 5499), and a low phenotype (LL, less than 3000). These three phenotypes were present in 34, 54, and 12 percent, respectively, of the normal subjects; in contrast, 5, 42, and 53 per cent of patients had these respective phenotypes. Pedigree analyses indicated that these phenotypes were inherited in an autosomal codominant manner. We conclude that the decreased number of C3b receptors in lupus is inherited, not acquired.
Adult↗