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PubMed1989

Quantification by ELISA of erythrocyte-bound C3 fragments expressing C3d and/or C3c epitopes in patients with factor I deficiency and with autoimmune diseases.

A sensitive ELISA assay for quantifying erythrocyte (E) bound C3 fragments was developed. The assay employs a double-antibody sandwich technique, using polyclonal anti-C3d or anti-C3c antibodies to quantify C3 fragments, expressing C3d and/or C3c epitopes in washed, detergent-solubilized E. The assay detected 50-120 molecules of C3d per E in healthy individuals. Antigens reacting with anti-C3c antibodies were also detected on E from normal individuals, but the density of C3c-epitopes was 0.9-2.4 times lower than that of C3d-epitopes. In 2 patients with congenital factor I deficiency significantly increased density of E-bound C3c- as well as C3d-antigen was observed. Plasma infusion in one of the patients induced a loss of E-bound C3c-antigens, indicating cleavage of E-bound C3b to iC3b and further to C3c and E-bound C3d. Loss of C3c-antigens also occurred following in vitro treatment with normal human serum of E from one of the patients. Two thirds of 22 patients with systemic lupus erythematosus (SLE) and of 18 patients with rheumatoid arthritis had significantly increased density of E-bound C3d, the highest density being 490 C3d molecules/E in an SLE patient. The density of E-bound C3d correlated with the plasma-C3d concentration, indicating that the coating of E with C3d reflects the degree of complement activation.

Afibrinogenemia↗
PubMed1982

A search for genetic influence in idiopathic inflammatory myopathy.

33 patients with idiopathic inflammatory myopathies (polymyositis or dermatomyositis) and 45 of their first-degree relatives were investigated in a search for any influence of genetic factors in these diseases. None of the relatives had evidence of an inflammatory myopathy but 13 had some other autoimmune disease. Mean serum IgG levels were reduced and serum C3c concentration increased both in patients and relatives. Levels of IgM were reduced and C4 increased in some groups of patients. The incidence of autoantibodies was increased in the patient group, particularly in those with isolated dermatomyositis or other systemic features, but not in the relatives. HLA, blood group and other genetic markers showed no deviation from normal population frequencies. Evidence favouring a genetic influence on the etiology of idiopathic inflammatory myopathy is restricted to disturbance of levels of some Ig and complement components, and for these there may be other explanations.

Adolescent↗
PubMed1983

The effects of total-body hyperthermia combined with anticancer drugs on immunity in advanced cancer patients.

As total-body hyperthermia (TBHT) therapy may lead to a reduction in the immune response of cancer patients because of the immediate effect of heat on lymphocytes, the authors studied the immunity of advanced cancer patients receiving combined TBHT and anticancer chemotherapy. A decrease was found in their lymphocyte blastogenesis, skin reactions to PPD and PHA, lymphocyte rosette formation, IgG, and C3c component. These parameters returned to their pretreatment levels at 1 week after completion of TBHT therapy. This result indicates that there is no necessity for giving special consideration to a reduction of cell-mediated immunity in TBHT therapy.

Adult↗
PubMedDate not supplied

Clq binding in serum in juvenile rheumatoid arthritis.

The Clq assay for antigen-antibody complexes was performed on 79 blood samples from 43 patients with juvenile rheumatoid arthritis (JRA). The results were compared with assays for the activation products of C3 (C3c,d), for the concentration of C3, for rheumatoid factor, and for antinuclear antibodies. A statistically significant association was found between Clq binding and positive tests for latex fixation and C3c,d in systemic and polyarticular JRA, but positive results of each assay were found independently. These 3 assays were usually negative in pauciarticular JRA. No relationship was found between Clq binding and C3 concentration or antinuclear antibodies.

Adolescent↗
PubMed2001

Expression of complement regulatory proteins on islets of Langerhans: a comparison between human islets and islets isolated from normal and hDAF transgenic pigs.

BACKGROUND: The expression of regulators of complement activity (RCAs) on islet cells may be of great importance for protecting them against complement-mediated lysis in the immediate posttransplant period after intraportal islet transplantation. We examined porcine and human islet cells for expression of RCA. We also examined to what extent human decay accelerating factor (hDAF) is expressed on adult and fetal islet cells isolated from hDAF transgenic (TG) pigs having a high transgene expression on endothelial cells. Moreover, the susceptibility of the various types of cells to lysis in human serum and blood was investigated. METHODS: Adult human islets (n=5), normal adult and fetal porcine islets (n=9 and n=8, respectively), and islets from adult and fetal hDAF TG pigs (n=5 and n=6, respectively) were examined. With islet single-cell suspensions and flow cytometry, adult human islet cells were examined for expression of hDAF (CD55), hCD59, and human membrane cofactor protein (hMCP; CD46), while porcine islet cells were examined for expression of pCD59 and pMCP. Islet cells from hDAF TG pigs were also examined for hDAF expression. Porcine peripheral blood lymphocytes, normal and hDAF TG porcine endothelial cell lines, a human endothelial cell line, and the human cell line U937 served as controls. Islet cytotoxicity was assayed after incubation of the islet cells with fresh human serum. Furthermore, adult islets from normal control pigs and hDAF TG pigs were exposed to fresh human blood in vitro for 60 min, and the inflammatory reaction elicited was compared between the different types of islets. RESULTS: All human islet cell preparations expressed hCD59, two of five expressed hMCP, but none expressed hDAF. Porcine islet cells expressed both pCD59 and pMCP. Normal adult porcine islet cells exposed to fresh human serum resulted in 74+/-5.4% cell lysis (mean+/-SEM, n=16). In comparison, only 1.3+/-2.8% (n=20, P<0.001) of human islet cells were lysed in the human serum. One islet cell preparation from an hDAF TG pig expressed small amounts of hDAF. This preparation from hDAF TG pigs bound significantly less C3c than did normal control islets (mean fluorescence ratio 16+/-2.2 and 58+/-4.3, respectively; P=0.046) and were partially protected from cell lysis in fresh human serum (47+/-10% and 78+/-18% cell lysis, respectively; P=0.046). The other four preparations from hDAF TG pigs were negative for hDAF and were equally susceptible to lysis as normal control islets. All fetal pancreatic islet cells from hDAF TG pigs analyzed were negative for hDAF expression. When exposed to fresh human blood in vitro, adult and fetal islets from hDAF TG pigs elicited equally strong inflammatory changes as did the normal control islets. The inflammatory changes were characterized by activation of the complement and coagulation systems, resulting in islet damage with "dumping" of insulin into the blood. CONCLUSIONS: Porcine and human islet cells express species-restricted complement regulatory proteins, with the human islet cells expressing mainly hCD59. A low expression of hDAF was detected on islet cells from one of five hDAF TG pigs. These islet cells displayed reduced islet cell cytotoxicity in fresh human serum. We conclude that protection from complement-mediated lysis will be important in the context of intraportal pig-to-human islet transplantation, and expression of a human RCA on islet cells should be beneficial in this context.

Animals↗
PubMed1996

Recombinant soluble human complement receptor type 1 inhibits antisperm antibody- and neutrophil-mediated injury to human sperm.

The pathogenesis of antisperm antibody (ASA)-mediated infertility is postulated to be related in part to complement (C)-dependent sperm dysfunction in the female genital tract. We have previously demonstrated that C can be involved in ASA-mediated sperm injury by the deposition of activated C3 fragments and the assembly of terminal membrane attack complex (C5b-9) leading to C3-mediated sperm binding to neutrophils or C5b-9-mediated sperm motility loss. This study evaluated the protective effect of recombinant soluble C receptor type 1 (sCR1) on ASA-and C-mediated neutrophil/sperm interaction, neutrophil aggregation, and sperm motility loss. Motile sperm with or without neutrophils were incubated in the presence of 10% C-fixing ASA+ serum or ASA- control sera in the presence or absence of sCR1. After defined incubation periods, the following neutrophil and sperm parameters were evaluated: 1) neutrophil aggregation (by the flow cytometric pulse processing method), 2) sperm phagocytosis (by light microscopy), 3) the deposition of C3 cleavage fragments (C3b, iC3b, and C3d) on motile sperm (by immunofluorescence flow cytometry), and 4) the relation between sperm motility loss and sperm-bound C3d. Only the coincubation of neutrophils with sperm in the presence of C-fixing ASA+ sera resulted in marked neutrophil aggregation (20.5 +/- 0.26% vs. 2.4% +/- 1.6; p < 0.0001) and a concomitant increase in neutrophils containing ingested sperm (71 +/- 5.8% vs. 3.5%; p < 0.0001). Soluble CR1 inhibited ASA- and C-mediated neutrophil aggregation by 46% and sperm phagocytosis by 57%. Motile sperm incubated with C-fixing ASA- sera showed a time-dependent increase in the binding of C3 fragments as detected by flow cytometry using anti-iC3b neoantigen, anti-C3c, and anti-C3d monoclonal antibodies (mAbs). A negative correlation (r2 = -0.930; p < 0.001) was found between the increase in sperm-associated C3d fluorescence and the percentage motile sperm in the presence of ASA- sera. Soluble CR1 (200 micrograms/ml) maximally inhibited the binding of anti-C3b, anti-C3c, and anti-C3d mAbs to sperm by 96%, 83%, and 72%, respectively. Thus, sCR1 abrogated the binding of C3 fragments to human sperm and fully protected sperm from C5b-9-mediated sperm immobilization. These findings suggested the therapeutic potential of sCR1 as an intravaginal pharmacophore to prevent C-dependent sperm dysfunction and related inflammatory events in the female genital tract.

Acrosome↗
PubMedDate not supplied

[Immunological changes in disease caused by vibrating instruments. Preliminary tests].

58 miners affected by VWF were studied by some immunological tests: electrophoresis, quantitantive immunoglobulin determination, latex test. C3c, C3PA and C4, cryoglobulin, ANA and ati-DNA antibody, L.E. cell. Slight hyperimmunoglobulinaemia G was observed in 31% of cases; this abnormality was significantly more frequent in patients also suffering for pulmonary silicosis. Authors indicate pneumoconiosis as an important confounding variable, which importance for epidemiological studies has not yet satisfactorily assessed.

Adult↗
PubMed2006

Histological differences in new-onset IgA nephropathy between children and adults.

BACKGROUND: It is suggested that IgA nephropathy (IgAN) manifests differently in children vs adults on the basis of biopsy findings. However, this has been difficult to establish owing to the uncertainty of the timing of disease onset in adult IgAN. We addressed this question by comparing both histology and leucocyte accumulation in biopsies of recently diagnosed childhood and adult IgAN. METHODS: Biopsies taken within 2 years from the onset of renal abnormalities in 33 childhood (10 +/- 3 years of age) and 38 adult (35 +/- 6 years) cases of IgAN were examined for histological changes (cellularity in mesangial, endocapillary and extracapillary areas, matrix expansion, adhesions/crescents and interstitial damage), glomerular deposition of immunoglobulin and complement, and the presence of macrophages, activated macrophages and T cells by immunohistochemistry. RESULTS: Glomerular hypercellularity owing to increased cells in mesangial area was prominent in paediatric IgAN and significantly greater than in adult IgAN. In contrast, glomerular matrix expansion, crescent formation and interstitial damage were more severe in adults compared to paediatric IgAN. Indeed, glomerular hypercellularity correlated with proteinuria in paediatric but not in adult IgAN, whereas glomerular matrix correlated with proteinuria and renal function in adult but not in paediatric IgAN. The degree of C3c deposition was significantly greater in paediatric IgAN, while deposition of fibrinogen was greater in adult IgAN. Glomerular and interstitial CD68+ macrophages and a subset of sialoadhesin (Sn)+ activated macrophages were identified in both paediatric and adult IgAN, being significantly greater in number in adult IgAN. Glomerular leucocyte infiltration correlated with proteinuria while interstitial leucocyte infiltration correlated with interstitial damage in both groups. However, only the subset of Sn+ macrophages gave a significant correlation with renal function, glomerular hypercellularity and glomerular matrix. CONCLUSIONS: This study has demonstrated significant differences in the early glomerular lesions of IgAN in children vs adults. Furthermore, Sn+ activated macrophages are implicated in the pathogenesis of IgAN in both patient groups. The prognostic significance of these findings warrants further study.

Adolescent↗
PubMed1986

Structural and functional studies on the human C3b/C4b receptor (CR1) purified by affinity chromatography using a monoclonal antibody.

A procedure was devised that has several advantages over previously described methods to purify CR1 from both erythrocytes (E) and the HL-60 promyelocytic cell line. Using a monoclonal antibody immunoaffinity column, CR1 was purified to homogeneity as assessed by silver staining and 2-D gel analysis. Protein purified by this method comigrates on SDS-PAGE with 125I surface-labeled CR1 isolated by immunoprecipitation or iC3-Sepharose affinity chromatograhy and can be specifically immunoblotted with a second monoclonal anti-CR1 antibody. Employing this method, CR1 can be purified to homogeneity in amounts adequate for both functional studies and biochemical microanalysis. Purified E CR1 is functionally active as assessed by its ability to specifically rebind to an iC3-Sepharose affinity column, act as a cofactor for I-mediated cleavage of C3b to C3c and C3d, g and to accelerate decay of both the classical and alternative pathway C3 convertases. Its specific activity is similar to that of CR1 purified by a method not employing the potentially denaturing washing and eluting conditions of immunoaffinity chromatography. The pIs of the two major E CR1 allotypes are both approximately 7.1. Using pooled human E CR1, an amino acid composition was derived which revealed a relatively high proline content. This has also been found in two functionally related and genetically linked complement-regulatory proteins, H and C4-binding protein, NH2-terminal sequencing of E CR1 and HL-60 CR1 was unsuccessful indicating that the NH2-terminus is blocked.

Amino Acid Sequence↗
PubMed1988

Synthesis of soluble C3 and C9 neoepitopes by human alveolar macrophages in vitro.

The aim of this study was to examine whether soluble neoepitopes of activated C3 (C3b, iC3b, C3c) and C9 are produced by human alveolar macrophages cultured in serum-free medium. There was a significant and inhibitable production of C3 and C9 neoepitopes and C9 by the macrophages from all donors, as detected by enzyme-linked immunosorbent assays based on monoclonal (bH6, aE11) and polyclonal (anti-C9) antibodies. A strong donor-dependent variation in the levels of the C3 neoepitope and C9 (five- to sevenfold) and the C9 neoepitope (twofold) was found. After 1 day (24 h) of incubation, the complement levels were largely unaltered. The presence of an exogenous alternative pathway activator (agarose beads) reduced the amount of soluble complement because of binding to the agarose. However, the relative fraction of C9 neoepitope versus C9 increased (two- to threefold), due to agarose-mediated activation of C9. The results demonstrate activation of the complement system in serum-free alveolar macrophage cultures, irrespective of the presence of a known complement activator.

Antibodies, Monoclonal↗
PubMedDate not supplied

Clinico-immunological aspects of vernal catarrh in hilly terrains of Himachal Pradesh.

Very few immunological studies in vernal catarrh have been conducted in India and abroad, but none in Himachal Pradesh in spite of its high incidence in the State. In the present study 25 patients of vernal catarrh residing at a height ranging between 1000 to 2500 meters above mean sea level have been evaluated. Their immunological status of serum and tears after detailed clinical assessment was studied by single radial immunodiffusion technique of Mancini et al. The values of serum IgA and IgM were significantly higher in patients than in controls. The serum IgE level had no significant difference. The IgG was significantly lower in patients with vernal catarrh. The values of tear IgM, IgE and IgA in these patients were significantly higher than in controls. However, in no case or control group C3C and C4 were detected in tears. The limbal type of vernal catarrh was found to be the most common in this part of the country. No mixed case was seen. Derangement of the immune system in the pathogenesis of vernal catarrh is suggested.

Adolescent↗
PubMed1985

Rapid purification of the human C3b/C4b receptor (CR1) by monoclonal antibody affinity chromatography.

The human C3b/C4b receptor (CR1) is a polymorphic glycoprotein that is expressed on erythrocytes, leukocytes and glomerular podocytes. Further structural analysis and molecular genetic studies would be facilitated by the availability of relatively larger amounts of purified CR1. Milligram quantities of CR1 were purified from erythrocyte membranes 10,000-fold with an average yield of 30-40% by a rapid procedure which utilized sequential chromatography on Matrex Red A and a monoclonal anti-CR1 antibody affinity column. The purified receptor was homogeneous by SDS-PAGE and consisted of the 2 most common alleles of CR1. Purified CR1 also retained its function of serving as a cofactor for the cleavage of C3b to iC3b, C3dg and C3c. The amino acid composition was typical of that of a globular protein and sequence analysis of the N-terminus of the purified CR1 revealed that it was blocked.

Amino Acid Sequence↗
PubMed1989

Selection of pre-operative haematobiochemical parameters for the identification of patients 'at risk of infection' undergoing surgery for gastro-intestinal cancer.

Sixty-three patients were given a complete laboratory screening before undergoing surgical treatment for cancer of the digestive tract. The values of all these parameters were correlated with the incidence of postoperative infections, with the aim of identifying those markers which could be useful for the pre-operative selection of the patients at risk of infection. Patients who developed postoperative infections showed a significant pre-operative reduction of total serum proteins (P less than 0.02), albumins (P less than 0.02), beta-globulins (P less than 0.01) and C3c (P less than 0.05), while alpha 1-globulins were slightly, but not significantly, increased. The possible clinical applications of these parameters, to develop a predictive model which may help identify the patients at risk of infection, are discussed.

Aged↗
PubMed1985

Identification of an additional class of C3-binding membrane proteins of human peripheral blood leukocytes and cell lines.

Proteins binding the third component of complement (C3) were isolated by affinity chromatography from surface-labeled solubilized membranes of human peripheral blood cells and cell lines. The isolated molecules were subjected to NaDodSO4/PAGE, and autoradiographs of these gels indicated that C3-binding proteins could be divided into three groups based on Mr: (i) gp200, an approximately 200,000 Mr molecule previously identified as the C3b/C4b receptor or CR1; (ii) gp140, an approximately 140,000 Mr molecule previously identified as the C3d receptor or CR2; and (iii) gp45-70, a heretofore unrecognized group of 45,000-70,000 Mr C3-binding molecules. The cell distribution, Mr, antigenic cross-reactivity, and specificity of gp45-70 were examined. Erythrocytes have no detectable gp45-70, but all leukocyte populations examined possess this group of molecules. On neutrophils and mononuclear phagocytes, CR1 is the predominant C3-binding glycoprotein, but gp45-70 is present on both cell populations and on macrophage and neutrophil cell lines. B plus null cells, chronic lymphocytic leukemia cells, and an Epstein-Barr virus-transformed B-cell line possess CR1, CR2, and gp45-70. On T cells and T-cell lines gp45-70 is the predominant or, in some cases, the only C3-binding protein isolated. gp45-70 is structurally characterized as a broad band or doublet with a mean Mr that is slightly different for each cell population. gp45-70 binds iC3, C3b, and C4b, but not C3d, indicating that the binding region is probably within the C3c portion of C3b. A polyclonal antibody to CR1 and monoclonal antibodies to CR1 and CR2 do not immunoprecipitate gp45-70. While gp45-70 has not been previously characterized on human cells, a C3b-binding glycoprotein of similar Mr is present on rabbit alveolar macrophages. We conclude that gp45-70 is an additional group of membrane proteins present on human leukocytes that possess ligand-binding activity for C3b.

B-Lymphocytes↗
PubMed1994

Further evidence for involvement of both cell mediated and humoral immunity in generalized vitiligo.

Immunohistochemical and immunoserological evidence supports the involvement of both cell-mediated and humoral mechanisms in the pathogenesis of melanocyte destruction in vitiligo. Punch biopsies from depigmented vitiliginous skin (VS), normal-looking pigmented skin (PS), and marginal skin (MS) from patients with generalized vitiligo (n = 15) were labeled with K 1.2.58, OKM1 (CD11b), Leu 11b (CD16), Leu 19 (CD56), IFN-gamma receptor, IL-2 receptor (CD25), IgG, IgM, C3c, and C3d MoAbs. In addition, in vitro effects of vitiligo sera (n = 13) on human newborn melanocytes (HMel) under different culture conditions were studied. The immunohistochemical findings showed absence of K 1.2.58+ epidermal melanocytes in VS and abnormal morphology in MS. In these areas, a few CD11b+ cells in the dermis and epidermis could be detected but no significant numbers of CD16+ or CD56+ cells were seen among the mononuclear cellular infiltrate. IL-2 and IFN-gamma receptors were clearly expressed by the cellular infiltrate. No significant deposition of complement or immunoglobulin was seen. The addition of vitiligo sera to HMel cultures induced a significant cellular proliferation. The stimulation of cell proliferation occurred regardless whether the sera were added alone or when preheated (56 degrees C for 1 hr) and then supplemented with a complement source (P < 0.01 at 2%, P < 0.001 at 10%, and P < 0.01 at 20% for sera alone) (P > 0.05 at 2%, P < 0.05 at 10%, and P < 0.01 at 20% for decomplemented sera plus complement).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1977

Serum glycoproteins in coronary artery disease.

Serum glycoprotein levels were compared in two groups of age- and sex-matched patients, 15 with coronary artery disease and 14 normal controls. While total glycoprotein levels were increased in the coronary group, significantly higher levels were found in only five of 16 glycoproteins--C3c haptoglobin, GC-globulin, alpha1-acid glycoprotein, and C3 activator--with no change in 10 other glycoproteins and significant decrease in transferrin. This study demonstrates what appears to be a glycoprotein profile in coronary artery disease and reviews possible interactions of glycoproteins with known risk factors in atherogenesis.

Arteriosclerosis↗
PubMed1976

Interaction of soluble C3 fragments with guinea pig lymphocytes. Comparison of effects of C3a, C3b, C3c, and C3d on lymphokine production and lymphocyte proliferation.

C3a, C3b, C3c, and C3d were generated from purified guinea pig C3 by trypsin treatment. These fragments were characterized immunochemically and functionally by rosette inhibition. C3b is capable of binding to both C3b and C3d receptors on lymphocytes whereas C3d binds only to C3D receptors. C3b stimulates guinea pig spleen cells to elaborate a macrophage chemotactic factor which is similar in m.w. to that generated in response to PHA or LPS and is antigenically unrelated to C3 or C5. In contrast, neither C3a, C3c, or C3d stimulate guinea pig lymphocytes. Neither C3 nor any of its major fragments induce cellular proliferation. These data are compatible with the hypothesis that C3b triggers spleen cells to release a macrophage chemotactic factor by cross-linking C3b and C3d receptors.

Animals↗
PubMed1990

Neoantigens in complement component C3 as detected by monoclonal antibodies. Mapping of the recognized epitopes by synthetic peptides.

The different fragments of the third complement component, C3, generated upon complement activation/inactivation have the ability to bind to several other complement components and receptors as well as to proteins of foreign origin. These multiple reactivities of C3 fragments are associated with a series of conformational changes occurring in the C3 molecule during its degradation. The conformations acquired by the different C3 fragments are also associated with the exposure of neoantigenic epitopes that are specific for (a) particular fragment(s). In order to study these epitopes and thus the conformational changes occurring in C3, monoclonal antibodies (mAbs) recognizing such epitopes were produced in Balb/c mice after immunization with denatured human C3. Two of the three antibodies (7D84.1 and 7D264.6) presented in this study recognized predominantly surface-bound iC3b, and one mAb (7D323.1) recognized both surface-bound and fluid-phase iC3b. Although none of the mAbs recognized any other fluid-phase C3 fragment, all three antibodies detected micro-titre-plate-fixed C3b and iC3b, but not C3c or C3d. In addition to the reaction with human C3, mAb 7D323.1 also bound to micro-titre-plate-fixed rabbit C3. The epitopes recognized by the three mAbs were further localized by using synthetic peptides that were designed on the basis of the differential binding of the mAbs to the C3 fragments. All three antibodies reacted with C3-(924-965)-peptide, which represents the region of C3 between the kallikrein-cleavage site (923-924) and the elastase-cleavage site (965-966). On the basis of the binding of the mAbs to five different overlapping peptides spanning the region between residues 924 and 965 of the human C3 sequence, and the sequence similarity between human C3 and rabbit C3 within this area, the epitopes recognized by these antibodies are mapped. The contribution of the individual amino acid residues in the formation of the epitopes is discussed.

Antibodies, Monoclonal↗