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PubMed1986

Anaphylatoxin formation in extracorporeal circuits.

Anaphylatoxin radioimmunoassay techniques have been employed to define both the temporal profile and the amount of complement activation taking place in two different types of extracorporeal circuits. Prospective studies of patients undergoing both maintenance hemodialysis and cardiopulmonary bypass provided essentially similar findings. In both cases, plasma C3a antigen levels proved to be the most accurate and sensitive indicator of intravascular complement activation. By contrast, plasma C5a levels varied little during the period of extracorporeal circulation. Instead, this anaphylatoxin retained considerable biologic activity in vivo as evidenced by its ability to promote granulocyte activation and transient granulocytopenia which was displayed by patients in both groups. Plasma levels of C4a antigen were not elevated during the period of extracorporeal circulation, suggesting that alternative pathway mechanisms were predominantly responsible for the complement activation taking place in both hemodialyzers and bypass oxygenators. However, classical pathway activation events could be documented when protamine sulfate was administered to heparinized patients after cardiopulmonary bypass. In this instance, elevated plasma levels of both C4a and C3a antigens were observed. Prospective studies also suggested that complement activation could be associated with the development of both acute and delayed clinical sequelae. Available data support the hypothesis that C5a anaphylatoxin might be the primary mediator of these undesirable effects of extracorporeal circulation. These types of investigations have contributed significantly to our understanding of the role of the anaphylatoxins in human disease and may be directly applied to facilitate design of more biocompatible medical devices.

Anaphylatoxins↗

PubMed1986

Comparative structural anatomy of the complement anaphylatoxin proteins C3a, C4a and C5a.

The anaphylatoxins are a family of proteins produced during the course of complement activation as the result of cleavage by specific serine proteases. These proteins are involved in a variety of biological functions, including inflammation. Comparative modeling techniques have been used to produce structures for C4a and C5a from the crystal structure of C3a. All three structures have conserved interior residues but very different external side chains and surface shapes and properties. Comparison of the anaphylatoxin structures and of the sequence conservation among different species suggests possible locations for their receptor binding sites and for their specificity residues which permit regulated proteolytic cleavage from precursor.

Amino Acid Sequence↗

PubMed2006

Thyroid autoimmunity and spontaneous cervical artery dissection.

BACKGROUND AND PURPOSE: The possibility that a disorder of immunity might have a role in the mechanism of local inflammatory alterations leading to spontaneous cervical artery dissection (sCAD) has been recently advocated. METHODS: We explored this hypothesis in a case-control study, including patients with sCAD (n=29) and patients with non-CAD ischemic stroke (non-CAD; n=29). Serum levels of antithyroperoxidase, antithyroglobulin, and antithyroid-stimulating hormone receptor antibodies, antinuclear antibodies, antineutrophil cytoplasmic antibodies, antidouble-stranded deoxyribonucleic acid antibodies, antiextractable nuclear antigen antibodies, rheumatoid factor, C3 and C4 complement fraction, and cryoglobulins were measured in all subjects. RESULTS: Antithyroid autoimmunity was found in 31.0% (9 of 29) of patients with sCAD and 6.9% (2 of 29) of patients with non-CAD ischemic stroke (P=0.041). CONCLUSIONS: Autoimmunity may be involved in the process of local inflammation related to sCAD occurrence. The hypothesis that the arterial disease might be one phenotypic expression of a generalized activation of immunity warrants further investigations.

Adult↗

PubMed2003

Dextran sulfate as a material for the preparation of a membrane for immunoisolation.

Bioartificial pancreas, in which the islets of Langerhans (islets) are enclosed in an artificial membrane to be protected from the host immune system, is expected to be a promising medical device to treat patients who suffer from insulin-dependent diabetes. Our strategy for preparation of a bioartificial pancreas involves utilizing a membrane including polymeric materials that can inhibit the complement. In our series of studies, we have examined interactions of various polyanions with the complement system to search for potential complement inhibitors. In this study, we concentrated our efforts to clarify the effects of dextran sulfate on the complement system. All of the dextran sulfates examined inhibited the complement activation through both classical and alternative pathways as previously reported. In addition to their inhibitory effects, a certain species of dextran sulfate (molecular mass 10 kDa, degree of sulfonation in a pyranose ring 1.99) specifically degraded C3 without complement activation and, thus, anaphylatoxins that trigger inflammatory reactions were not generated. These facts suggest that a membrane including dextran sulfate effectively protects the islet cells from humoral immunity in addition to not triggering inflammatory reactions. These properties of the membrane make it suitable for a bioratificial pancreas.

Bioartificial Organs↗

PubMed1994

The synthesis of a water soluble complement activating polyacrylic acid-IgG polymer.

Polyacrylic acid-IgG polymer (PAA-IgG) activates the classical and alternative pathway of complement as shown by specific Clq-(IgG-PAA) interaction and the generation of C4d, Bb, C3b, C3a and C5a. This water soluble and stable PAA-IgG polymer represents a model substance for the study of humoral and cellular inflammatory mechanisms, mediated by the complement system.

Acrylic Resins↗

PubMed1996

Blood protein interactions with titanium surfaces.

Protein adsorption and complement activation were studied on thin evaporated films of titanium (Ti). The surfaces were cleaned in either a radio frequency (RF) plasma unit, or washed sequentially in trichloroethylene, acetone, ethanol, and water. Both methods resulted in hydrophilic surface with low carbon contamination on the outermost oxide (approximately 11-13 at%). In situ ellipsometry suggested that Ti is an intrinsic coagulation activator in vitro, since significant amounts of factor XII (F XII) and high molecular weight kininogen (HMWK) were found on the surfaces after 1 min incubation in heparin plasma. Ellipsometry, performed after serum incubations ranging from 15 s to 30 min showed that the total amount of serum proteins and the deposition of antibodies to complement factor 3c (C3c) increased with serum incubation time. ELISA methods showed increased levels of free iC3b in serum after 10 min incubation of the surfaces, but no detectable amounts of C3 convertase fractions C4d or Bb. Ellipsometric results indicated, however, an increased deposition of antibodies to CIq and IgG on Ti after short serum incubation times. The combined results indicate that Ti-surfaces initially activate complement through the classical pathway. The activation then continues via a positive amplification loop where increased amounts of C3 are deposited on the surfaces via the alternative pathway.

Acetone↗

PubMed1996

Blood protein interactions with chromium surfaces.

Protein adsorption, contact activation, and complement activation were studied on thin evaporated films of chromium (Cr) in vitro. The surfaces were, prior to the experiments, cleaned in either ethanol and water, or in a basic peroxide solution (RCA standard clean 1, SC-1). Surface spectroscopic studies of the outermost oxides showed a significant reduction of carbon contaminants after washing in SC-1 but also suggested an increase in the oxidation state as compared with the ethanol-washed surfaces. In situ ellipsometry combined with antibody techniques was used to determine protein deposition and antibody binding onto surfaces after incubations in heparin plasma or in normal serum. Incubation times from 1 to 10 min in serum showed increased depositions of serum and antibodies to complement factor 3c (C3c) and was larger on ethanol-washed surfaces than on surfaces washed in SC-1. ELISA methods indicated increased amounts of iC3b in serum for both surfaces, but no presence of C3 convertases (C4d or Bb fractions). A low or transient complement activation via the classical pathway was indicated on ethanol washed Cr, since deposition of secondary antibodies to complement factor Iq (CIq) was observed only after short incubation times in serum. No procoagulant activity of Cr was indicated, since only low amounts of antibodies to factor XII (F XII), prekallikrein (PKK), and high molecular weight kiniogen (HMWK) bound to the surfaces after incubations in heparin plasma. These results were confirmed using a colorimetric assay where the relative amounts of free plasma kallikrein was assessed using a chromogenic substrate, H-D-Pro-Phe-Arg-pNA (S-2302).

Adsorption↗

PubMed1988

Accentuated formation of the terminal C5b-9 complement complex in patient plasma precedes development of the adult respiratory distress syndrome.

Extensive studies have been conducted to determine the pathogenesis of the adult respiratory distress syndrome (ARDS) by investigating the role of complement, a mediator of inflammation. Complement activation products have been detected in blood samples from patients during ARDS. However, the individual complement components that have been assessed only indicated generalized inflammation, and none could unequivocally discriminate the onset of this acute inflammatory lung injury. In this two-year prospective study of 87 septic patients, 22 of whom developed ARDS (25%), we determined complement activation by quantifying the terminal complement complex (TCC), C5b-9. The TCC is a stable complement by-product formed following activation of either the classical or alternative pathways. Our results show that plasma TCC concentrations increased an average of 110% (p = 0.002) two days prior to the onset of ARDS and also transiently increased an average of 45% (p = 0.01) immediately preceding its resolution. Furthermore, plasma TCC concentrations were a more sensitive measure of this acute inflammatory lung injury than levels of C3a desarginine, C4a desarginine, C5a desarginine, and total hemolytic complement activity. We conclude that a temporal association exists between accentuated formation of plasma TCC and the development and also resolution of septic ARDS. Therefore, we suggest that researchers include plasma TCC concentrations in clinical studies when they could use a potential early indicator for ARDS.

Complement Activation↗

PubMed1993

Immunogenetic analysis of silicosis in Japan.

We previously reported that a gene in linkage disequilibrium with HLA-Bw54, DR4, and DRw53 might control the susceptibility to silicosis (K. Honda et al. 1988. N. Engl. J. Med. 319:1610). To further define the HLA-linked gene and other genetic factors for predisposition of silicosis, we determined for HLA-DQ and DP alleles using the polymerase chain reaction and sequence-specific oligonucleotide probes and made a restriction fragment length polymorphism (RFLP) analysis of the fourth component of complement (C4) genes, immunoglobulin lambda variable chain (IGLV) gene, and T-cell receptor alpha and beta genes in 46 Japanese patients with silicosis. The frequency of DQB1*0401 (relative risk [RR] = 2.2, P < 0.02) was increased and that of DQB1*0601 (RR = 0.36, P < 0.01) was decreased in the patients. RFLP analysis of C4 and IGLV genes showed significant association between silicosis and a specific RFLP pattern of C4A3-C4B5 allotype (RR = 2.3, P < 0.05) and that of IGLV 5.3 kb (RR = 0.33, P < 0.003). No other genetic markers showed significant association. Statistical analyses of the associated genetic markers revealed that the HLA-Bw54 was the allele that showed primary association with silicosis and the frequencies of the C4 and HLA-DQ alleles were suggested to be increased due to their linkage disequilibrium with the HLA-Bw54. We conclude that the major gene for silicosis may be mapped near the HLA-B locus.

Adolescent↗

PubMed1975

Metabolism of properdin in normal subjects and patients with renal disease.

Properdin deposition has been recognized in glomeruli of patients with acute and chronic nephritis and lupus nephritis, and low serum properdin levels have been found in these disorders. These findings suggest that properdin may be involved in the production of glomerular damage and that low properdin levels may be due to hypercatabolism. The study was designed to examine the metabolism of properdin in normal subjects and to look for an abnormality in five patients with systemic lupus erythematosus with renal involvement and in six patients with membranoproliferative glomerulonephritis or dense deposit disease (MPGN). Highly purified human properdin was prepared by elution from zymosan, followed by DEAE-cellulose and carboxymethyl-Sephadex chromatography, and labeled with 125I by the iodine monochloride method. Parameters of metabolism were determined by monitoring plasma and urinary radioactivity at frequent intervals after the intravenous injection of 1-2 muCi of labeled material. The fractional catabolic rate (FCR) of properdin in normal subjects was found to have a very narrow range of 0.78-1.0,% of the plasma pool per hour (mean 0.95%). In systemic lupus erythematosus, the FCR was regularly elevated with a range of 1.21-2.30% (mean 1.70%). In MPGN, FCR was elevated in three patients (1.22, 1.94, and 2.08%) and within or below the normal range in three (0.78, 1.00, and 1.00%). Properdin levels were reduced in two patients who had the highest FCR's noted in the study. Properdin synthetic rates in normals varied from 4.1 to 14.3 mug/kg per h (mean 9.1) and was not found to be reduced in any patient. Properdin catabolism was found to be normal in a patient deficient in the C3b inactivator. These studies show that properdin is hypercatabolized in patients with renal disease and that decreased properdin levels when they occur in these patients can be entirely explained on the basis of this hypercatabolism.

Adolescent↗

PubMed1976

Herpes gestationis. Immunopathology and characterization of the HG factor.

Five patients with herpes gestationis, a blistering disease of pregnancy, were studied immunologically. All had in vivo deposition of C3 in a linear band along the basement membrane zone of lesional and normal-appearing skin, the location of early blister formation. Immunoglobulin deposition was more variable, though four patients had evidence of in vivo bound IgG at the same site. A circulating, complement binding herpes gestationis factor was demonstrated in the sera of four of the patients, its concentration unrelated to the activity of clinical disease. Characterization of this factor by sucrose gradient ultracentrifugation, specific absorption studies, and papain digestion indicates that it is an IgG. Evidence exists for involvement of both the classical and alternate complement pathways in vivo, though in vitro studies implicate the classical pathway as the primary route of complement activation. Three offspring were studied, none with clinical involvement; one showed in vivo deposition of C3 at the basement membrane zone of normal skin and a second showed the herpes gestationis factor in cord blood.

Absorption↗

PubMed1978

Surface markers of complement receptor lymphocytes.

Normal blood lymphocytes bearing complement receptors (CRL) were divided into two populations, one expressing both CR1 (C4b-C3b receptor) and CR2 (C3d receptor) and a second expressing only CR1. Nearly all of the population that expressed both CR1 and CR2 also bore membrane surface immunoglobulins (Ig) and Ia antigens. The majority of cells that had only CR1 lacked detectable surface Ig. These Ig- CR1+ CR2- cells could be distinguished from the majority of monocytes and immature granulocytes, in that the latter ingested latex particles and expressed CR2 as well as CR1. The Ig- CR1+ cells were further subdivided into an Ia-bearing subpopulation and another that lacked Ia. Among the Ig- Ia- CR1+ cells, one third formed spontaneous rosettes with sheep erythrocytes while all of the remaining CRL were erythrocyte-rosette negative. Essentially all CRL in normal blood had IgG Fc receptors, but a qualitative heterogeneity in the Fc receptors of Ia+ CRL vs. Ia- CRL was observed in their binding of different immune complex systems.

Antigens, Surface↗

PubMed1979

Deficient serum bactericidal activity against Escherichia coli in patients with cirrhosis of the liver.

The serum bactericidal activity (SBA) of cirrhotic patients was compared with that of normal individuals using the release of (51)Cr from radiolabeled Escherichia coli as the assay method. 80% (22/27) of patients were found to have deficient SBA against at least one of three smooth, serum-sensitive test strains of E. coli. Cirrhotic patients were found to have normal levels of serum lysozyme. Although some patients were mildly hypocomplementemic, this abnormality did not correlate with the presence of a bactericidal defect. Bactericidal antibody in normal and cirrhotics' sera was limited to the immunoglobulin (Ig)M class. Purified IgM from patients with deficient SBA against E. coli 0111 had lower concentrations of bactericidal antibody for that E. coli than did IgM from normal sera; the calculated bactericidal activity of total serum IgM was also lower. The bactericidal defect in cirrhotic serum could be completely corrected by either human antiserum to the homologous strain of E. coli or by purified, normal human IgM. However, because higher concentrations of IgM were required to restore normal SBA to a cirrhotic's serum than to agammaglobulinemic serum, there may be an inhibitor of bactericidal antibody in addition to a deficiency of bactericidal IgM antibody to E. coli in the serum of patients with cirrhosis. The bactericidal activity of the alternative complement pathway was also assessed. Sera from cirrhotic patients had no deficit in SBA attributable to the alternative complement pathway. In fact, in some, the activity of the alternative complement pathway was supernormal, compensating in part for the deficit in IgM-mediated SBA.

Antibodies, Bacterial↗

PubMed1980

Nephritic factor of the classical pathway of complement: immunoglobulin G autoantibody directed against the classical pathway C3 convetase enzyme.

A factor, functionally characterized by its capacity to stabilize the normally labile classical pathway C3-converting complex of the classical pathway of complement, has been isolated from the serum of one patient with a case of acute glomerulonephritis, subsequent to a cutaneous infection. The factor confers long-lived stabilization of classical pathway C3 convertase complexes formed both in the solid (sensitized sheep erythrocytes bearing activated C1 and the classical pathway C3 convertase) and fluid phase. The half-life of such stabilized C3-cleaving enzymes extended beyond several hours at 37 degrees C. The stabilizing activity was associated with a protein fraction immunochemically identified as immunoglobulin (Ig)G, a sizeable population of which exhibited a gamma chain of 60,000 daltons. The IgG-associated stabilizing activity was found to bind to the classical pathway C3 convertase enzyme via a fragment bearing the antigen-binding site of the molecule [F(ab)(2) and F(ab)]. Such binding was demonstrable for classical pathway and not for alternative pathway C3 convertase. Thus, the stabilizing factor behaves like an autoantibody to the C3-converting complex of the classical pathway of complement. The binding of the antibody to the enzyme affords protection of the latter against decay-degradation. By analogy with the nephritic factor of the alternative pathway situation where IgG autoantibodies specifically bind to alternative pathway C3 convertase enzymes and protect them from degradation, the functionally unusual IgG in our patient was designated as the nephritic factor of the classical pathway. Indirect evidence suggests that nephritic factor of the classical pathway-IgG might be of the IgG3 subclass.

Adult↗

PubMed1984

Biosynthesis of the human C3b/C4b receptor during differentiation of the HL-60 cell line. Identification and characterization of a precursor molecule.

The C3b receptor (C3bR) of the human promyelocytic leukemia cell line (HL-60) was induced by incubating these cells with dimethylsulfoxide (DMSO) or retinoic acid. A majority of differentiated (DMSO- or retinoic acid-treated) but not undifferentiated cells formed rosettes with C3b-coated erythrocytes and were morphologically mature granulocytes. HL-60 cells were surface- or biosynthetically labeled and then solubilized in 1% Nonidet P-40 in the presence of multiple protease inhibitors. The C3bR was isolated either by immunoprecipitation with anti-C3bR antibodies or by affinity chromatography with hemolytically inactive components in which the internal thioester bond within the alpha-chain was cleaved (iC3)- or iC4-Sepharose. Autoradiographs of NaDodSO4-polyacrylamide gels indicated that the surface-labeled C3bR on the differentiated cells had an Mr of 210,000 (nonreduced) or 240,000 (reducing conditions). The bulk (approximately 85%) of the radiolabeled material that was isolated from biosynthetically labeled cells co-migrated with the surface-labeled band. A small fraction (approximately 15%) of the biosynthetically labeled material that was isolated by affinity chromatography or immunoprecipitation had an Mr of 188,000, which did not correspond to any surface-labeled band. This putative precursor molecule was characterized by pulse-chase experiments and by analysis of its carbohydrate. In pulse-chase (15-min pulse) studies of differentiated cells, only the 188,000-mol wt molecule was detected at 0 h. By 2 h, greater than 80% of counts had chased from the 188,000 to the 210,000-mol wt molecule. Treatment of these two molecules with endoglycosidases indicated that the 188,000-mol wt molecule possessed high mannose oligosaccharides, while the mature C3bR had complex oligosaccharides. We conclude from these data that the 188,000-mol wt molecule is a precursor of the C3b receptor of HL-60 cells. Other experiments indicated that the half-maximal time for newly synthesized receptor to attain an Mr of 210,000 was 45 min, and that the t1/2 for the disappearance of the receptor on the surface of differentiated HL-60 cells in tissue culture was approximately 10 h. The ability to observe the induction of the C3b receptor as the HL-60 cell line differentiates is an instructive model system to study the biosynthesis of a human integral membrane receptor glycoprotein.

Cell Differentiation↗

PubMed1985

Human histocompatibility leukocyte antigen (HLA) haplotype frequencies estimated from the data on HLA class I, II, and III antigens in 111 Japanese narcoleptics.

In order to deduce the predominant haplotypes in Japanese narcoleptics, we have studied a total of 111 Japanese patients with narcolepsy and six multiple-case families for HLA class I and class II antigens, and for class III HLA-linked complement markers. In Japanese narcoleptics, the most frequent haplotypes were B35-DR2, B15-DR2, and B51-DR2. These haplotypes were rare in normal Japanese population. In contrast, the most frequent haplotype of HLA-DR2 in normal Japanese, A24-C blank-Bw52-C4A*2 B*Q0-BF *S-C2*C-DR2-DQw1, had a decreased frequency to one-third of the normal controls. Haplotypes B35-DR2, B15-DR2, and B51-DR2, which were more frequent among Japanese narcoleptics, were different from the haplotype found more frequently among Caucasoid narcoleptics, A3-Cw7-B7-DR2-DQw1. Haplotype analysis on six families showed that B35-DR2 and other rare haplotypes in normal Japanese were associated with narcolepsy. There were four cases without any signs of narcolepsy among 19 subjects with the disease susceptibility haplotypes. This finding suggests an incomplete penetrance of hypersomnia. Haplotype analysis of family members was also useful for the early detection of the high risk children to narcolepsy.

Complement C2↗

PubMed1993

The association between hepatitis C virus infection and in vitro activation of the complement system.

The phenomenon of in vitro activation of the classical complement pathway at low temperatures (4-21 degrees C) is known as cold activation, and has been suggested to be associated with non-A, non-B hepatitis. We re-examined the association by using newly developed markers of hepatitis C virus (HCV) infection. Twenty-one cases randomly selected from those fulfilling the screening criteria of complement cold activation all showed evidence of HCV infection. More than half of 55 HCV antibody-positive cases selected randomly from our laboratory samples showed a tendency towards cold activation, whereas none of the HCV antibody-negative sera showed cold activation. All the HCV antibody-positive cases were negative in cold activation when CH50 was assayed with plasma. These results, taken together, indicate that cold activation of the complement system is strongly associated with HCV infection.

Cold Temperature↗

PubMed1991

Activation of complement by Treponema denticola.

Oral spirochetes have been shown to be associated with periodontal diseases and are present in increased numbers in lesions of greater severity. In this study, the interaction of Treponema denticola with human complement, a major antibacterial defense system, was examined. For each of two strains of T. denticola, it was found that both the classical and alternative pathways of human complement were activated in human serum upon incubation at 37 degrees C. C3 fragments were deposited on the surface of this organism following complement activation; the fragments bound included both of the major C3-derived opsonic fragments C3b and iC3b. Under incubation conditions identical to those carried out for complement activation in serum, T. denticola failed to degrade purified, hemolytically-active C3, although it readily degraded inactivated C3. Thus, despite the documented proteolytic activity of this organism, complement activation and deposition of complement-derived opsonins may be important defense mechanisms in the control of infections with T. denticola.

Complement C3↗