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PubMed1991

Biomedical polymers differ in their capacity to activate complement.

Conventionally, complement activation by biomedical polymers has been evaluated by determining the C3a concentration in the fluid phase only. According to this criterion, biomaterials such as hemodialysis membranes made from cellulosic or various synthetic polymers were classified as activators or nonactivators of complement. Since certain membranes bind large quantities of C3a from the fluid phase, classification based on fluid-phase C3a concentration has in some instances been inaccurate. As follows from the comparison of complement activation by cuprophane and polyacrylonitrile membranes, the capacity of a biomedical polymer to activate complement is not determined by the number of potential covalent binding sites on its surface. Biomaterial itself may lack hydroxyl and/or amino groups, and yet it may activate C3 in human serum very efficiently. Some of the biomaterials may also bind unactivated/unfragmented C3 whether in the absence or presence of other serum proteins. In addition, binding of factor B (a promotor of C3 activation) and binding of factor H (an inhibitor of C3 activation) to certain biomaterials have been found to be independent of complement activation and unaffected by the presence or absence of C3. Thus, it is becoming apparent that the requirements for the formation and stability of the C3 convertase on artificial surfaces differ from those on biological membranes, and that the relative magnitude of binding of factor B and factor H to the surface per se cannot be used as a reliable indicator of the capacity of the biomaterial to activate complement. Further studies are necessary to elucidate the molecular mechanisms of C3 and C5 activation on the surfaces of biomedical polymers.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Proteins↗

PubMed1999

Proteolytic destruction of functional proteins by phagocytes in human peritonitis.

BACKGROUND: Besides phagocyte-derived oxidative autoaggression, proteolytic destruction of functional proteins in the peritoneal cavity may also be involved in the pathomechanism of secondary peritonitis. To evaluate the pattern of proteolysis, 43 patients undergoing initial operation for acute peritonitis (n = 30) or scheduled abdominal lavages (Etappenlavage) for resolution of persistent peritonitis (n = 13) and 16 surgical patients with abdominal exudation without peritonitis were enrolled in our study. MATERIALS AND METHODS: Thirty blood samples and purulent exudates were taken simultaneously in each peritonitis group at the surgical interventions. Sixteen clear exudates were obtained from patients with post-operative non-infectious irritations. The following parameters were measured: (a) elastase (from neutrophils) and cathepsin B (from monocytes/macrophages); (b) alpha1-proteinase inhibitor (alpha1PI) and overall cysteine proteinase inhibitor capacity; and (c) opsonic activity and degradation products of fibrinogen, complement C3 and immunoglobulin IgG. RESULTS: Circulating levels of phagocyte proteinases and of alpha1PI were significantly elevated, whereas antigen concentrations and opsonic activity of C3 and IgG were slightly reduced in peritonitis patients compared to healthy volunteers. No degradation products were detectable in patients' blood. Discharge of phagocyte proteinases was even more pronounced in both types of peritonitis exudates. Although most of the elastase was complexed with alpha1PI, active elastase and its specific fibrinogen split product was found along with significantly reduced inhibitory capacity for elastase and cysteine proteinases. Local opsonic activity was dramatically diminished because of proteolytic degradation of C3 and IgG. Despite some phagocyte proteinase release, no destruction of functional proteins was seen in clear exudates. CONCLUSIONS: Higher values of extracellularly released phagocyte proteinases concomitant with lower opsonin activity in exudates from patients with persistent peritonitis can be taken as a further hint of the involvement of local proteolysis-induced pathomechanisms in the development of lethal multiple organ failure, which occurred more frequently in patients with persistent peritonitis (54%) than in those with acute peritonitis (27%).

Adolescent↗

PubMed2003

Complete proteinogram of cerebrospinal fluid and its contribution to the diagnostics of inflammatory and autoimmune diseases of the central nervous system.

Complete evaluation of cerebrospinal fluid proteinogram represents a routine request of the clinician in the analysis of CSF in the Czech Republic. It comprises the measurement of concentrations of acute phase proteins (CRP, orosomucoid, haptoglobin, transferrin, prealbumin), immunoglobulins (IgG, IgA, IgM), compressive markers (albumin, fibrinogen), markers of CNS tissue destruction (apolipoproteins A-I, A-II, Apo B), complement components (C3, C4), alpha-1-microglobulin, beta-2-microglobulin, and proteinase inhibitors (alpha-1-antitrypsin, antithrombin III). Therefore, 19 CSF proteins of precisely verified clinical relevance are routine parameters for the assessment of the functional state of the blood-CSF barrier, presence of the intrathecal synthesis of immunoglobulins, inflammatory changes and verification of CNS tissue destruction. Evidence of these clinically relevant and independent parameters enabled the detection of the presence of autoimmune and neuroinfective diseases of CNS, even in clinical cases where the basic CSF parameters do not express relevant changes, or they are of a bordering or non-specific character. Clinically typical and the most significant abnormalities in the CSF proteinogram represent themselves a new access to a contemporary CSF analysis. Despite the fact that assessment of CSF proteins and their analysis is quite a difficult field in laboratory medicine, it is now routinely requested and routinely performed in the Czech Republic.

Autoimmune Diseases of the Nervous System↗

PubMed1995

Tissue expression of human complement inhibitor, decay-accelerating factor, in transgenic pigs. A potential approach for preventing xenograft rejection.

Since complement-mediated hyperacute rejection of xenografts prevents the use of pigs as organ donors to man, the development of transgenic animals expressing species-specific complement inhibitors could provide a strategy for overcoming hyperacute rejection. The complement inhibitor, human decay-accelerating factor (hDAF), prevents the assembly of C3 and C5 convertases. In this article, the first histologic analysis of hDAF expression in pig tissues, specifically expression in endothelial cells of pigs transgenic for hDAF, is described. Twenty-seven transgenic pigs were categorized into 4 groups based on the expression patterns in endothelial, vascular smooth muscle, and squamous epithelial cells of skin biopsy specimens. Skin biopsy specimens permitted evaluation of the pigs without the need to kill them or to perform invasive procedures. Sixteen cases demonstrated endothelial cell staining. Complete necropsy evaluation, available in 14 of the 27 pigs, correlated with the skin biopsy specimen expression of hDAF. The immunoperoxidase data matched identically with the presence of the mRNA transcript in 25 of the 26 cases where RNA data were available. Also, the staining patterns of 6 transgenic pig founders and their 9 offspring (total of 9 founder-offspring pairs) correlated. Since transgenes are variably expressed in different cell types and since tissue lysates represent a melange of cell types, histologic evaluation for protein expression in tissues from transgenic animals will be critical if they are to be bred to become clinical organ donors. In addition to endothelial expression of hDAF, its expression on vascular smooth muscle cells may be important in preventing tissue damage when breaks in the endothelium occur.

Animals↗

PubMed1989

[A case of hereditary angioneurotic edema associated with systemic lupus erythematosus].

A 33-year-old woman noticed recurrent and sudden attacks of subcutaneous swelling of the extremities and face since the age of 4 years. Sometimes the attacks involved colicky abdominal pain. Her mother and younger sister had episodes of recurrent swelling of the extremities as well. Complement studies revealed low CH50, C1q, C4, and C1 inhibitor levels, with normal C3 and C5 levels. Similar reductions of CH50 C4 and C1 inhibitor levels were observed in her mother, older, and younger sisters. Therefore, she was diagnosed as hereditary angioneurotic edema. In addition, she was diagnosed as having a butterfly rash at the age of 20 years and had a history of solar sensitivity. Histologically the facial lesion showed liquefaction degeneration of the basal cell layer. Direct immunofluorescent staining of the affected skin lesion showed basement membrane-zone staining of IgG and IgM. Laboratory studies revealed lymphopenia and positive ANF. On the basis of the above findings, hereditary angioneurotic edema associated with systemic lupus erythematosus was diagnosed.

Adult↗

PubMed1987

Modulation of monocyte complement synthesis by interferons.

Recombinant Escherichia coli-derived gamma-interferon has been shown to stimulate synthesis of the second component of complement (C2), factor B and C1 inhibitor, but to inhibit synthesis of the third component (C3). alpha- and beta-interferons stimulate synthesis of factor B and C3 inhibitor, inhibit C5 synthesis but do not alter synthesis of C2. alpha- and beta-interferons act synergistically with gamma-interferon to enhance both factor B and C1-inhibitor synthesis.

Cells, Cultured↗

PubMed1993

Activity of C1 esterase inhibitor in patients with vascular leak syndrome after bone marrow transplantation.

Vascular-leak syndrome (VLS) is a common complication in the first 3 weeks after bone marrow transplantation (BMT). The patients present with weight gain, generalized edema, ascites, pericardial or pleural effusions, tachycardia, arterial hypotonia, and/or pre-renal failure. The aim of our study was to investigate the role of the complement system in VLS. The protein concentrations of C3 and C4 were studied by immunodiffusion, and total hemolytic complement activity was studied by assessment of CH50. C1 esterase inhibitor (C1 Inh), the major inhibitor of the classical pathway of complement, was assessed by a functional test. Activation of complement was assessed by C4d (a C4 activation product). Twelve patients were followed prospectively from start of conditioning therapy to day +21 after bone marrow transplantation. Eight of 12 patients did not develop VLS. These patients had an increase of C3 between day +9 and day +13 (range: 1.3- to 1.5-fold, median: 1.4-fold), C4 (range: 1.3- to 1.9-fold, median: 1.4-fold), CH50 (range: 1.3- to 1.6-fold, median: 1.4-fold), and C1 Inh (range: 1.2- to 1.5-fold, median: 1.3-fold). Four of 12 patients developed VLS. C1 Inh activity was decreased to 0.60- to 0.80-fold. This decrease began 2-6 days prior to clinical diagnosis of VLS (n = 3), or at onset of VLS (n = 1). Patients with VLS showed elevated C4d concentrations (up to 2.4 mg/dl, upper normal threshold value: 0.9 mg/dl). Patients with VLS reveal an activated state of the complement system which is accompanied by a reduced activity of C1 Inh. Insufficient control of complement activation may contribute to VLS in patients after BMT.

Adolescent↗

PubMed1984

Role of complement in the immune response.

Evidence has accumulated that shows that fragments of C3 are potent inhibitors of immune responses. A low-molecular-weight fragment of C3 and fragments possessing leukocyte-mobilizing activity have been shown to block both antigen- and mitogen-induced human T cell proliferation, and to block mixed lymphocyte culture responses and the generation of cytotoxic lymphocytes. The same fragments inhibit the development of secondary in vitro antibody responses of rat lymphocytes. C3b can be shown to inhibit the polyclonal activation of human lymphocytes by pokeweed mitogen, but it has no effect on T cell proliferation or on the generation of cytotoxic T cells. We now propose that different C3 fragments selectively act on various lymphocyte subsets and thus play a profound role in regulating both immune effector functions and the intensity of the immune response.

Animals↗

PubMed1996

Factor J, an inhibitor of the classical and alternative complement pathway, does not inhibit esterolysis by factor D.

Factor J (FJ) is an inhibitor of the classical and alternative complement pathways. On the classical pathway factor J disrupts the C1 component, and on the alternative pathway, factor J disrupts the C3 convertase (C3b,Bb) by a direct interaction of FJ with the components C3b and Bb. The aim of this work was to verify whether FJ could have any effect on factor D proteolytic activity since previous experiments could not rule out an eventual inhibition by factor J on factor D enzymatic activity. For this purpose, the reactivity of serine proteinase factor D was determined by using two peptide thioester substrates, Z-Lys-SBzl.HCl and Z-Lys-Arg-SBzl.2HCl, in the presence and in the absence of factor J. Kinetic studies evidenced that FJ did not affect the enzymatic activity of factor D in any case.

Complement C1 Inactivator Proteins↗

PubMed2002

Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice.

Abnormal accumulation of beta-amyloid (Abeta) in Alzheimer's disease (AD) is associated with prominent brain inflammation. Whereas earlier studies concluded that this inflammation is detrimental, more recent animal data suggest that at least some inflammatory processes may be beneficial and promote Abeta clearance. Consistent with these observations, overproduction of transforming growth factor (TGF)-beta1 resulted in a vigorous microglial activation that was accompanied by at least a 50% reduction in Abeta accumulation in human amyloid precursor protein (hAPP) transgenic mice. In a search for inflammatory mediators associated with this reduced pathology, we found that brain levels of C3, the central component of complement and a key inflammatory protein activated in AD, were markedly higher in hAPP/TGF-beta1 mice than in hAPP mice. To assess the importance of complement in the pathogenesis of AD-like disease in mice, we inhibited C3 activation by expressing soluble complement receptor-related protein y (sCrry), a complement inhibitor, in the brains of hAPP mice. Abeta deposition was 2- to 3-fold higher in 1-year-old hAPP/sCrry mice than in age-matched hAPP mice and was accompanied by a prominent accumulation of degenerating neurons. These results indicate that complement activation products can protect against Abeta-induced neurotoxicity and may reduce the accumulation or promote the clearance of amyloid and degenerating neurons. These findings provide evidence for a role of complement and innate immune responses in AD-like disease in mice and support the concept that certain inflammatory defense mechanisms in the brain may be beneficial in neurodegenerative disease.

Alzheimer Disease↗

PubMed1982

Complement behavior in infectious mononucleosis: possible mechanisms for the prevention of immune complex injury.

The acute-phase complement reaction was examined in patients with uncomplicated infectious mononucleosis (IM). Concentrations of both complement and complement inhibitor protein were significantly elevated during the acute phase, and turnover studies with purified 125I-labeled C3 showed this increase to result from increased C3 synthesis. Nine of 16 patients had evidence of in vivo complement activation during this period. Despite high levels of C1q-binding immune complexes in most acute-phase sera from patients with IM, the capacity of these sera to solubilize immune precipitates in vitro was normal. In contrast, four of five sera from patients with active systemic lupus erythematosus showed reduced solubilization. The level of C3b inactivator in sera from patients with IM and the percentage conversion of C3 after in vitro complement activation by aggregated IgG were inversely correlated (P less than 0.01). It is proposed that an acute-phase complement reaction limits immune complex-mediated injury to tissue by maintaining those complement functions that are required for the effective processing of circulating antigen/antibody material.

Adolescent↗

PubMed1990

Tissue plasminogen activator inhibitor in patients with systemic lupus erythematosus and thrombosis.

OBJECTIVE: To examine the relations among tissue plasminogen activator antigen, plasminogen activator inhibitor, the lupus anticoagulant, and anticardiolipin antibodies in patients with systemic lupus erythematosus. DESIGN: Prospective study of blood samples (a) from selected patients with systemic lupus erythematosus whose disease was and was not complicated by a history of thrombosis or recurrent abortions, or both, and (b) from a series of healthy controls with a similar age and sex distribution. SETTING: University based medical clinic. SUBJECTS: 23 Patients with definite systemic lupus erythematosus (American Rheumatism Association criteria), of whom 11 (eight women) aged 26-51 had a history of thrombosis or recurrent abortions, or both, and 12 (10 women) aged 23-53 had no such history. 15 Healthy subjects (10 women) aged 25-58 served as controls. MAIN OUTCOME MEASURES: Tissue plasminogen activator concentrations, plasminogen activator inhibitor activities, detection of the lupus anticoagulant, and values of anticardiolipin antibodies in the two groups of patients and in the patients with a history of thrombosis or abortions compared with controls. Other measurements included concentrations of proteins that are known to change during the acute phase of systemic lupus erythematosus--namely, fibrinogen, C3 and C4, and C reactive protein. RESULTS: Patients with a history of thrombosis or abortions, or both, had significantly higher values of tissue plasminogen activator and plasminogen activator inhibitor than patients with no such history. A significant correlation between tissue plasminogen activator and plasminogen activator inhibitor (r = 0.80) was found only in the patients with a history of complications of their disease. The lupus anticoagulant was detected in six of the 11 patients with a history of thrombosis or abortions when tested by measuring the activated partial thromboplastin time but was found in all 11 patients when tested by measuring the diluted activated partial thromboplastin time. Nine of these 11 patients had raised values of anticardiolipin antibodies. The findings showed no relation to the activity of the disease. CONCLUSIONS: A significant correlation between tissue plasminogen activator concentrations and plasminogen activator inhibitor activities was found only in patients whose systemic lupus erythematosus was complicated by a history of thrombosis or recurrent abortions. The findings show that these patients have raised plasminogen activator inhibitor activities, and the frequent association between these raised activities and the presence of the lupus anticoagulant suggests that the two may be linked.

Abortion, Habitual↗

PubMed1987

Distinct sets of acute phase plasma proteins are stimulated by separate human hepatocyte-stimulating factors and monokines in rat hepatoma cells.

A subline of the rat hepatoma (H-35) cells has been identified which responds to hepatocyte-stimulating factors (HSFs) of human squamous carcinoma cells by increased synthesis of all major rat acute phase plasma proteins. The regulation occurs at the level of mRNA. Two HSFs (HSF-I and HSF-II) have been purified from conditioned medium of the squamous carcinoma cells. HSF-I is a protein with an Mr = 18,000 and pI 5.5, and HSF-II is a glycoprotein with an Mr = 34,000 and a broad, neutral to basic charge. In H-35 cells, HSF-I predominantly stimulates the synthesis of complement C3 and haptoglobin and acts synergistically with dexamethasone to stimulate alpha 1-acid glycoprotein. HSF-II stimulates cysteine protease inhibitor, alpha 1-antichymotrypsin, alpha 1-antitrypsin, fibrinogen, and hemopexin, and acts synergistically with dexamethasone to stimulate alpha 2-macroglobulin. Each HSF is between 10 and 100 times less effective in regulating proteins of the other set. Human tumor necrosis factor and interleukin-1 increase complement C3, haptoglobin, and alpha 1-acid glycoprotein, as does HSF-I, but are unable to modulate any of the other acute phase proteins. The monokines differ from HSF-I is their low activity in HepG2 cells and rat hepatocytes.

Acute-Phase Proteins↗

PubMed2002

[Distribution of the ABO blood groups and the HP, TF, GC, PI and C3 serum proteins in Yakuts].

In Yakut populations examined, polymorphisms of immunological and serum protein markers, including AB0 and Rhesus blood groups, HP, TF, GC, PI and C3, were revealed. Gene frequencies for the systems studied fell into the following ranges: AB0 system: r, 0.514 to 0.663; p, 0.136 to 0.306; q, 0.110 to 0.337; haptoglobin HP*1: 0.214 to 0.431; transferrin TF*C: 0.700 to 1.0; group specific component GC*1: 0.821 to 0.978; PI*M1 proteinase inhibitor (or alpha 1-antitrypsin) PIM1: 0.860 to 0.946; and third component of the complement C3*F: 0.031 to 0.143.

ABO Blood-Group System↗

PubMed1997

Complement-inhibiting peptides identified by proximity to indels in the C3/4/5 protein family.

To find protein-protein interactive sites in complement component C3, we examined regions of C3 that are proximal to sites of length polymorphism or indels in the C345 protein family. We reasoned that indels probably mark protein interactive sites because they usually involve residues at protein surfaces. To test for the involvement of individual indels, we examined the effects on complement function of synthetic peptides corresponding to indel-proximal segments of C3. We inferred that if such a segment made direct contact with a C3 binding protein, then the corresponding peptide might also bind to that protein and inhibit binding to C3. Twenty-one peptides were tested; four of these inhibited complement-mediated erythrocyte lysis at < or =100 microM and complement-mediated killing of Escherichia coli at about threefold higher levels. These results indicate that the four peptides act as specific inhibitors of complement. They also suggest that indels can be effective guides for locating interactive sites in C3 and in any protein that is a member of a protein family. Because only a linear sequence is required, a focus on indels may be particularly useful for identifying interactive sites in proteins for which a three-dimensional structure is unavailable.

Amino Acid Sequence↗

PubMed2002

Structural aspects and design of low-molecular-mass complement inhibitors.

We present a mini-review on the structure-based design of three promising complement inhibitors. Firstly, we review compstatin, a 13-residue cyclic peptide that binds to C3 and inhibits the cleavage of C3 to C3a and C3b. Secondly, we review a six-residue cyclic peptide that binds to C5aR and antagonizes the binding of C5a to its receptor C5aR. Finally, we review three small molecules that bind to Factor D and inhibit the enzymic action of Factor D, during which Factor D proteolytically cleaves Factor B in complex with C3 or C3b.

Animals↗

PubMed1995

Polymyxin B stimulates production of complement components and cytokines in human monocytes.

Polymyxin B (PmB), an agent often used to neutralize the effects of bacterial lipopolysaccharide (LPS), was shown to exert a dose-dependent stimulatory effect on the biosynthesis of C3, factor B, interleukin-6 (IL-6), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in human monocytes. A low dose of PmB (1 to 5 micrograms/ml) efficiently suppressed the LPS-induced (1 or 100 ng/ml) production of IL-6, GM-CSF, and factor B, but not the C3 production induced by 100 ng of LPS per ml. A reduced level of GM-CSF may have contributed to the persisting high C3 concentrations and the apparent lack of LPS inhibition in the latter situation, since GM-CSF is an inhibitor of monocyte C3 biosynthesis.

Complement C3↗

PubMed2002

Polystyrene derivatives as candidates for extracorporeal adsorption of Factor VIII antibodies in the management of haemophiliac patients.

BACKGROUND AND OBJECTIVES: This article presents a new approach for removing the Factor VIII inhibitors (anti-FVIII) in haemophiliac patients by immunoadsorption using an affinity matrix. MATERIALS AND METHODS: Ten blood samples from haemophiliac patients with anti-FVIII were assayed for antibodies, total immunoglobulins, procoagulant proteins and complement C3 protein after circulation over one or two columns filled with the polymers under investigation. RESULTS: These new synthetic sorbents are able to remove in vitro 90% of anti-FVIII from haemophiliac plasma with inhibitors (up to 540 Bethesda Units/ml). Neither coagulation factor adsorption nor effects on complement system activation were observed. CONCLUSIONS: The data presented clearly show that these polymers allow a rapid and efficient reduction of inhibitor titre. In view of the parameters studied, these polymers fulfil the requirements for use in a blood purification process to decrease high inhibitor titres without losing essential proteins.

Autoantibodies↗