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PubMed1986

Sensitivity of antiproteases, complement factors and C-reactive protein in detecting pancreatic necrosis. Results of a prospective clinical study.

Thirty-five patients with acute pancreatitis underwent serum monitoring of alpha-1-protease inhibitor, alpha-2-macroglobulin, complement factors C3 + C4, and C-reactive protein (CRP). Edematous interstitial pancreatitis was shown to be present in 13 patients by contrast-enhanced computed tomography (CT) and laparotomy (n = 3). Necrotizing pancreatitis was confirmed by laparotomy (n = 21) and contrast-enhanced CT. There were significant differences between the serum values of all measured parameters in the two morphologically defined pancreatitis groups. The best discriminating factors were CRP and alpha-2-macroglobulin, showing 95% and 85% overall detection rates for pancreatic necrosis, respectively.

Acute Disease↗

PubMed1990

Sequence similarity between alpha 2-macroglobulin from the horseshoe crab, Limulus polyphemus, and proteins of the alpha 2-macroglobulin family from mammals.

1. Purified alpha 2-macroglobulin (alpha 2M) from the American horseshoe crab, Limulus polyphemus was cleaved with trypsin and 20 of the tryptic peptides were sequenced and compared with the sequences of human alpha 2M, rat alpha 1M, alpha 2M, and alpha 1-inhibitor 3, and human complement proteins C3 and C4. 2. Ten of the peptides (233 residues), including that containing the thiol ester site, could be aligned unambiguously with stretches in mammalian alpha 2M, with a degree of identity greater than 30%. 3. The 12-residue thiol ester-containing peptide of Limulus alpha 2M showed 67% identity with the same stretch of human alpha 2M.

Amino Acid Sequence↗

PubMed1978

Translocation of a hydrocarbon fluorescent probe between Epstein-Barr virus and lymphoid cells: an assay for early events in viral infection.

Translocation of the hydrocarbon fluorescent probe diphenylhexatriene (DPH) between membranes was studied by fluorescence polarization (P) analysis. First, using a model system, the high P value (0.324) of DPH-labeled cholesterol/phosphatidylcholine liposomes and the low P value (0.157) of DPH-labeled phosphatidylcholine liposomes allowed detection of DPH translocation between interacting liposomes. This was monitored by the change in P in either direction. Early events during cell-virus interactions were similarly studied by monitoring DPH translocation. The P value of DPH-labeled Epstein-Barr Virus (EBV) was significantly higher (0.350-0.392) than the P value of DPH-labeled lymphoid cells (0.238-0.289). Hence, DPH translocation could be detected by changes in P following incubation of DPH-labeled EBV and nonlabeled cells. A marked decrease in P was observed after incubation of DPH-labeled EBV with either nonlabeled lymphoblastoid Raji cells or fresh human B lymphocytes. However, only a slight decrease in P was obtained when DPH-labeled EBV was incubated with either nonlabeled fresh human T lymphocytes or fresh T or B rabbit lymphocytes. Moreover, incubation of fresh human B lymphocytes with the purified C3 component of complement (a putative inhibitor for the EBV receptor) prior to the addition of DPH-labeled EBV abolished the observed decrease in the P value. Most of these experiments were carried out with both the P3HR-1 and the B95-8 strains of EBV. DPH translocation, as determined by fluorescence polarization analysis, is, therefore, measuring some early event during interaction of this enveloped virus and mammalian cells. The potential applicability of this technique to other viruses is illustrated by an experiment with Semliki Forest virus.

Cells, Cultured↗

PubMed1984

[Immunopathology in 35 cases of chronic urticaria].

Although urticaria is usually held to be a type 1 hypersensitivity reaction, it may also be the cutaneous manifestation of vasculitis mediated by immune complexes. In this study of 35 patients with chronic urticaria, the authors attempted to specify the prevalence of vasculitis and its possible correlations with particular clinical and/or immunological findings. In 10 cases, lymphocyte subpopulations were also studied, using monoclonal antibodies. Patients included 21 women and 14 men, aged 19 to 80. In each patient: a) systemic signs were looked for by history taking and physical examination; b) a skin biopsy was examined by optic microscopy and direct immunofluorescence; c) the following biological investigations were done: blood count, sedimentation rate, protein electrophoresis and immunoelectrophoresis, IgE, B virus markers, circulating immune complexes, anti-nuclei and anti-ADN antibodies, latex and Waaler-Rose tests, total complement, C3, C4, and C1 esterase inhibitor. Visceral involvement and various immunological disorders are most common in those patients with leukoclastic (n = 7) or mononuclear (n = 9) vasculitis. These patients, as well as those recently studied in the literature, have idiopathic chronic urticaria, the least severe of urticarial vasculitis.

Adult↗

PubMed1995

Complement inhibition with an anti-C5 monoclonal antibody prevents acute cardiac tissue injury in an ex vivo model of pig-to-human xenotransplantation.

Prevention of hyperacute xenograft rejection in the pig-to-primate combination has been accomplished by removal of natural antibodies, complement depletion with cobra venom factor, or prevention of C3 activation with the soluble complement inhibitor sCR1. Although these strategies effectively prevent hyperacute rejection, they do not address the relative contribution of early (C3a, C3b) versus late (C5a, C5b-9) activated complement components to xenogeneic organ damage. To better understand the role of the terminal complement components (C5a, C5b-9) in hyperacute rejection, an anti-human C5 mAb was developed and tested in an ex vivo model of cardiac xenograft rejection. In vitro studies demonstrated that the anti-C5 mAb effectively blocked C5 cleavage in a dose-dependent manner that resulted in complete inhibition of both C5a and C5b-9 generation. Addition of anti-C5 mAb to human blood used to perfuse a porcine heart prolonged normal sinus cardiac rhythm from a mean time of 25.2 min in hearts perfused with unmodified blood to 79,296, or > 360 min when anti-C5 mAb was added to the blood at 50 micrograms/ml, 100 micrograms/ml, or 200 micrograms/ml, respectively. In these experiments, activation of the classical complement pathway was completely inhibited. Hearts perfused with blood containing the highest concentration of anti-C5 mAb had no histologic evidence of hyperacute rejection and no deposition of C5b-9. These experiments suggest that the activated terminal complement components C5a and C5b-9, but not C3a or C3b, play a major role in tissue damage in this porcine-to-human model of hyperacute rejection. They also suggest that targeted inhibition of terminal complement activation by anti-C5 mAbs may be useful in clinical xenotransplantation.

Acute Disease↗

PubMed1978

Serum proteins in heavily burnt patients.

Several serum proteins, such as prealbumin, protease inhibitors, immunoglobulins, metalloproteins and inflammatory glycoproteins were determined in the sera of heavily burnt patients by radial immunodiffusion. An increase of acute phase reactant glycoproteins (orsomucoid, haptoglobin, haemopexin, C-reactive protein), C3-complement, immunoglobulins, prealbumin and of the protease inhibitors (a1-antitrypsin, a2-macroglobulin) was found. For some proteins, such as prealbumin, haemopexin, immunoglobulins, this increase was preceeded by a decrease on days 3 to 5 post-burn. The time course of the increase was variable, faster for some patients and slower for others: orosomucoid, C-reactive protein, C3-complement reached peak values between days 6 and 8; immunoglobulins and hemopexin decreased then towards normal values. No significant increase was found for ceruloplasmin, transferrin, beta2-glycoprotein, a2-SH glycoprotein and GC-globulin. It is proposed that the selective overproduction of the above mentioned proteins may be related to the stimulation of acute-phase reactant protein synthesis by the liver as a result of tissue breakdown produced by the circulating proteases and especially by elastases and collagenases as was shown previously (Miskulin et al., 1978; Moati et al., 1978a).

Blood Proteins↗

PubMed1983

[Immune complex and complement levels in spontaneous abortions and normal pregnancy].

We gave attention to the following as specific immunological tolerance factors in pregnancy: a) the serum levels of circulated immune complex (IC), b) serum complement levels (C1q, C3, C4, C1-Inhibitor). The results were as follows: In spontaneous abortions measured by C1q binding test (Zubler et al.) IC levels did not differ significantly from those in normal pregnancies in the first trimester, but in both cases, IC levels were slightly higher than the levels in nonpregnant women. C1q and C1-Inhibitor levels in normal pregnancies were significantly lower than in nonpregnant women, and both levels in spontaneous abortions were significantly higher than in normal pregnancies. In cases of artificial and spontaneous abortions, increased IC levels were rapidly lowered to the normal range within 7 days after treatment and lowered C1q and C1-Inhibitor levels also returned to the normal range within 7 days. But these trends were more remarkable in artificial abortions. However, C3 and C4 levels did not change after treatment in either case. A negative correlation between complement levels (C1q, C3, C4) and IC levels in the third trimester was demonstrated in our study.

Abortion, Spontaneous↗

PubMed2001

Complement activation by apoptotic endothelial cells following hypoxia/reoxygenation.

Reperfusion of ischaemic tissue initiates an inflammatory reaction that increases tissue injury. Complement activation at the endothelium contributes to this inflammation. This study investigated the mechanism of complement activation following reoxygenation of hypoxic human umbilical vein endothelial cells (HUVEC) as a model for complement activation observed on endothelium in reperfused ischaemic tissue. HUVEC cultured in 1% oxygen followed by reoxygenation activated the classical complement pathway resulting in C3 deposition. There was an increase in apoptotic cells in these cultures that was demonstrated by binding of fluorescein isothiocyanate-Annexin V and staining for hypodiploid nuclei. To determine if apoptotic HUVEC activate complement, uniformly apoptotic cells were produced by serum and growth factor deprivation. These cells, but not the control HUVEC, activated the classical complement pathway in the absence of antibody or other serum factors. To determine if apoptotic cells in the reoxygenated cultures were activating complement, fluorescent analysis was done. Annexin V binding and C3d deposition on cells from reoxygenated cultures showed complete concordance on the subpopulation of apoptotic cells. In addition, complement activation following reoxygenation of HUVEC was eliminated by treatment of the cultures with a caspase inhibitor during reoxygenation. These results suggest that oxidative damage to endothelial cells during reoxygenation initiates apoptosis with exposure of phosphatidylserine. Apoptotic cells directly activate the classical pathway of complement by binding C1. Activation of complement at the endothelium may contribute to the inflammatory response as well as clearance and repair.

Amino Acid Chloromethyl Ketones↗

PubMed1999

In vivo role of complement-interacting domains of herpes simplex virus type 1 glycoprotein gC.

Immune evasion is critical for survival of viruses that establish persistent or recurrent infections. However, at the molecular level, little is known about how viruses evade immune attack in vivo. Herpes simplex virus (HSV)-1 glycoprotein gC has two domains that are involved in modulating complement activation; one binds C3, and the other is required for blocking C5 and properdin (P) binding to C3. To evaluate the importance of these regions in vivo, HSV-1 gC mutant viruses were constructed that lacked one or both gC domains and studied in a murine model of infection. Each gC region of complement regulation contributed to virulence; however, the C3 binding domain was far more important, as virus lacking this domain was much less virulent than virus lacking the C5/P inhibitory domain and was as attenuated as virus lacking both domains. Studies in C3 knockout mice and mice reconstituted with C3 confirmed that the gC domains are inhibitors of complement activation, accounting for a 50-fold difference in virulence between mutant and wild-type viruses. We conclude that the C3 binding domain on gC is a major contributor to immune evasion and that this site explains at a molecular level why wild-type virus resists complement attack.

Animals↗

PubMed2002

Crry, but not CD59 and DAF, is indispensable for murine erythrocyte protection in vivo from spontaneous complement attack.

Decay-accelerating factor (DAF) and CD59 are 2 glycosylphosphatidylinositol-anchored membrane proteins that inhibit complement activation at the C3 and C5b-9 step, respectively. CD59 is considered critical for protecting erythrocytes from spontaneous complement attack, as deficiency of CD59 or CD59/DAF, but not of DAF alone, on human erythrocytes renders them sensitive to complement lysis in paroxysmal nocturnal hemoglobinuria syndrome. To evaluate the relative roles of CD59 and DAF in vivo, we have generated and studied a CD59 knockout and a CD59/DAF double-knockout mouse. CD59-deficient and CD59/DAF-double-deficient mouse erythrocytes were highly sensitive to antibody-induced complement lysis in vitro, yet neither CD59 knockout nor CD59/DAF double-knockout mouse developed spontaneous hemolytic anemia. Consistent with the latter observation, erythrocytes from the 2 strains of mutant mice were shown to have a normal lifespan in vivo. In contrast, mouse erythrocytes deficient in complement receptor 1 (CR1)-related gene y (Crry), a membrane C3 inhibitor with DAF and membrane cofactor protein activities, were rapidly eliminated from the circulation by a complement-dependent mechanism. Compared with DAF-deficient erythrocytes, Crry-deficient erythrocytes incurred higher levels of spontaneous C3 deposition in vivo. These findings demonstrate that CD59 and DAF are not indispensable on murine erythrocytes. Rather, effective C3 regulation on the cell surface, provided by Crry rather than DAF, is necessary for mouse erythrocytes to resist spontaneous complement attack. Our results raise the possibility that proper control of C3 activation may also be critical on human erythrocytes, where CR1 but not DAF could be the principal regulator of spontaneous C3 activation.

Animals↗

PubMed1985

Guillain-Barré syndrome following danazol and corticosteroid therapy for hereditary angioedema.

A case of hereditary angioedema secondary to C1 esterase inhibitor deficiency associated with lupus-like nephritis is reported. The patient was initially treated with both corticosteroids and danazol and subsequently had Guillain-Barré syndrome together with appearance of circulating immune complexes and an increase in total complement and C1q, C3, C4, B, and C1 esterase inhibitor levels. Guillain-Barré syndrome might be secondary to danazol therapy since this drug could increase both circulating immune complex production and complement synthesis, thereby providing additional substrate for the underlying immune complex disease. Normalization of complement might therefore be hazardous in lupus with underlying complement deficiency states.

Adolescent↗

PubMed2002

Genetic-biochemical criteria for individual sensitivity in development of occupational bronchopulmonary diseases.

Human individual sensitivity to health-hazardous occupational factors and probability of developing chronic lung diseases depend on genetic variation of serum and erythrocytic proteins. The present work was aimed at studying the phenotypes of serum and erythrocytic proteins in patients with occupational respiratory diseases. We studied 7 highly polymorphic genetic systems the varieties of which may be connected with development of bronchopulmonary pathology (BPP) and the immune status of the body: proteinase inhibitor (Pi), third component of the complement (C3), transferrin (Tf), group-specific component of blood serum (Gc), haptoglobin (Hp), erythrocytic glyoxalase (Glo) and phosphoglucomutase (PGM) in patients with chronic bronchitis, silicosis, occupational bronchial asthma and in the control group consisting of Moscow population not exposed to occupational hazards and apparently healthy workers of an engineering plant. Considerable differences were revealed in genetic structure of the patients with bronchopulmonary pathology as compared with the apparently healthy people along a series of Integrated system: proteinase inhibitor (Pi), C3, Tf, Gc, PGM. Comparison of the study groups by significant differences in the aggregate of the genetic information obtained suggests that 5 (HP, C3, Tf, Pl, PGM1) of the 7 studied systems showed the hereditary features of silicosis. The gene carriers Hp*2, C3*F, PGM1*2-, TF*D, GC*R due to peculiar biochemical processes appear to have less adaptive potentialities and a greater likelihood of the disease on exposure to industrial factors. The examined patients with chronic bronchitis showed an increase in the variant of GC*2 and of a rare variants of proteins GC*R and Pi*S, the patients with occupational bronchial asthma showed an increase in the variant of Hp*2 and of a rare variant Pi*S. Such studies could be useful for assessment and forecast of individual risk of occupational diseases.

Alleles↗

PubMed1991

Regulation of acute phase reaction by transforming growth factor beta in cultured murine hepatocytes.

Transforming growth factor-beta (TGF beta 1), a multipotent immunoregulatory peptide produced by human platelets, has been shown to stimulate the synthesis of fibrinogen, contrapsin, complement component C3, and alpha-1-proteinase inhibitor by murine hepatocytes cultured for 2 days in DMEM containing 1 microM insulin and dexamethasone and 0.2% BSA. In the range of 10 pg to 10 ng/ml TGF-beta 1 did not elicit any change in albumin secretion. Two main inflammatory cytokines: interleukin-6 (IL-6) and interleukin-1 (IL-1), known to stimulate two different subsets of murine acute phase plasma proteins, failed to increase contrapsin and alpha-1-proteinase inhibitor production. Epidermal growth factor (EGF) in the concentration 1 ng to 10 ng/ml effectively counteracted the stimulatory effect of TGF-beta 1 on acute phase protein production. TGF-beta 1-induced fibrinogen protein levels were associated with increased beta-fibrinogen mRNA content. TGF-beta 1 appears to be an additional physiological factor responsible for the direct stimulation of normal mouse hepatocytes to acute phase response.

Acute-Phase Proteins↗

PubMed1969

C3 leukotactic factors produced by a tissue protease.

When various rat tissues are incubated in homologous serum, a factor chemotactic in vitro for neutrophils is generated. The amount of chemotactic activity is a function of duration of incubation and the quantity of heart tissue or serum employed. Addition of trypsin inhibitor or antibody to the third component of complement (C3) precludes generation of chemotactic activity. In addition, antibody to C3 ablates chemotactic activity even after its formation. Purified human C3 (beta(1C)-globulin) effectively substitutes for serum in the generation of chemotactic activity by heart tissue. The active product, as determined by gel filtration or by ultracentrifugal analysis in a sucrose density gradient, appears to be a cleavage product of C3 with a molecular weight of approximately 14,000. In addition, a larger C3 fragmentation product varying in molecular weight, depending upon experimental conditions, is also found. The protease in rat heart tissue capable of cleaving C3 into chemotactic fragments is a serine esterase with trypsin-like properties and can be inhibited by organophophorous compounds or trypsin inhibitors. The use of amino acid esters in the manner of competitive substrate inhibition confirms the trypsin-like nature of the protease. The presence of a protease in heart, and presumably in other normal tissues, capable of fragmenting C3 into factors with chemotactic activities may explain the development of the acute inflammatory response when tissues are non-specifically injured. If true, this would reinforce the role of the complement system in the mediation of nonimmunologically induced inflammation.

Amino Acids↗

PubMed1987

The role of prostaglandins in C3a-mediated suppression of human in vitro polyclonal antibody responses.

Suppression of polyclonal antibody responses in human peripheral blood mononuclear cell cultures by human C3a appears to involve the release of endogenous prostaglandins from monocytes. C3a was found, under the experimental conditions employed, to activate the cyclooxygenase pathway of arachidonic acid metabolism with the release of large amounts of the prostaglandin E2 species. Suppression of the protein A-induced polyclonal antibody response by C3a is abrogated by the prostaglandin synthesis inhibitor indomethacin. In addition, physiologic amounts of exogenous PGE2 were able to inhibit polyclonal antibody secretion in a manner similar to the suppression observed when C3a was added to culture. These results suggest that C3a-induced release of prostaglandins could be a major element in immunosuppression induced by C3a.

Antibody Formation↗

PubMed1991

Acquired C1 inhibitor deficiency associated with systemic lupus erythematosus affecting the central nervous system.

A 22 year old woman with systemic lupus erythematosus affecting the central nervous system had acquired C1 inhibitor deficiency. She was admitted for treatment of psychotic behaviour, but showed no signs of angioedema. The serum complement profile of the patient showed normal C3 concentration and a depletion of C4, C2, C1 inhibitor, and C1q. Her parents had normal complement profiles. An extremely reduced C4 concentration may lead to involvement of the central nervous system in systemic lupus erythematosus.

Adult↗

PubMed2005

[Regression of glomerulosclerosis in a girl with C3 nephropathy].

Regression of glomerular sclerosis was documented in experimental models as a result of RAA system blocking and/or cyclosporin A (CsA) treatment. Here we present a case of a girl suffering from nephrotic syndrome (NS) in whom unusual healing of glomerular changes appeared. First time the girl was admitted to our department at the age of 4 year with 2 years history of steroid-dependent NS. Kidney biopsy studied in light microscopy revealed 11 glomeruli among which 5 were totally sclerosed and the others showed mesangial proliferation and segmental mesangial matrix expansion. Diffuse interstitial mononuclear cells infiltration was also visible. In fluorescence microscopy only granular C3 and fibrinogen deposits were seen. C3 nephropathy was diagnosed and cyclophosphamide therapy started. As no effects appeared, CsA was introduced together with angiotensin converting enzyme inhibitor (ACEI) enalapril for two years without any relapse during treatment. Prednisone was gradually reduced and finally stopped after a year. On the second biopsy performed to assess CsA nephrotoxicity among 16 glomeruli evaluated in light microscopy only 1 was sclerosed, while the others presented just mild mesangial proliferation. No interstitial changes were found. Fluorescence showed IgA and IgM added to glomerular C3 deposits. CsA was then stopped and after 4 months relapses and steroid-dependency appeared again, so CsA was reintroduced. Actually the girl is 8-year-old, remission of NS has been observed for six months. As a conclusion we would like to suggest that treatment with CsA and ACEI may cause glomerular healing even in a case of advanced glomerulosclerosis.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1983

Complement and protease inhibitors in the mucocutaneous lymph node syndrome.

Total hemolytic activity of serum (CH50), complement components C3 and C4, alpha 1antitrypsin (alpha 1AT), alpha 1antichymotrypsin (alpha 1X), antithrombin III (AT III), alpha 2 macroglobulin (alpha 2M), and inter-alpha-inhibitor (I-alpha-I) were measured in 23 Japanese and 19 European children with the Mucocutaneous Lymph node Syndrome (MCLS) during the acute phase of disease. Second sera, obtained after day 20 were available from 18 Japanese and 10 European children. In 28 out of 31 children with mild disease, as assessed by the coronary risk score of Asai and Kusakawa, complement was normal or elevated during the acute phase. In 10 out of 11 children with high risk scores, CH50 was below the normal range. One child in this group had ECG changes during the acute phase, one patient died and two others developed coronary aneurysms. C1I was elevated in all 42 cases, alpha 1AT in 40, and alpha 1X in 38 patients. alpha 1AT was depressed in two children, one of whom developed an aneurysm. One of the four children with depression of alpha 1X died of myocardial infarction. Decreased concentrations of AT III, alpha 2M and I-alpha-I were frequent and tended to mark the more severe courses of the disease. A third group of 20 children was evaluated 5 weeks to 6 months after the acute illness. Mean concentrations of all five protease inhibitors were completely normalized in this group. The results of this study indicate that consumption of complement and of protease inhibitors occurs in many cases of MCLS during the acute phase. Determination of CH50 appears to be useful to identify high risk patients early in the course of their illness. Transient deficiency of substances for control of inflammation may in part be responsible for the severe vascular lesions seen in some patients.

Alpha-Globulins↗