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PubMed1989

Activation of the complement system in primary sclerosing cholangitis.

Recent evidence, including the presence of circulating immune complexes, suggests that abnormalities of humoral immunity may be important in the pathogenesis of primary sclerosing cholangitis. The aim of the present study was to determine whether activation of the complement system is present in patients with this disease, as this would be supportive evidence of a role for circulating immune complexes in primary sclerosing cholangitis. Plasma complement fragments C3d and C4d, and serum C3 and C4, their respective parent molecules, have been assayed. Both C3d and C4d were elevated in patients with primary sclerosing cholangitis compared with patients with extrahepatic obstructive cholestasis and normal controls (p less than 0.01 in all instances). C3 was elevated in both patient groups, in whom it was similar, compared with normal controls (p less than 0.001 in both cases), whereas C4 was similar in all groups. Elevated levels of circulating immune complexes were identified in 21 of 24 (88%) patients with primary sclerosing cholangitis, but in none of the normal controls. These findings support the hypothesis that in primary sclerosing cholangitis circulating immune complexes are associated with activation of complement via the classical pathway.

Adult↗
PubMed1984

Quantitation of human protein S in the plasma of normal and warfarin-treated individuals by radioimmunoassay.

Protein S was purified from human plasma and used to raise monospecific antibodies. A double antibody equilibrium radioimmunoassay was constructed and met all the requirements for a sensitive, accurate and specific determination of Protein S. The sensitivity of the assay was between 8-250 ng of Protein S/ml and the coefficient of variation was 2-6% within assays and 13-19% between assays. Complement C4b-binding protein or Protein C did not effect the measurement of Protein S. Complete competition with parallel slopes of inhibition was seen among purified Protein S and plasma from normal and warfarin-treated individuals indicating immunochemical identity and validating the measurement of Protein S in plasma. The concentration of Protein S in normal plasma (n=24) was 23.4 +/- 4.42. micrograms/ml and in plasma from warfarin-treated individuals (n=24) was 12.6 +/- 3.92 micrograms/ml. Thus, a common feature of individuals undergoing warfarin therapy is the reduction of approximately 50% in the concentration of each of the vitamin K-dependent proteins.

Antibodies, Monoclonal↗
PubMed1988

Plasma protein S activity measured using Protac, a snake venom derived activator of protein C.

Functional activity of protein S, a cofactor of activated protein C-dependent inhibition of blood coagulation, in human plasma was measured by using Protac, a snake venom derived activator of protein C. This assay appeared to be specific for protein S, because 1) the activated partial thromboplastin time of protein S-depleted plasma depended on the purified protein S added in the presence of Protac; and 2) the level of protein C in plasma sample (0 to 10 micrograms/ml) had no influence on the clotting time. The cofactor activity of protein S in the plasma of normal men (n = 16) and women (n = 14) was 99.4 +/- 23.8% and 98.6 +/- 24.5% respectively. The protein S activity in the plasma of pregnant women at pre- and post-partum (n = 14), and that in the plasma of patients under warfarin therapy (n = 20) were 46.2 +/- 18.9%, 45.8 +/- 19.6% and 24.0 +/- 15.7%, respectively. In these plasmas, the levels of protein S activity were lower than those of total protein S antigen, but were similar to those of free protein S antigen. In 16 patients out of two families with congenital protein S deficiency, the protein S activity, the free antigen and the total antigen were 9.4 +/- 6.9%, 13.3 +/- 4.6% and 57.4 +/- 20.7%, respectively. There was no significant relationship between the level of protein S activity and that of a complemental C4b-binding protein antigen in any of these patients.

Female↗
PubMed1990

Experimental neonatal syphilis in a susceptible (C4D) and a resistant (Albany) strain of guinea pig.

Despite similar levels of natural antibodies and treponemicidal activity, 83% of fourth complement component-deficient (C4D) mother guinea pigs developed ulcerative lesions to a challenge of 5 x 10(7) Treponema pallidum, whereas 75% of offspring 1 to 5 days old were temporarily (2-3 months) resistant to development of dermal lesions. In contrast, only 17% of Albany-strain mothers developed small papular lesions, while 68% of 1- to 5-day-old newborns developed large papular or ulcerative lesions within 9-15 days postinfection. These findings, together with the late development of both dermal lesions and antibodies in C4D neonates, preclude the concept of an antibody-associated natural resistance. T. pallidum infection in either C4D or Albany neonates was not associated with depletion of any particular cell population in lymphoid tissue. However, marked age- and strain-dependent histologic differences were noted. Histologic examination of lymph nodes and spleens from 17-day-old and 3- to 4-month-old animals showed that maturation of lymphoid tissues in C4D animals lagged behind the Albany strain at either age. Moreover, 75% of C4D newborns contained significantly higher levels of immunomodulatory alpha 1 fetoprotein than Albany neonates. The possibility that differences in susceptibility to T. pallidum infection between C4D and Albany guinea pigs as neonates and again as adults is the result of genetically associated changes in immunologic recognition is discussed.

Animals↗
PubMed1996

Complement activation by 3-mercapto-1,2-propanediol immobilized on gold surfaces.

Thiol-modified surfaces are chemically well defined and suited for surface biological model experiments and biomaterials research. 3-Mercapto-1,2-propanediol (mercaptoglycerol, MG), immobilized on gold, spontaneously binds immunoglobulins from human serum and activates the complement system. The surface-bound complement factors were detected by ellipsometry-antibody techniques. The overall complement activation was subsequently corroborated independently with enzyme immunosorbent assay (EIA) and sheep and chicken erythrocyte haemolytic complement techniques. EIA experiments indicated elevated levels of C4d, but no significant increase of factor Bb was evident in the test serum from the MG system. The haemolytic assays show that MG surfaces consume complement factors from both pathways. Ellipsometry revealed that immunoglobulin G (IgG) and complement factor 1q (C1q) are transiently antibody detectable on MG after exposure to whole serum by the use of antibody techniques. Complement factor 3 (C3), C2, C4 and properdin could be detected on the surface, but not factors H and B. The total adsorbed mass and particularly C3 antibody deposition were suppressed by using EGTA-Mg2+ serum. The results suggest that MG surfaces initially activate complement via the classical pathway. Other IgG binding surfaces also appear to behave in a similar manner.

Animals↗
PubMed1983

Cleavage of membrane-bound C3b and C3bi by viable human neutrophils (PMN).

Cleavage of C3 by purified leukocyte enzymes and crude extracts of human polymorphonuclear leukocyte (PMN) granules has been reported. We demonstrate that viable PMN mediate the cleavage of erythrocyte-bound C3b and C3bi via cell-associated proteases. Greater than 50% of 125IC3(x) was released from EAC43bix during a 5-min incubation with viable PMN at 37 degrees C. More than a 30-min incubation was required for substantial release from EAC43bx. Culture fluids from PMN suspensions had limited cleaving ability; cleavage of cell-bound C3bx and C3bix was only partially reduced when PMN were preincubated with high levels of soluble C3 which completely blocked EAC43b rosettes. Thus, cell-to-cell contact between opsonized erythrocytes and viable PMN with surface-associated proteases are responsible for cleavage of these opsonic sites. The effect of defined protease inhibitors on PMN cleaving activity as well as on purified leukocyte elastase was examined. Phenylmethylsulfonyl fluoride (PMSF) and the leukocyte elastase inhibitor, methoxy-succinate-alanine-alanine-valine-chloromethyl ketone (MeO) each inhibited cleavage of C3b by 90% and C3bi by 60%. In contrast, the cathepsin-G inhibitor, benzyloxy-carbonyl-glycine-leucine-phenylalanine-chloromethyl ketone (Z) inhibited C3b and C3bi cleavage by less than 20 and less than 5%, respectively. Ethylenediaminetetra-acetate (EDTA), which had a minimal effect on soluble leukocyte elastase, also inhibited PMN-related release. Thus, elastase appeared to be the principle but not the only enzyme responsible for cleavage of C3b and C3bi. PMSF and MeO had a minimal effect on the activity of purified C3bINA (Factor I); and PMN-mediated release of C3b fragments was not inhibited by anti-Factor I and anti-beta 1H (Factor H) IgG and Fab. Thus, these control proteins are not involved in the PMN-mediated cleavage under study. PMN-mediated cleavage of C3b was also inhibited when PMSF- and MeO-treated PMN were washed to remove the fluid phase phase protease inhibitor before adding EAC43b. This suggests that proteases localized in the PMN membrane, prior to the adherence of EAC43b, are responsible for C3b cleavage. Normal human serum was effective in blocking PMN-mediated release activity, while serum from alpha 1 antitrypsin-deficient patients was minimally effective. This suggests a mechanism for the in vivo regulation of PMN-mediated release of C3b and C3bi from opsonized particles by the natural plasma protease inhibitors.

Amino Acid Chloromethyl Ketones↗
PubMed1987

A monoclonal antibody which can distinguish between the two isotypes of human C4.

A monoclonal antibody to Human C4 (L003) has been shown to bind to the polymorphic C4d fragment of the alpha-chain of C4. Another monoclonal antibody (L001) was shown to bind to the beta-chain. L003 reacts differently with the two isotypes of C4, C4-A and C4-B. The equilibrium constant of L003 for C4-B is approx. 7-fold higher than that for C4-A, while L001 has similar affinity for both C4 types. Also, L003 binding to C4-A is very much more pH dependent than is its binding to C4-B. These observations explain the very useful property of L003 in being able to separate the two isotypes by affinity chromatography.

Antibodies, Monoclonal↗
PubMed1988

Association of complement allotype C4B2 with anterior uveitis.

We have studied allotypes of the fourth component of complement (C4) in 44 patients with inflammatory eye disease in order to define genetic susceptibility factors further. Twenty-six patients had uveitis (18 had anterior uveitis) and 18 patients had retinal vasculitis. There was an increased incidence of the C4B2 allotype in patients with anterior uveitis (pc less than 0.002), especially in HLA B27 positive males. In contrast, there was no increased incidence of specific allotypes in patients with posterior uveitis or retinal vasculitis. This genetic association may form part of a disease susceptibility supratype in patients with anterior uveitis.

Alleles↗
PubMed1990

Complement-activated oligodendroglia: a new pathogenic entity identified by immunostaining with antibodies to human complement proteins C3d and C4d.

Clusters of oligodendroglial fibers were identified immunohistochemically in human brain tissue with antibodies to the complement proteins C3d and C4d in several neurological disorders. These included Pick's, Huntington's, Parkinson's and Alzheimer's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy and Shy-Drager syndrome. These complement-activated oligodendroglia occurred in selected areas of gray and white matter. They were rarely observed in control tissue. Immunogold electron microscopy established that the C4d antibody was attached to degenerating myelin sheaths. These data indicate attachment of classical complement pathway proteins to selective oligodendroglia in several neurological disorders.

Brain Diseases↗
PubMed1995

Chronically administered 3-nitropropionic acid induces striatal lesions attributed to dysfunction of the blood-brain barrier.

3-Nitropropionic acid (3-NPA), an irreversible inhibitor of succinate dehydrogenase, was administered to rats and the characteristics of the neuronal damage were investigated. Injections of 3-NPA (15 mg/kg s.c.) every 2 or 3 days for 1-2 weeks induced a mild neuronal loss and neutrophil invasions in the striatum (STR). The same administration for 4 weeks induced specific symmetric lesions in the lateral STR although the size was variable in each animal. Inside the lesions, strong neutrophil invasions and a strong immunoreaction for IgG, C3 as well as complement factor C3b/C4b receptor (C3b/C4br) were detected. Lesioned sites lost the immunoreaction for GFAP while the marginal areas contained abundant GFAP-labeled astrocytes around the vessels. In intoxicated animals, there was a weak but stout immunoreaction for IgG and C3b/C4br localizing around vessels in the STR even when there were no lesions or neuronal loss. The data suggest that the blood-brain barrier dysfunction is responsible for the specific vulnerability of the STR for the toxin.

Animals↗
PubMed1998

Studies on protein adsorption and activation of complement on hydrated aluminium surfaces in vitro.

Adsorption of human plasma and serum proteins onto hydrated aluminium was studied by ellipsometry/antibody techniques, and soluble complement components iC3b, Bb, and C4d with commercial ELISA plates. Aluminium that was incubated in plasma for 1 min bound significant amounts of anti-lipoproteins (anti-LP), no antibodies against contact activation of coagulation proteins, and no anti-fibrinogen (anti-Fib). Time course studies with serum revealed increasing deposition of anti-C3c with time. Complement factor 1q (C1q) was antibody detectable only after short-time serum incubations, but no anti-IgG and anti-properdin bound to the protein film at any time. Anti-C3c was not deposited after exposure of the surfaces to Clq-depleted serum. Intriguingly, and in spite of increasing deposition of C3 to the surface with time, the combined ellipsometry and ELISA results gave no unequivocal proof of activation of complement by hydrated aluminium.

Adsorption↗
PubMed1999

Immunohistochemical analysis of arterial wall cellular infiltration in Buerger's disease (endarteritis obliterans).

PURPOSE: The diagnosis of Buerger's disease has depended on clinical symptoms and angiographic findings, whereas pathologic findings are considered to be of secondary importance. Arteries from patients with Buerger's tissue were analyzed histologically, including immunophenotyping of the infiltrating cells, to elucidate the nature of Buerger's disease as a vasculitis. METHODS: Thirty-three specimens from nine patients, in whom Buerger's disease was diagnosed on the basis of our clinical and angiographic criteria between 1980 and 1995 at Nagoya University Hospital, were studied. Immunohistochemical studies were performed on paraffin-embedded tissue with a labeled streptoavidin-biotin method. RESULTS: The general architecture of vessel walls was well preserved regardless of the stage of disease, and cell infiltration was observed mainly in the thrombus and the intima. Among infiltrating cells, CD3(+) T cells greatly outnumbered CD20(+) B cells. CD68(+) macrophages or S-100(+) dendritic cells were detected, especially in the intima during acute and subacute stages. All cases except one showed infiltration by the human leukocyte antigen-D region (HLA-DR) antigen-bearing macrophages and dendritic cells in the intima. Immunoglobulins G, A, and M (IgG, IgA, IgM) and complement factors 3d and 4c (C3d, C4c) were deposited along the internal elastic lamina. CONCLUSION: Buerger's disease is strictly an endarteritis that is introduced by T-cell mediated cellular immunity and by B-cell mediated humoral immunity associated with activation of macrophages or dendritic cells in the intima.

Adult↗
PubMed1984

Covalent binding efficiency of the third and fourth complement proteins in relation to pH, nucleophilicity, and availability of hydroxyl groups.

The binding of [3H]glycerol and [3H]putrescine to C3 was studied in a fluid-phase system using trypsin as the C3 convertase. The binding of glycerol showed little variation in the pH range between 6.0 and 10.0. The binding of putrescine (pKa = 9.0) is rather ineffective below pH 7.5 but becomes more efficient as the pH of the reaction mixture increases. These results agree with the contention that the final step of the binding reaction is the transfer of the acyl group of the exposed thio ester of C3 to a nucleophile since the nucleophilicity of hydroxyl groups is rather independent of pH whereas only the unprotonated form of amino groups is nucleophilic. The inefficient reaction of amino groups with the exposed thio ester of C3 is also supported by the study of the inhibitory activity of serine and its two derivatives, N-acetylserine and O-methylserine, to the binding of [3H]glycerol to C3. N-Acetylserine showed an inhibitory activity equivalent to that of serine, whereas O-methylated serine showed only minimal activity. It can be concluded, therefore, that serine reacts with the thio ester of C3 by its hydroxyl group but not by its alpha-amino group. The ability of the alcohol group of various alkanes to inhibit the binding of [3H]glycerol to C3 was also studied. The primary alcohols inhibit the binding reaction with an efficiency that is similar to glycerol, and there are no significant differences in the binding efficiencies of methanol, ethanol, 1-propanol, and 1-butanol.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohols↗