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Biomedical subjects

S Meri

Publications and source records attributed to S Meri.

54 records · Page 3Linked to original sources
PubMed1990

Human protectin (CD59), an 18-20-kD homologous complement restriction factor, does not restrict perforin-mediated lysis.

Human protectin (CD59) is an 18-20-kD membrane glycoprotein that restricts lysis of human erythrocytes and leukocytes by homologous complement. By directly incorporating protectin into membranes of heterologous cells we observed that protectin did not prevent perforin-mediated killing, whereas complement killing was effectively restricted. Further, no significant enhancement of cell-mediated killing or target killing by purified perforin was observed with anti-protectin antibodies. Thus, in contrast with complement lysis, restriction of lysis by protectin does not apply to cell-mediated killing.

Animals↗
PubMed1990

A mechanism of activation of the alternative complement pathway by the classical pathway: protection of C3b from inactivation by covalent attachment to C4b.

In this work we studied the role of the classical pathway complement component C4b in the activation of the alternative pathway. It was found that nascent C3b attaches with high efficiency to C4b and that C3b in C4bC3b complexes is protected from inactivation by factors H and I. Activation of C3 by factors B and D in the presence of Mg2+ ions and excess C4b led to 35% incorporation of nascent C3b into C4bC3b complexes in the fluid phase. In comparison, when human IgG was tested as an acceptor under similar conditions, only 12% of generated C3b was incorporated into IgGC3b complexes. The half-life time of dissociation of C3b from purified C4bC3b complexes was approximately 2.3 h at 37 degrees C. C4b in these complexes protected C3b from inactivation as effectively as any known alternative pathway activator. Thus, C3b bound to C4b was tenfold more stable than free C3b or C3b bound to a nonactivating surface. In comparison, the protection provided by attachment to human IgG was only 67% of that of C4b. The results provide an explanation for observations of alternative pathway recruitment following classical pathway activation and for the stability of the classical pathway C5 convertase on surfaces which do not provide protection for C3b from factors H and I.

Complement C3-C5 Convertases↗
PubMed1990

Discrimination between activators and nonactivators of the alternative pathway of complement: regulation via a sialic acid/polyanion binding site on factor H.

The alternative complement pathway is capable of discriminating human cells and tissues from a wide variety of potential pathogens. It has been recently demonstrated that attachment of complement component C3b to activator-derived molecules (e.g., small polysaccharides) restricts inactivation of C3b by factors H and I in a manner similar to activator surfaces. It is now shown that restriction is reversed by certain soluble polyanions (e.g., sialoglycopeptides, heparin, or dextran sulfate) that mimic the effects of sialic acid and glycosaminoglycans on human cells and tissues. Fluid-phase polyanions enhanced binding of factor H to C3b attached to activating particles, indicating that the effect resulted from increased affinity between C3b and factor H. The enhancement was specific for activator-bound C3b since no enhancement was observed on nonactivating particles. While several polyanions could cause this effect, some polyanions could not, indicating specificity. The active polyanions also inhibited lysis of cells via the alternative pathway. The binding site for sialic acid appears to reside on factor H, since factor H bound to heparin-agarose and to sialic acid-bearing fetuinagarose, whereas C3b bound to neither under the same conditions. These observations suggest that occupation of a specific site on factor H by polyanions induces an increase in the C3b-H affinity, resulting in discrimination of host cells and tissues from alternative pathway-activating foreign cells.

Animals↗
PubMed1990

Acute schistosomiasis mansoni in Finnish hunters visiting Africa: need for appropriate diagnostic serology.

Three symptomatic and 3 asymptomatic patients with acute schistosomiasis mansoni are described. The index case presented with fever and eosinophilia 4-6 weeks after swimming in the Pipi River of the Central African Republic, suggesting acute schistosomiasis (Katayama fever). A fortunate early diagnosis led to early treatment of these schistosomiasis patients. Diagnosis was obtained based on the finding of one Schistosoma mansoni egg in the index case and positive serology in all cases. A commercially available passive haemagglutination test for serum bilharzia antibodies was negative in all cases prior to, and 2 weeks after treatment. However, antibodies against gut-associated antigens (GAA) of adult S. mansoni worms could be demonstrated using the indirect immunofluorescence technique. These cases illustrate the importance of using appropriate diagnostic assays for the early demonstration of infection by schistosomes in previously unexposed "nonimmune" patients with atypical symptoms and in asymptomatic individuals at risk even after brief exposure to schistosome-containing water in endemic countries. Careful (and repeated) stool examination and appropriate serological tests are the keys to prompt diagnosis of S. mansoni infection.

Adult↗
PubMed1990

Human protectin (CD59), an 18,000-20,000 MW complement lysis restricting factor, inhibits C5b-8 catalysed insertion of C9 into lipid bilayers.

Human cells are relatively resistant to lysis by the homologous complement system. Here we describe the mechanism of action of a recently discovered and widely distributed 18,000-20,000 molecular weight (MW) membrane glycoprotein (CD59), which appears to act as a major protective element against complement-mediated lysis (hence called protectin). When incorporated into heterologous erythrocyte membranes, protectin efficiently prevented cell lysis by human serum. Neutralization with antibody of the naturally occurring protectin on human erythrocytes or on nucleated K562 cells increased their susceptibility to lysis by homologous complement. During complement activation, protectin became incorporated into the membrane attack complex (MAC). By interacting with newly exposed regions in the C5b-8 complex and in aggregating C9 it limited the number of C9 molecules associating with the C5b-8 complex to a C8:C9 ratio of 1:1.5 instead of a normal average of 1:3.5. The results demonstrate directly that protectin is a powerful inhibitor of complement cytolysis and acts by inhibiting the C5b-8 catalysed insertion of C9 into the lipid bilayer.

Antigens, Differentiation↗
PubMed1990

High frequencies of B8, DR3 and C4A null alleles and immunological disorders in a family of four generations.

In a Finnish family covering four generations many members had immunological symptoms or disorders (mostly skin or joint oriented) with the presence of the B8 antigen positive Major Histocompatibility Complex (MHC) haplotype. Immunological parameters including the presence of autoantibodies, quantitative analysis of the complement components C4, Factor B (BF) and C3 and the serum capacity to inhibit immune precipitation were investigated in relation to the genetic MHC markers. The results showed the importance of the high frequency of the C4A null alleles to these disorders.

Adolescent↗
PubMed1990

Value of C-reactive protein in reflecting the magnitude of complement activation in children undergoing open heart surgery.

The kinetics of C-reactive protein (CRP) were studied prospectively in 30 children (aged 21 days - 16 years) undergoing open heart surgery. CRP was related to the kinetics of total haemolytic complement, complement C3a and postoperative complications. Two (7%) patients died and ten (33%) had postoperative complications. The patients with complications were younger (p less than 0.035), underwent longer perfusions (p less than 0.001) and had longer aortic cross-clamping times (p less than 0.003). The mean peak CRP level after surgery (108 mg/l) was reached, on the average, in 43 h. No statistical difference in CRP concentrations was found between the complication and non-complication groups. Extensive complement activation was seen in every patient. CRP did not reflect the magnitude of complement activation induced by cardiopulmonary bypass. The patient sample was too small to draw reliable conclusions about the value of CRP in detecting postoperative complications after open heart surgery in children.

Adolescent↗
PubMed1989

Plasmin and fibronectin degradation in chronic secretory otitis media.

Mucoid effusions from 39 children with secretory otitis media, altogether 42 specimens, were analyzed for proteolytic activity using radial caseinolysis procedures, for fibronectin using a solid-phase enzyme immunoassay, and for fibronectin fragmentation using immunoblotting. All samples contained proteolytic activity, tentatively identified as plasmin on the basis of comigration with purified human plasmin in zymographic analysis. In 19 specimens the plasmin level exceeded 1 microgram/mg of protein; the highest value recorded was 18.7 micrograms/mg. Low levels of net plasminogen activator activity were found in 12 specimens and identified as urokinase according to comigration with the urokinase standard in zymography. Fibronectin was detected in all but one of the 42 specimens; in seven specimens the levels exceeded those in normal plasma, calculated per milligram of total protein. Extensive fragmentation of fibronectin was found in 19 specimens, correlating with high plasmin levels. The results are indicative of an ongoing proteolytic process in secretory otitis media and suggest that plasmin-caused degradation of the fibronectin-containing basement membrane and subsequent formation of granulation tissue may be involved in the development of adhesive middle ears.

Child↗
PubMed1988

Complement activation and HLA-B27.

The efficiency of complement activation was studied in sera from HLA-B27 positive and negative subjects (27 with previous yersinia arthritis and 35 controls). Activation of complement with zymosan induced higher mean levels of the anaphylatoxin C3a in HLA-B27 positive sera (mean (SD) 7.40 (1.66) mg/l) than in HLA-B27 negative sera (6.41 (1.79) mg/l). Similarly, higher levels of C3d,g, another C3 breakdown fragment, were obtained in HLA-B27 positive sera after Escherichia coli 0111:B4 lipopolysaccharide treatment (17.6 (3.7)% v 15.0 (3.8)%). The differences occurred irrespective of previous arthritis, complement C4 or Bf phenotype, or variation in background complement levels. The findings suggest that an increased responsiveness to complement activators may contribute to the pathogenesis of HLA-B27 associated inflammatory diseases.

Adult↗
PubMed1988

Complement activation during cardiopulmonary bypass in children.

Complement activation was evaluated prospectively in serial serum and plasma samples from 30 children, who underwent cardiopulmonary bypass operations. Each patient showed a decrease in total hemolytic C levels and increase in C3 activation product (C3a desArg and C3bi/c) levels. In 11 of the 30 patients surgery was associated with a complication: death (2), respiratory failure (RF, 9), septicaemia (4), postpericardiotomy syndrome (PPS, 1) and pancreatitis (1). Patients suffering from RF were younger, underwent longer perfusions and had somewhat more extensive changes in the C system, although no direct correlation between high C3a desArg levels and RF existed. Instead, the increase in C3a desArg was in linear correlation with the perfusion time. Most complications during the latter postoperative period were associated with distinct episodes of lower grade C activation.

Cardiopulmonary Bypass↗
PubMed1988

Organ-specific autoimmunity and HLA-DR antigens as markers for beta-cell destruction in patients with type II diabetes.

Islet cell antibodies (ICAs), thyrogastric antibodies, and HLA-DR antigens were determined in 204 patients with type II (non-insulin-dependent) diabetes controlled with diet and/or oral hypoglycemic agents (NIR) and in 108 age-matched patients who required insulin to control their hyperglycemia (IR). beta-Cell function measured as C-peptide response to glucagon was evaluated in relation to the presence of ICAs and HLA-DR antigens. The IR patients differed from the NIR patients with respect to higher frequency of ICAs (P less than .001), thyroid antibodies (P less than .02), and the HLA antigen DR4 (P less than .02). The highest frequency of ICAs and thyroid antibodies was observed in female insulin-treated subjects (51.2 and 46.4%). Patients who were heterozygous for HLA-DR3/DR4 showed significantly higher frequency of ICAs (P less than .01) and complement-fixing ICAs (P less than .001) than patients without the heterozygous form DR3/DR4. Neither the presence of ICA alone nor DR3/DR4 alone was associated with a significant impairment of beta-cell function. However, when both ICA and DR3/DR4 were present in a diabetic individual, beta-cell function was markedly impaired (P less than .001), suggesting that both genetic and autoimmune factors are necessary to facilitate the process leading to beta-cell destruction of the patients. Our findings suggest that type II diabetes is a heterogeneous disorder including at least two major subgroups, which can be further characterized by HLA-DR antigens and organ-specific antibodies.

Autoantibodies↗
PubMed1986

Human tumor cells synthesize and secrete alpha-2-macroglobulin in vitro.

In previous studies we showed that human sarcoma and melanoma cell lines synthesize and secrete into culture medium a glycoprotein, migrating in urea sodium dodecyl sulfate-polyacrylamide gel electrophoresis at Mr 140,000. It is not detected in cultures of the corresponding normal cells. Conditioned medium of the melanoma cell line HMB-2, producing among the cell lines tested the largest amounts of this glycoprotein, has now been used as a source for purification of the protein. NH2-terminal amino-acid sequence determination of the purified glycoprotein showed that it is identical to human alpha 2-macroglobulin (alpha 2M). Rabbit antibodies raised against the glycoprotein specifically reacted in immunoblotting and immunodiffusion tests with alpha 2M present in human plasma. Likewise, these antibodies immunoprecipitated from the conditioned media of 35S-methionine-labelled melanoma and osteosarcoma cell lines the protein which had a molecular weight corresponding to alpha 2M. alpha 2M was also synthesized and secreted by 2 strains of fetal lung fibroblasts but not by fetal skin fibroblasts or adult skin fibroblasts autologous to the osteosarcoma cell line.

Cells, Cultured↗
PubMed1985

Complement activation by antigenic fractions of Entamoeba histolytica.

Complement (C) activation induced by Entamoeba histolytica in normal non-immune human serum was studied by testing in vitro the ability of different fractions of the trophozoites to cause C3 breakdown. Whole trophozoites were found to activate both alternative and classical C pathways. The antibody-independent classical pathway (MgEGTA inhibitable) C activating capacity was found to greatly increase after disruption of the cell membrane by sonication. Subsequent analysis after differential centrifugation and ion exchange chromatography of the membrane/particulate fractions showed, that this activity was not due to DNA, which has been shown to have the similar characteristics, but to other, as yet unidentified components. A rather homogenous membrane fraction obtained by elution with 0.4 M Tris-HCl, pH 8.1 (described as 4M) and some cytoplasmic constituents obtained after gel chromatography retained a moderate degree of alternative pathway C3 activating capacity seen with intact trophozoites. Thus, it seems, that serum contact to the outer surface of E. histolytica trophozoites leads to C activation via both pathways with cell death as the result and to subsequent release of more efficiently classical pathway activating components. These phenomena probably have an important role in the inflammatory process in invasive amoebiasis.

Animals↗
PubMed1985

Complement levels and C3 breakdown products in open-heart surgery: association of C3 conversion with the postpericardiotomy syndrome.

The role of the complement system in the pathogenesis of the post-pericardiotomy syndrome (PPS) was evaluated in a prospective study by measuring the levels of complement (C) components, total haemolytic complement activity and circulating C3 breakdown products in serial plasma and serum samples of 45 patients undergoing open-heart surgery. A consistent reduction in the levels of C3 and C4 but not of factor B was seen on the second post-operative day. During the second post-operative week the antigenic levels of each C component increased significantly. At this time six patients developed the post-pericardiotomy syndrome. Circulating C3 conversion products (C3bi and C3c) were demonstrated in the plasma samples from five of these patients by the immunofixation technique, the mean conversion percentage being 14.3 +/- 10.6. The samples from 15 of the 39 other patients also showed C3 conversion, but the mean percentage was significantly lower (4.5 +/- 6.1%, P less than 0.05). Before the second post-operative week C3 conversion was rare in both groups. The C3d levels of plasma samples, as detected by rocket immunoelectrophoresis, followed a similar pattern. Reduced total haemolytic complement activity was found in three patients suffering from the PPS. These results suggest a role for complement in the non-infectious, inflammatory response during the late post-operative period after open heart surgery, and especially in the post-pericardiotomy syndrome.

Adolescent↗
PubMed1985

Complement activation by circulating serum factors in human glomerulonephritis.

Factors with the ability to induce a minimum of 20% C3 conversion in normal human serum (NHS) were demonstrated in the sera of nine glomerulonephritis (GN) patients. The nature of these factors was heterogeneous allowing their division into at least three different groups. First, in three cases (membranoproliferative or acute GN) they exhibited the characteristics of C3 nephritic factor, an IgG autoantibody stabilizing the alternative pathway (AP) C3 convertase, C3bBb. Secondly, the serum of one patient (SLE like syndrome, mixed cryoglobulinaemia) with an activator of both pathways and profound hypocomplementaemia showed a temperature-dependent precipitation against autologous and homologous polyclonal IgG. Immunochemical analysis suggested this activity to be due to a monoclonal IgM kappa rheumatoid factor. By gel filtration the C3 converting activity was found in the high molecular weight fractions containing the cryoprecipitable IgM-IgG complexes. Finally, in five cases the exact nature of C-activating factors remained unknown. In four of these the factors were heat labile (30 min at 54 degrees C) C activators in association with post-streptococcal glomerulonephritis. The results suggest that the various C activating factors, possibly distinct from 'classical' immune complexes, are indicators of different types of pathogenetic mechanisms in certain forms of GN.

Adult↗
PubMed1984

Complement in chronic secretory otitis media. C3 breakdown and C3 splitting activity.

Occurrence of in vivo C3 breakdown and in vitro C3 splitting activity was studied in serum and middle-ear effusion (MEE) samples from 30 children with chronic secretory otitis media (SOM). The MEE showed strongly elevated levels of both low- and high-molecular-weight C3 breakdown products, along with decreased factor B, C4, and C3 levels. Total hemolytic complement component activity was virtually absent from MEE. The MEE fluids were found to contain C3 splitting factors as demonstrated by their high capacity to convert C3 in vitro from fresh normal human serum. This activity was not inhibited by the classic complement pathway inhibitor, 0.01M ethylene glycol tetra-acetic acid with 0.005M magnesium chloride. The results suggest that a strong local complement activation has taken place and that the factors responsible are present in the MEE of patients with SOM.

Antigen-Antibody Complex↗
PubMed1981

An immunofluorescence assay for complement activation by the classical pathway.

The functional integrity of classical complement pathway components was determined by an immunofluorescence (IFL) assay based on the capacity of cytoskeletal intermediate filaments (IMF) to bind C1q and to activate the complement pathway. The assay uses IMF-rich capillary endothelium of human term placentae as complement-activating substrate. IFL staining for bound C1q, C4 and C3 was demonstrated after incubation of the tissue sections with normal human sera in dilutions up to 1 : 80. Known inhibitors of C1q binding and inhibitors fo C3 convertase formation prevented binding of complement components. Eight of 100 sera from patients showed negative or reduced binding of complement whereas all of 100 control sera from healthy individuals were positive in the assay. Four negative patients' sera were studied further: 3 had markedly reduced hemolytic activity and normal levels of C3 and C4. The IFL assay for complement activation provides a simple method of evaluating complement deficiencies and of studying mechanisms and inhibitors of complement activation.

Autoantibodies↗