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PubMed2000

The effect of the antithyroid drug propylthiouracil on the alternative pathway of complement in rats.

The effect of propylthiouracil (PTU) on the lytic activity of complement in rat serum was investigated in vivo. Rats (180+/-10 g) were treated daily by gavage with PTU doses of 1-50 mg/200 g body weight for time intervals ranging from 1 to 30 days. Serum classical pathway (CP) and alternative pathway (AP) activities were determined 24 h after the last dose. A single dose of 50 mg/200 g body weight was administered to additional groups and the animals were sacrificed after periods of 1-48 h. The results showed a relatively small reduction ( approximately 30%) in CP activity, evident only in animals treated with 50 mg of PTU for three weeks. However, a clear and opposite effect of PTU, an increase in lytic activity reaching values up to 180% of controls, was observed on AP activity. This effect was seen at all PTU doses used, and occurred within 4 days of treatment with the highest dose. Maximum activity was observed at intermediate intervals, depending on the PTU dose, with a return to control levels occurring after the longer periods of treatment. The lytic activity of serum from animals treated with a single PTU dose of 50 mg/200 g body weight and sacrificed 1-48 h after dosing did not differ from controls. Serum levels of thyroid hormone (triiodo L-thyronine, T3, and thyroxine, T4) were determined in representative groups of treated animals (injected with 5 mg of PTU/200 g body weight/day). These were either undetectable or considerably lower than those of controls. The serum PTU levels of these rats increased for up to 22 days, reaching values of 2-4 microg/ml.PTU is described in the literature as a modulator of both cellular immune responses and antibody production. Upon complement activation fragments of complement components bind to immune complexes and to specific receptors on cells of the immune system. Thus, alteration in AP activity caused by PTU treatment suggests a possible mechanism by which the drug exerts its modulatory effect. Increased complement AP activity might affect events as antigen presentation and hence the onset and course of the immune response.

Animals↗
PubMed1983

Steroids inhibit activation of the alternative-amplification pathway of complement.

Previous studies have demonstrated the ability of methylprednisolone sodium succinate to inhibit complement activation. Two other glucocorticosteroids and three different soluble steroids which lacked glucocorticoid activity were found in the present study to have the capacity to inhibit lysis of sheep erythrocytes by the alternative-amplification pathway. These compounds also inhibited fluid-phase consumption of B in a reaction mixture that contained purified C3b, B, and D, indicating that they exert a direct effect on the generation of alternative amplification pathway convertase. These findings suggest that the capacity to inhibit convertase generation by glucocorticosteroids in high concentration is independent of glucocorticoid activity.

Complement Activation↗
PubMed1977

Host cell modification of lymphocytic choriomeningitis virus and Newcastle disease virus altering viral inactivation by human complement.

Complement in human serum inactivated several enveloped viruses, but for some viruses the degree of inactivation depended on their passage history. In short, human serum detected cell-induced modifications of virions. Normal human serum, lacking detectable neutralizing antibodies to the virions, inactivated lymphocytic choriomeningitis virus (LCMV) and Newcastle disease virus (NDV) when the viruses were passed through some cell lines but not others. Host cell modification was further documented with LCMV since antibody to the cell (in conjunction with a complement source) inactivated virus produced by that cell. The mechanism by which human serum inactivated LCMV passed through L cells was determined. By using serum immunochemically depleted in the classical complement pathway component C4 and/or the alternative complement pathway component factor B, as well as other methods, it was shown that LCMV was inactivated via the classical complement pathway. Absorption and immune precipitation experiments indicated that the inactivation of LCMV by complement was mediated by natural antibody directed against the host (L-929) cell. NDV grown in chick embryo cells could be unactivated by either complement pathway in the absence of the other. A requirement for antibody could not be demonstrated in the NDV system. On the basis of these data it is proposed that alterations in virulence dependent upon passage of the virus in cells or animals may be partially explained by changes in virus sensitivity to human serum inactivation.

Animals↗
PubMed1985

Opsonic requirements for phagocytosis of Legionella micdadei by polymorphonuclear leukocytes.

The roles of the classical and alternative pathways of complement activation and of antibody in the phagocytosis of Legionella micdadei by polymorphonuclear leukocytes were studied. Normal serum was treated with the appropriate chelators or with heat to inactivate the classical, alternate, or both pathways of complement activation. Normal and complement-depleted sera with or without antibody were employed as opsonins for L. micdadei in phagocytosis assays. There was no difference in the phagocytosis of L. micdadei promoted by normal serum and either C4-deficient serum or serum in which the classical pathway had been inactivated. Both normal and classical pathway-deficient sera promoted significantly greater phagocytosis than did sera in which the alternate pathway or both the alternate and classical pathways had been inactivated. Thus, polymorphonuclear leukocyte phagocytosis of L. micdadei in the absence of antibody required an intact alternate pathway. Specific antibody partially restored opsonization to sera deficient in the alternate or both complement pathways, but phagocytosis was still significantly less than that with the alternate pathway intact.

Antibodies↗
PubMed1983

Effects of T-2 mycotoxin on bovine serum proteins.

Mycotoxin T-2 (0.5 mg/kg of body weight) was administered orally to mixed-breed beef calves. Serum protein fractions, immunoglobulin (Ig) G, IgM, and several complement protein concentrations were studied in control and toxin-treated calves. Total protein, albumin, and globulin concentrations all decreased in toxin-treated calves as compared with that in controls. Similarly, the concentrations of alpha-, beta 1-, and beta 2-globulin fractions were reduced in the toxin-treated calves more than those in controls. The IgG and IgM values were lower in toxin-treated calves than those in the controls. Complement proteins Bbov (of the alternate pathway) and the 3rd component of complement were lower in the toxin-treated calves. The fragment of Bbov activation, B gamma 2, was increased after toxin treatment, indicating that activation of the alternate complement pathway was responsible for at least some of the reduction of the 3rd component of complement.

Animals↗
PubMed2006

Age-related macular degeneration--emerging pathogenetic and therapeutic concepts.

Today, the average life expectancy in developed nations is over 80 years and climbing. And yet, the quality of life during those additional years is often significantly diminished by the effects of age-related, degenerative diseases, including age-related macular degeneration (AMD), the leading cause of blindness in the elderly worldwide. AMD is characterized by a progressive loss of central vision attributable to degenerative and neovascular changes in the macula, a highly specialized region of the ocular retina responsible for fine visual acuity. Estimates gathered from the most recent World Health Organization (WHO) global eye disease survey conservatively indicate that 14 million persons are blind or severely visually impaired because of AMD. The disease has a tremendous impact on the physical and mental health of the geriatric population and their families and is becoming a major public health burden. Currently, there is neither a cure nor a means to prevent AMD. Palliative treatment options for the less prevalent, late-stage 'wet' form of the disease include anti-neovascular agents, photodynamic therapy and thermal laser. There are no current therapies for the more common 'dry' AMD, except for the use of antioxidants that delay progression in 20%-25% of eyes. New discoveries, however, are beginning to provide a much clearer picture of the relevant cellular events, genetic factors, and biochemical processes associated with early AMD. Recently, compelling evidence has emerged that the innate immune system and, more specifically, uncontrolled regulation of the complement alternative pathway plays a central role in the pathobiology of AMD. The complement Factor H gene--which encodes the major inhibitor of the complement alternative pathway--is the first gene identified in multiple independent studies that confers a significant genetic risk for the development of AMD. The emergence of this new paradigm of AMD pathogenesis should hasten the development of novel diagnostic and therapeutic approaches for this disease that will dramatically improve the quality of our prolonged lifespan.

Age Factors↗
PubMed1995

Lack of functional similarity between complement factor H and anticardiolipin cofactor, beta 2-glycoprotein I (apolipoprotein H).

Beta 2-glycoprotein I (beta 2-GPI) is a 50 kDa protein in human plasma composed of five repeating complement control protein modules thereby closely resembling complement factor H which has 20 such units. Both beta 2-GPI and factor H (150 kDa) have binding sites for negatively charged polyions. beta 2-GPI has been shown to act as a cofactor for antiphospholipid antibodies upon their binding to anionic phospholipids. In factor H the polyanion recognition site participates in the discrimination between alternative pathway activating and non-activating surfaces. In light of the structural similarity between beta 2-GPI and factor H we have examined whether beta 2-GPI has a role in the alternative complement pathway recognition process. Both activators (zymosan) and non-activators (sheep erythrocytes) of the alternative complement pathway were coated with C3b. Radiolabelled factor H was observed to recognize C3b on both surfaces, whereas beta 2-GPI bound to neither. In competition experiments beta 2-GPI could not prevent the association of 125I-H with either non-activator or activator bound C3b. Conversely, factor H could not replace beta 2-GPI as a cofactor for antiphospholipid antibodies upon their binding to anionic phospholipids. It is concluded that beta 2-GPI and factor H, despite similarities in structure, exhibit distinct, non-overlapping functions.

Animals↗
PubMed1983

[Role of immunoglobulins in the activation of complement].

Depending on their class and sub-class, immunoglobulins may activate the complement by the classical pathway or by the alternative pathway. This activating property depends on how immunoglobulins are associated. Activation by the classical pathway implies binding to, and activation of C1. Binding is essentially an ion type interaction between C1q and--in the case of human IgG's for instance--the C gamma 2 domain. It has recently been investigated in depth by various techniques, such as inhibition of the C1q--IgG interaction by chemical compounds or by peptides isolated from C gamma 2. Activation of C1 seems to involve some elements of C gamma 3. In addition to initiating the classical pathway, immunoglobulins may act as acceptors of the classical C3-convertase (C4b C2a); a structure accepting the newly formed C4b is present in the Fab portion of IgG. It would appear that optimal functioning of the complement system is achieved when the C1 activating site and the C3-convertase forming site are close together on the IgG molecule, since the newly born peptidic fragments have a very short life. Immunoglobulins may activate the alternative pathway via their Fab portion. This property is directly related to the ability of Ig's to accept nascent C3b, which probably includes that of accepting nascent C4b as described above. In the alternative pathway C3-convertase may form when structural conditions around IgG-bound C3b encourage binding of B to C3b rather than the intervention of I and H factors which degrade C3b. The Ig-C3b interaction responsible for activation of the alternative pathway may also be directly involved in solubilization of immune complexes during activation of complement.

Animals↗
PubMed1998

Structure of 3,4-dichloroisocoumarin-inhibited factor D.

Factor D (D) is a serine protease essential in the activation of the alternative complement pathway. Only a few of the common serine protease inhibitors inhibit D, binding covalently to the serine hydroxyl of the catalytic triad. 3,4-Dichloroisocoumarin (DCI) is a mechanism-based inhibitor which inhibits most serine proteases and many esterases, including D. The structure of the enzyme:inhibitor covalent adduct of D with DCI, DCI:D, to a resolution of 1.8 A is described, which represents the first structural analysis of D with a mechanism-based inhibitor. The side chain of the ring-opened DCI moiety of the protein adduct undergoes chemical modification in the buffered solution, resulting in the formation of an alpha-hydroxy acid moiety through the nucleophilic substitution of both Cl atoms. The inhibited enzyme is similar in overall structure to the native enzyme, as well as to a variety of isocoumarin-inhibited trypsin and porcine pancreatic elastase (PPE) structures, yet notable differences are observed in the active site and binding mode of these small-molecule inhibitors. One region of the active site (residues 189-195) is relatively conserved between factor D, trypsin, and elastase with respect to amino-acid sequence and to conformation. Another region (residues 214-220) reflects the amino-acid substitutions and conformational flexibility between these enzymes. The carbonyl O atom of the DCI moiety was found to be oriented away from the oxyanion hole, which greatly contributes to the stability of the DCI:D adduct. The comparisons of the active sites between native factor D, DCI-inhibited factor D, and various inhibited trypsin and elastase (PPE) molecules are providing the chemical bases directing our design of novel, small-molecule pharmaceutical agents capable of modulating the alternative complement pathway.

Animals↗
PubMedDate not supplied

[Levels of various components of the classical and alternative pathways of complement activation in diabetes mellitus patients].

The state of the complement system was studied in 91 patients with insulin dependent and in 47 patients with non-insulin dependent diabetes. A study was made of the quantity of hemolytically effective molecules of some components C2, C4, C3, C5 of classic and factors B and D of alternative pathway of activation. Complement components were studied for control in 51 healthy blood donors. Antigens B8 and B18 of the HLA-histocompatibility system were studied in parallel in 24 patients and 21 donors. A significantly raised level of components C3 and C4, factors B and D was revealed in the patients with insulin dependent diabetes as compared to the controls (p less than 0.05). In non-insulin dependent diabetes C4, factors B and D were significantly raised and the level of C5 was lowered (p less than 0.05). In the patients with insulin dependent diabetes having antigens B18 the level of C3 was raised and the level of C4 was lowered as compared to the controls. The level of factors B and D was also lower than that in the diabetic patients. An analysis of the content of the complement components in 31 diabetic patients with diabetic nephropathy indicated a decrease in the levels of components C3 and C5 and an increase in the content of C4 (p less than 0.001) as compared to the normal. Diabetes was accompanied by considerable variations as compared to normal values characterizing the state of the complement system and reflecting, to a certain extent, the main features of the pathogenesis of disease.

Complement C2↗
PubMed1990

Salmonella O antigen-specific oligosaccharide-octyl conjugates activate complement via the alternative pathway at different rates depending on the structure of the O antigen.

Artificial Salmonella serogroup B, D or Cl-specific glycolipids were prepared by covalently linking oligosaccharides corresponding to two O-antigen repeating units, obtained by phage enzyme hydrolysis of native O-antigenic polysaccharides, to octyl residues. Sheep erythrocytes coated with the artificial glycolipids were studied for their ability to consume C3, when incubated in C4- deficient guinea pig serum. Salmonella C1 (0-6,7) glycolipid-coated erythrocytes consumed C3 40% more efficiently than Salmonella D (0-9,12) glycolipid-coated erythrocytes, and 10-times more efficiently than Salmonella B (0-4,12) glycolipid-coated erythrocytes. These results resemble C3 consumption by Salmonella C1, D, and B cells and by sheep erythrocytes coated with purified lipopolysaccharides of these O-specificities. The results prove directly that in a particulate system C3 activation via the alternative pathway depends on the structural properties of the O-antigenic side chain. Structures as small as octasaccharides, or as two O-antigenic repeating units, are sufficient for triggering C3 activation, but the magnitude of activation depends on the nature of the monosaccharides. Apparently, neither the core oligosaccharide nor Lipid A of lipopolysaccharide are required for C3 activation via the alternative pathway.

Animals↗
PubMed1997

Steady state approximation in the minimal model of the alternative pathway of complement.

Complement is a response mechanism of the immune system. Two initiation pathways have been characterized for complement. The classical pathway is antibody mediated while the alternative pathway is not. Since the alternative pathway is independent of antibodies, it is always active. For the alternative pathway we have previously developed a minimal model. Using parameters within physiological bounds, the model showed complex behavior also within physiological bounds. Thus the model seems to be an appropriate representation of the alternative pathway response. By applying a steady state assumption to the Michaelis Menten step of the minimal model, we reduce the number of variables from six to five. A comparison between the dynamics of the minimal and contracted models reveals that the two descriptions may not be compatible. Although both systems show chaotic behavior it occurs in different regions of parameter space.

Journal Article↗
PubMed1983

The brush border of proximal tubules of normal human kidney activates the alternative pathway of the complement system in vitro.

The aim of this investigation was to study complement fixation by normal human kidney tissue. C fixation was assessed on acetone-fixed sections of frozen human kidney. In addition, C consumption following incubation of normal fresh human serum with tubular or glomerular fractions of human kidney was measured. The results are consistent with the interpretation that the brush border of proximal tubules of human kidney activates the C system via the alternative pathway. It is suggested that this activation may occur in vivo in patients with a non-selective proteinuria.

Complement Activation↗
PubMed2003

Simple method to distinguish between primary and secondary C3 deficiencies.

Due to the increasing numbers of reported clinical cases of complement deficiency in medical centers, clinicians are now more aware of the role of the complement system in the protection against infections caused by microorganisms. Therefore, clinical laboratories are now prepared to perform a number of diagnostic tests of the complement system other than the standard 50% hemolytic component assay. Deficiencies of alternative complement pathway proteins are related to severe and recurrent infections; and the application of easy, reliable, and low-cost methods for their detection and distinction are always welcome, notably in developing countries. When activation of the alternative complement pathway is evaluated in hemolytic agarose plates, some but not all human sera cross-react to form a late linear lysis. Since the formation of this linear lysis is dependent on C3 and factor B, it is possible to use late linear lysis to routinely screen for the presence of deficiencies of alternative human complement pathway proteins such as factor B. Furthermore, since linear lysis is observed between normal human serum and primary C3-deficient serum but not between normal human serum and secondary C3-deficient serum caused by the lack of factor H or factor I, this assay may also be used to discriminate between primary and secondary C3 deficiencies.

Animals↗
PubMed1989

Activation of the classical complement pathway in brain tissue of Alzheimer patients.

Positive immunohistochemical staining of Alzheimer brain tissue was obtained with antibodies to proteins associated with classical, but not the alternative, complement pathway. Clq, C3d, C4d are fractions of complement proteins that bind to tissue when the classical complement pathway is activated. Antibodies to these fractions stained senile plaques, dystrophic neurites and some neurofibrillary tangles. C5b-9 is the membrane attack complex which promotes cell lysis when assembled on the plasma membrane. An antibody to a neoantigenic site on this complex stained dystrophic neurites and many neurofibrillary tangles, but not extracellular amyloid. Properdin and fraction Bb of factor B, two proteins that bind to tissue when the alternative complement pathway is activated, were not detected immunohistochemically.

Aged↗