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PubMed1993

Human IgG in immune complexes bound to human erythrocyte CR1 is recognized differently than human IgG bound to an erythrocyte surface antigen.

We have developed several methods, including a new use of magnetic cell separation techniques, to examine how human IgG bound to human erythrocytes can be recognized. We find that human IgG in complement-opsonized immune complexes bound to erythrocyte CR1 is less accessible to several probes than human IgG bound to the rhesus antigen on erythrocytes. These findings suggest that the mechanism by which immune complexes are removed and cleared from erythrocyte CR1 in the circulation is different from the mechanisms which lead to splenic clearance of IgG sensitized erythrocytes.

Antigen-Antibody Complex↗
PubMed1994

An enzyme-linked immunosorbent assay for complement regulatory proteins and membrane-bound immunoglobulins on intact red blood cells.

We have developed an ELISA technique to examine RBC-bound molecules in autoimmune disorders. In particular, the technique has enabled us to investigate the role of some complement regulatory proteins in immune complex transport and to suggest that decay accelerating factor (DAF) may be involved in this process. In both autoimmune haemolytic anaemia (AHA) and systemic lupus erythematosus (SLE) a sub-set of individuals was identified, on the basis of patterns of complement receptor 1 (CR1) expression on RBC. In these patients, CR1 identified using the monoclonal antibody E11 was low or absent whereas CR1 identified using a DAKO monoclonal antibody (C3RTo5) was present at normal levels.

Anemia, Hemolytic, Autoimmune↗
PubMed1991

The effect of soluble complement receptor type 1 on hyperacute allograft rejection.

A major obstacle to successful organ transplantation in sensitized recipients is antibody-mediated hyperacute rejection. We hypothesized that human recombinant soluble complement receptor type 1 (sCR1), which inhibits activation of the complement cascade at multiple stages, would delay this process. Using a well-established model of hyperacute rejection, 21 Lewis rats each received three successive ACI rat skin grafts which resulted in high serum titers of ACI-specific antibodies. These hypersensitized Lewis rats then received heterotopic ACI cardiac allografts. Immediately prior to allograft reperfusion, sCR1 at 3 mg/kg (n = 11) or an equivalent volume of phosphate-buffered saline (PBS) (n = 10) was administered intravenously. Five minutes following allograft reperfusion, hemolytic complement activity was reduced by 63 +/- 2% (SEM) in the sCR1 group vs 25 +/- 3% in the PBS group (P less than 0.0001, Wilcoxon rank sum test (WRST)). Graft survival in the sCR1 group was prolonged to 32.0 +/- 4.47 hr vs 3.25 +/- 0.81 hr in the PBS group (P less than 0.0001, WRST). Serial histologic examination of allografts showed that sCR1 therapy prevented the early development of luminal platelet thrombi in the allograft coronary vessels. This study demonstrates that a single 3 mg/kg dose of sCR1 significantly prolongs ACI cardiac allograft survival in the hypersensitized Lewis rat recipient. Complement inactivation, mediated by sCR1, may prove useful for transplantation in sensitized recipients.

Acute Disease↗
PubMed1990

Cell differentiation in Wilms' tumor (nephroblastoma): an immunohistochemical study.

Using an indirect immunoperoxidase technique, we tested frozen specimens from 12 Wilms' tumors with monoclonal antibodies (MoAbs) reacting against a large panel of molecules including laminin, fibronectin, cytokeratin, vimentin, villin, CD24, CALLA/CD10, CR1, CD26, class I and class II major histocompatibility complex (MHC) molecules, and endothelium factor VIII. These molecules were chosen because they are markers of specific segments of the mature kidney and because their loss or acquisition is indicative of different steps of human nephrogenesis. KI67 MoAb was used to evaluate the proliferating activity of the cells. The blastemal component (cell compact areas) of Wilms' tumors consisted of vimentin-positive cells with a fibronectin network. However, signs of epithelial maturation were present in compact areas where cytokeratin-positive cells producing laminin were observed. The cells exhibited a high degree of proliferating activity. The tubule formations consisted of cytokeratin-positive cells and had a defined laminin border. All the cells, whether in compact areas or in tubules, were strongly CD24-positive. Some tubular formations showed signs of proximal maturation with the presence of CALLA, CD26, and even villin. In four cases class I-MHC molecules were expressed by some tubular cells. Large cystic cavities present in five cases were edged by cytokeratin, CD24-positive cells, or by vimentin, CALLA, CR1-positive cells. Some glomeruloid bodies, present in two cases, were also composed of vimentin, CALLA, and CR1-positive cells which correspond to the mature podocyte phenotype. The interstitial tissue contained mainly laminin and fibronectin network with macrophages and few CD3 lymphocytes. The presence of large cells with muscular differentiation was noted; round vimentin and CD26-positive cells were also seen. The endothelial cells of the vessels exhibited vimentin, factor VIII, and class I and class II MHC molecules as do mature cells, but in some cases the endothelial cells lacked class II molecule expression and were CALLA-positive. These results which confirmed and extended those previously described show that cell differentiation in Wilms' tumor mimics that observed during metanephros development. Moreover, this study shows that tumoral cells in nephroblastoma share several antigens with cells from lymphoid lineage (CD24, CALLA, and CD26) as do developing and mature kidney cells. Such cell phenotype dissection provides a useful and reliable tool for testing the influence of various factors on the development of hetero-transplanted or cultured Wilms' tumors.

Antigens, CD↗
PubMed1983

Monoclonal antibodies to human complement receptor (CR1) detect defects in glomerular diseases.

The complement receptor for C3b of the epithelial cells of human glomeruli is structurally and functionally very similar or identical to CR1, the complement receptor for C3b and C4b present on the membrane of red cells and leukocytes. Four monoclonal antibodies directed against separate epitopes of CR1 react with an antigen in the glomeruli, which appears to be present on the epithelial podocytes. Moreover, the monoclonal antibodies very effectively inhibit the binding of C3b-bearing red cells to the glomeruli. The pattern of immunofluorescence of the receptor was normal or slightly altered in patients with minimal change disease, mesangial proliferative glomerulonephritis (GN), or idiopathic membranous GN. Glomeruli with endocapillary proliferation showed some attenuation of staining. Glomeruli in which the capillary tuft architecture was altered, or of patients with systemic lupus erythematosus, or of patients with diffuse diabetic nephropathy tended to have few foci or no staining for the receptor. No correlation was found between the intensities of staining of the C3b receptor and of C3 antigen deposited in the glomeruli.

Amyloidosis↗
PubMed1985

Low capacity of erythrocytes to bind with immune complexes via C3b receptor in patients with systemic lupus erythematosus: correlation with pathological proteinuria.

Erythrocytes from 51 patients with systemic lupus erythematosus and 75 controls were tested for the capacity to bind aggregated human gamma-globulin labeled with radioiodine in the presence of complement. Both in patients and controls, a trimodal distribution of binding capacity was observed. Low (less than 9% of the added radioactivity), intermediate (9-17%), and high binding (more than 17%) were observed in 13, 58, and 29% in controls and in 49, 43 and 8% in lupus patients. The low binding capacity of erythrocytes persisted even after patients entered remission following steroid therapy. A genetic control of binding capacity was supported by familial surveys. Prevalence of pathological proteinuria was significantly higher in patients with low binding capacity than those with intermediate or high binding capacity (16/25 vs 7/26, P less than 0.01). These results indicate that an impaired physiological disposal of immune complexes via the erythrocyte C3b receptor in lupus patients may contribute to the development of renal involvement.

Adolescent↗
PubMed1985

Ontogenesis of the glomerular C3b receptor (CR1) in fetal human kidney.

Ontogenesis of the glomerular C3b receptor (CR1) was studied in kidneys from 16 fetuses aged from 9 to 32 weeks, using immunohistochemical techniques and the F(ab')2 fragment of a monospecific rabbit antibody to CR1, and adherence of C3b-coated sheep erythrocytes. By indirect immunofluoresence, anti-CR1 stained presumptive glomerular epithelium from the end of the S-body stage of nephron differentiation. Staining increased with visceral epithelial cell proliferation and with differentiation of the nephron from the subcortical to the juxtamedullary part of the fetal kidney. Using electron microscopy and an indirect immunoperoxidase technique, CR1 antigen was detected on the plasma membrane in the basolateral part of primitive podocytes from the late S-body stage, following the acquisition by podocytes of the capacity to synthetize a basal lamina. Endothelial cells and mesangial cells did not stain for CR1 antigen. CR1 antigen was expressed by podocytes from the same stage of glomerular differentiation as was the CALLA antigen. Glomerular expression of CR1 on podocytes preceded that of Ia on glomerular endothelial cells. C3b-bearing sheep erythrocytes only adhered to clover-like lobulated glomeruli at a late stage of glomerular differentiation. Glomerular CR1, a specific marker of glomerular capillary epithelial cells is one of the earliest markers expressed by resident glomerular cells during renal ontogenesis.

Fetus↗
PubMed1986

Inherited deficiencies of complement and complement-related proteins.

The complement cascade and cell-surface proteins related to the complement system are critically important to host defense, immune complex catabolism, and possibly immunoregulation. Genetically determined deficiency states have been described for many complement proteins as well as for fluid phase and cell-borne inhibitors of the complement cascade and cellular complement receptors. Autoimmune diseases and enhanced susceptibility to infection are the dominant clinical manifestation of these deficiencies. Classical pathway deficiencies and low numeric expression of erythrocyte C3b receptors (CR1) are typically associated with autoimmune disorders, while alternative pathway, terminal component, and leukocyte iC3b receptor (CR3) defects predispose to pyogenic bacterial disease. This distinction is not absolute, however, and both classes of disease may appear in most of the reported deficiency states. Specific pharmacologic therapy exists for C1-inhibitor deficiency (hereditary angioedema). Management of other complement deficiencies currently involves sustained diagnostic suspicion and meticulous management of complicating diseases.

Anaphylatoxins↗
PubMed1986

Phagocyte defects.

Although inherited forms of phagocyte defects affect a small proportion of the general population, their clinical course can be altered dramatically by a physician's awareness of these diseases and modifications of the approach to and treatment of affected patients. The most common syndromes are chronic granulomatous disease of childhood (CGD), the Chediak-Higashi syndrome (CHS), the hyperimmunoglobulin-E-recurrent infection (Job's) syndrome (HIE), and myeloperoxidase (MPO) deficiency. CGD patients have defects in the oxidative metabolism involved in killing catalase-positive organisms. CHS patients have giant granules defective in fusing with phagosomes and subsequent killing of ingested organisms. HIE patients have abnormal chemotaxis and elevated IgE levels and are susceptible to skin infections with Staphylococcus aureus and recurrent sinopulmonary infections. MPO-deficient patients often go undetected since they rarely have recurrent infections unless they have a concomitant disease such as diabetes mellitus. Patients with a recently described syndrome, C3bi receptor deficiency, have recurrent bacterial infections and persistent leukocytosis, and their neutrophils have abnormal adherence and phagocytosis. The absence of specific granules is a more rare entity but these patients also have recurrent infections thought to be secondary to a chemotactic defect and a minor abnormality of microbial killing exhibited by their neutrophils. This review will focus on the clinical presentation and management of these patients.

Chediak-Higashi Syndrome↗
PubMed1986

Complement, membrane glycoproteins, and complement receptors: their role in regulation of the immune response.

To determine the effect of complement on the normal antibody response we studied seven patients with genetically determined complement component deficiencies, guinea pigs deficient of C4 and C2, respectively, and two patients whose neutrophils and monocytes lack the C3bi receptor. Patients deficient of early complement components (C4, C2, C3) have abnormal antibody responses to the T-cell-dependent antigen, bacteriophage phi X 174. Complement-deficient guinea pigs (C4, C2) produce less antibody than normal guinea pigs and are unable to maintain measurable antibody levels; during secondary immunization they fail to develop amplification and to switch from IgM to IgG. This defect can be overcome by increasing the antigen dose or by injecting normal guinea pig serum at the time of the primary (but not the secondary) immunization. Patients with deficiency of the C3bi receptor were shown to have a significantly depressed antibody response to T-dependent antigens. We postulate that the contribution of complement to the mature humoral immune response is related to activation of C3. The initial production of IgM following antigen injection leads to antigen-antibody complexes which interact with complement, to be nonspecifically trapped by C3b and C3bi receptors on B cells or macrophages. Thus antigen is selectively accumulated within the lymphoid organs and in turn may entrap antigen-specific B cells by interaction of the trapped antigen with surface immunoglobulin. As a result, close approximation between antigen, antibody, and a network of specific and nonspecific lymphoid cells is initiated, allowing generation of specific memory cells and initiation of a prompt mature antibody response on subsequent exposure to antigen.

Animals↗
PubMed1986

Interaction between immune complexes and C3b receptors on erythrocytes.

We studied the interaction between immune complexes (IC) and C3b receptors (CR1) on erythrocytes (E) and showed that activation of the classical complement pathway is essential for the binding of IC to CR1, that C3b inactivator (I) and beta 1H (H) are essential for the release of IC from CR1, that CR1 retain the capacity to bind IC after repeated binding and release of IC, and that on the other hand, IC lose the capacity to bind to CR1 after repeated binding and release. These results suggest a dynamic in vivo interaction between IC and CR1 on E which are supposed to transport IC to the reticuloendothelial system. CR1 on E, with a help of I and H, might make IC less harmful to the tissues in the process of releasing IC from E.

Antigen-Antibody Complex↗
PubMed1986

Correlative expression of C3b receptors in the glomerulus and on erythrocytes.

The reactivity of glomerular C3b receptors (CR1) measured by the number of sheep erythrocytes bearing C3b (EAC) that adhered to glomeruli in frozen sections, was compared with the reactivity of erythrocyte CR1, which was determined by immune adherence hemagglutination (IAHA), in 22 patients with renal and non-renal diseases. Among seven patients with primary glomerulonephritis whose erythrocytes were positive for IAHA, the reactivity of glomerular CR1 was high in five. In the remaining two, the reactivity of glomerular CR1 was low, accompanied by severe sclerotic glomerular changes. Erythrocytes from five of six patients with systemic lupus erythematosus were IAHA negative, and their glomeruli failed to produce adherence of EAC, even in three cases in which there were no detectable C3 deposits or histopathological changes. In the other nine patients without appreciable glomerular changes, the reactivity of glomerular CR1 was low in three along with negative erythrocyte IAHA, whereas the remaining six exhibited high CR1 reactivity both in glomeruli and on erythrocytes. The results indicate a close correlation between the expression of CR1 in the glomerulus and on erythrocytes.

Antigen-Antibody Complex↗
PubMed1986

Anti-C3b-receptor (CR1) antibodies in patients with systemic lupus erythematosus.

Using an enzyme-linked immunoadsorbent assay, IgG in the plasma and purified IgG from 2 patients with systemic lupus erythematosus (SLE) were found to strongly react with purified C3b receptor (CR1) insolubilized on microtiter plates. The amount of IgG that bound to CR1 in 201 plasma samples from 179 other patients with SLE did not significantly differ from that which bound in 72 control samples from normal individuals. Purified IgG from the patients with anti-CR1 reactivity did not inhibit CR1 function in vitro. The number of CR1 antigenic sites expressed on erythrocytes from both patients was much lower than that observed in a normal population and in the lowest range of the decreased numbers found in patients with SLE. The occurrence of anti-CR1 antibodies in patients with SLE could provide an acquired mechanism for decreased expression of CR1 through antigenic modulation of the receptor on precursor cells and/or alter the function of cells of the immune system bearing C3b receptors.

Animals↗
PubMed1987

Immunohistochemical study of intrathyroidal lymph follicles.

Tissue samples from 76 cases of thyroid disease containing germinal centers (GCs) were selected from 396 cases of various thyroid diseases for immunohistochemical analysis of the GC and follicular dendritic cell (FDC). These 76 cases included 28 cases of thyroid cancer, 23 of chronic thyroiditis, 12 of nontoxic goiter, 8 of adenoma, and 5 of Graves' disease. In many lymphoid GCs IgG, IgM and kappa and lambda light chains were detected with a lacy dendritic pattern. Only thyroglobulin (Tg), among the various thyroid-associated antigens sought, was stained in GCs and was found in the same distribution as immunoglobulins. Tg was found in all of the disease categories studied. Moreover, early components in the classical complement (C) pathway, that is, C1q, C4, C3c, C3d, and C5, were detected in almost all GCs in the thyroid tissues in a lacy dendritic pattern. C3d was intensely positive and was seen also by immunoelectron microscopy on the cell surface of FDCs. It is concluded that not only immunoglobulins but also Tg and early C components are closely related to the GC and FDC in the intrathyroidal lymph follicle.

Antigens↗
PubMed1988

Surface expression of Gp 165/95, the complement receptor CR3, as a marker of disease activity in systemic Lupus erythematosus.

Complement-derived peptides capable of activating neutrophils appear in plasma during flares of systemic lupus erythematosus (SLE). One possible consequence of such activation is an increased expression of the surface adhesion promoting heterodimer gp165/95 (the complement receptor CR3). The quantity of gp165/95 was measured by indirect immunofluorescence using a monoclonal antibody of the CD11b group. Mol, directed to the alpha chain. Eighty-three percent of 26 patients with SLE expressed gp165/95 on their neutrophil surface to a greater extent than normals. The highest levels of surface gp165/95 were found in patients with the most severe disease, who also had the highest levels of the circulating anaphylatoxin C3a (mean = 560 ng/ml versus 147 ng/ml in controls). There was a negative correlation between expression of gp165/95 and absolute neutrophil count. Five individuals followed serially demonstrated an increase in surface gp165/95 during disease flares which returned to normal with clinical improvement. These data support the hypothesis that the neutrophils of patients with active SLE recruit increased numbers of gp165/95 molecules to their surface in respose to complement activation; these activated neutrophils bearing increased numbers of adhesion promoting gp165/95 may contribute to endothelial injury in SLE.

Antibodies, Monoclonal↗
PubMed1990

Immune complexes bind preferentially to specific subpopulations of human erythrocytes.

Primate erythrocytes have complement receptors (CR1) that, both in vivo and in vitro, bind immune complexes (IC) opsonized with C3b. The present study was undertaken to determine whether the ability of human erythrocytes to bind IC is a characteristic shared by all erythrocytes. Binding of IC to erythrocytes probably involves the interaction of several C3b molecules with several CR1 clustered in small areas of the erythrocyte surface. To identify IC binding CR1 clusters, we first assessed the binding to erythrocytes of fluorescein-labeled polystyrene beads coated with monoclonal anti-CR1 antibodies (anti-CR1-beads) and second, performed IC. The binding of these ligands to erythrocytes was evaluated by immunofluorescence microscopy and flow cytometry. We found that only a fraction of erythrocytes from normal individuals bound anti-CR1-beads specifically and the percentage of erythrocytes able to bind beads increased with increasing numbers of CR1 per erythrocyte. However, the number of anti-CR1-beads bound per erythrocyte varied among cells from the same individual. We demonstrated further that the erythrocyte binding sites for anti-CR1-beads are also binding sites for opsonized IC. This was shown by demonstrating that anti-CR1-beads inhibited the binding of opsonized IC to erythrocytes and opsonized IC inhibited the binding of anti-CR1-beads to erythrocytes. Incubation of erythrocytes with opsonized IC, followed by FITC-labeled secondary antibodies, confirmed that indeed only a fraction of erythrocytes is capable of binding opsonized IC and that the binding sites for IC occupy small regions on the erythrocyte membrane. By contrast, we demonstrated that greater than 90% of erythrocytes express CR1. In conclusion, only some erythrocytes have the capacity to bind IC. Differences in the ability of erythrocytes to bind IC are probably related to differences in the clustering of CR1 in the erythrocyte membrane. Anti-CR1-beads identify erythrocyte binding sites for IC. These beads should prove useful to assess the changes that occur in the erythrocyte CR1 after exposure to IC in vivo.

Antibodies, Monoclonal↗