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PubMed1996

Inhibition of classical complement activation by sera from HIV-1-positive patients.

It was shown that gp120/160-coupled CD4+ T cells could be lysed by complement activation, but the target cell lysis was strongly inhibited by the majority of HIV-1-positive sera. Significantly more sera from HIV-1-infected patients with CD4+ T cell count higher than 500 microl (N = 38) as well as from patients with 200-500/microl (N = 32) showed strong inhibition of complement activation as compared to sera from those with less than 200 CD4+ T cells/microl (N = 28) (P = 0.0064 and 0.0012, respectively). Consequently, highly significant correlation between CDL inhibitory activity and CD4+ T cell count in HIV-1-infected patients was found by Spearman's rank order analysis (R = 0.399, P < 0.001). CH50 titer and functional C1-inhibitor level were significantly lower in inhibitory as compared to the noninhibitory sera (P < 0.001) and to controls (P < 0.001). The C3 activation products-C3-circulating immune complexes were not increased in inhibitory sera (P = 0.014) suggesting that inhibition of complement activation occurred at or before C3 activation level. C4d fragments and antigenic C1-INH concentration were significantly increased in both categories of HIV-1-positive sera, P < 0.001. These findings indicate that persistent and massive stimulation of complement system with HIV-1 envelope glycoproteins during all stages of the disease induced impairment of classical pathway activation by an inhibitory factor in a majority of patients, which might contribute to the onset of opportunistic infections and AIDS.

Complement Activation↗
PubMed1987

Determination of C4b.C4-bp complex formed by the activation of classical complement pathway using an enzyme-linked immunosorbent assay.

We developed a quantitative enzyme-linked immunosorbent assay (ELISA) for the detection of C4b.C4-bp complex by incubating the sample on anti-C4-bp-coated plate and then developing with HRP-labeled anti-C4. The amount of C4b.C4-bp complex, generated in vivo by the interaction of purified C4b with C4-bp or normal human serum with aggregated human IgG, was measured by the ELISA. The complex, however, rapidly decreased in serum by the action of factor I. Six out of the 100 plasma samples from patients with various diseases were found positive in the ELISA. One plasma sample from a patient with SLE showed high level of C4b.C4-bp complex with decreased levels of factor I, C4, C4-bp and CH50. These results suggest that the detection of C4b.C4-bp complex is useful for monitoring the diseases in which the classical pathway activation is expected.

Arthritis, Rheumatoid↗
PubMed1977

Hereditary deficiency of the third component of complement in a child with fever, skin rash, and arthralgias: response to transfusion of whole blood.

A previously well 34-month-old male presenting with fever, skin rash, and arthralgias was found to lack C3 by immunochemical (undetectable) and hemolytic (1% normal) assays. No infectious agent could be demonstrated. Protein levels of Clq. C4, C5, properdin, and C3b-INA and hemolytic activities of complement components C1 to C9 except C3 were normal or elevated; total hemolytic complement activity was 13% of normal and was reconstituted by purified C3. Properdin factor B was 702 (normal 175 to 275) mug/ml, and was not cleaver upon addition of zymosan or cobra venom factor. The serum had normal immune adherence activity, but was deficient in ability to opsonize Candida albicans for uptake and Escherichia coli for killing by neurophils, generate neutrophil chemotactic factors and inhibit the growth of E. coli; these activities were restored by purified C3. A transfusion of 320 ml 1-hour-old normal whole blood on the fifty-second day resulted in transitory elevation of the C3 level to 25 mg/dl with a fall-off (approximately 2 1/2% per hour) to undetectable levels by 69 hours; it was followed by disappearance of the skin rash and arthralgias and return to normal of the previously elevated temperature and CRP levels. C3 levels in family members (seven of 24 half-normal), lack of anti-C3 activity, normal C3b-INA levels and a normal rate of catabolism of transfused C3 indicated that the deficiency was inherited with autosomal codominance and involved decreased synthesis of C3. Thus, this child is a unique individual with inherited C3 deficiency presenting with absence of repeated infections, whose symptoms of fever, skin rash, and arthralgia were abated by whole blood transfusion.

Blood Transfusion↗
PubMed1978

Inhibition of the classical and alternative pathways by amino acids and their derivatives.

Effects of various aminoacids and their derivatives on the classical pathway and alternative pathway of the complement were studied. Leupeptin, acetyl-leucyl-leucyl-arginal, inhibited CH50 and Cl-esterase, but did not inhibit the alternative pathway. When aminoacids of carbon chains of the order of seven were used, arginine and lysine had stronger effects than trans-aminomethyl cyclohexane carboxylic acid (t-AMCHA), cis-aminomethyl cyclohexane carboxylic acid (cis-AMCHA) and epsilon aminocaproic acid (EACA). SH-compounds, cysteine, homocysteine and glutathione, had the strongest inhibitory effects among these aminoacids on both classical and alternative pathways. When effects on Cl esterase were compared, arginine, lysine, t-AMCHA, cis-AMCHA and EACA had weak inhibition while SH-compounds showed strong inhibition. Poly-L-lysine, which had extremely strong inhibition of CH50, had no inhibition of Cl esterase. The inhibitory effects of antifibrinolytic agents, EACA and t-AMCHA, were weak but when effects on early parts of the classical pathway, C(1,4,2)H50 were tested, some inhibitory activities were recognized. Thus inhibitory effects of these agents were due to their activities on the early parts of the classical pathway.

Amino Acids↗
PubMed1984

Inhibition of complement activation on the surface of cells after incorporation of decay-accelerating factor (DAF) into their membranes.

Decay-accelerating factor (DAF), extracted from the stroma of human erythrocytes, was purified to homogeneity and incorporated into the membrane of sheep red cell complement intermediates, where its functional properties were analyzed. Incorporation of DAF into the cell membranes was temperature dependent, took place on pronase- or trypsin-treated erythrocytes, and did not depend on prior deposition of antibody, C1 or C4. Serum lipoproteins (high and low density) effectively inhibited DAF incorporation, but had no effect on the activity of DAF after its association with the cell membrane. The incorporated DAF could not be removed from the red cell surface by repeated washings in the presence of high salt concentration but was solubilized when the stroma were extracted with 0.1% Nonidet P-40. The presence of DAF in the membrane of EA did not affect the deposition of C1 and C4, but as few as 10(2) DAF molecules per cell profoundly inhibited the assembly of C3 and C5 convertases of both the classical and alternative pathways. The DAF inhibitory effect on EAC14 or EAC43 was not overcome by supplying an excess of C2 or factor B, but the alternative pathway C3 convertase could be assembled in the presence of Ni++, or nonphysiological concentrations of Mg++, which enhances the binding affinity of factor B for C3b. The DAF effect on EAC14 or EAC143 was entirely reversed by treating the cells with specific anti-DAF antibodies, showing that DAF did not alter the structure of C4b or C3b. Taken together, the experimental evidence suggests that DAF interacts directly with membrane-bound C3b or C4b and prevents subsequent uptake of C2 and factor B. DAF can function only within the cell membrane. Indeed, the decay dissociation of the C4b2a enzyme on DAF-containing sheep intermediates was not changed by varying the cell concentration. DAF-treated EA had no influence on the decay of nontreated EAC142 present in the same mixture. Moreover, the inhibitory activity of intact human erythrocytes on C4b2a was not blocked by antibodies to DAF, but was abolished by antibodies to the C3b/C4b receptor (CR1). When incorporated into the membrane of rabbit erythrocytes, human DAF inhibited their lysis by human complement. In conclusion, on the basis of these and previous results, it appears that DAF plays a central role in preventing the amplification of the complement cascade on host cell surfaces.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Human T lymphocytes expressing the C3b/C4b complement receptor type one (CR1, CD35) belong to Fc gamma receptor-positive CD4-positive T cells.

The phenotypic characteristics of human T lymphocytes expressing the C3b/C4b complement receptor type one (CR1, CD35) were investigated using dual-color surface immunofluorescence and cytofluorometric analysis of stained peripheral blood mononuclear cells (PBMC) from normal individuals. Two to ten percent of PBMC coexpressed CR1 and the CD5, CD2, or CD3 antigen. CR1 was detected on a subset of CD4+ T lymphocytes but not on CD8+ or on Leu-7+ lymphocytes. Costaining for CR1 and for the CD4 subpopulation markers anti-Leu-8, TQ1, OKT17, 2H4, and 4B4 indicated that CR1 on lymphocytes may be coexpressed with any of these phenotypic determinants. All CR1+ lymphocytes expressed Fc gamma receptors (Fc gamma Rs) as assessed by their ability to bind biotinylated dimeric human IgG. The expression of CR1 was increased in mixed lymphocyte reaction with kinetics similar to those of HLA-DR antigen expression. Coexpression of CR1 and Fc gamma R+ may provide a subset of CD4+ lymphocytes with an enhanced ability to bind and respond to C3-bearing complexes of IgG and antigen.

Animals↗
PubMed1986

Isolation of a human erythrocyte membrane protein capable of inhibiting expression of homologous complement transmembrane channels.

Erythrocytes are poorly lysed by homologous complement, whereas they are readily lysed by heterologous complement. This phenomenon had been attributed to an interference by the cell surface with the action of complement components C8 and C9. To isolate the responsible membrane constituent, detergent-solubilized human erythrocyte (EH) membranes were subjected to affinity chromatography by using human C9-Sepharose. The isolated protein had a mass of 38 kDa and, incorporated into liposomes, was highly effective in inhibiting complement-mediated channel expression, including the C5b-8, membrane attack complex, and tubular polymer of C9 channels. Antibody produced to the 38-kDa protein caused a 20-fold increase in reactive lysis of EH by isolated C5b6, C7, C8, and C9. The antibody did not enhance C5b-7 uptake, but it affected C9 binding to the target cell membrane. Antibody to human decay-accelerating factor, used as a control, had no effect on reactive lysis of EH. Anti-38-kDa protein did not enhance the action on EH of C8 and C9 from other species, indicating that the action of this regulatory protein is species specific. It was therefore termed homologous restriction factor (HRF). Blood cells other than erythrocytes, such as polymorphonuclear leukocytes, also exhibited cell-surface HRF activity. In immunoblots of freshly isolated EH membranes, anti-38-kDa HRF detected primarily a 65-kDa protein, suggesting that the 38-kDa protein constitutes an active fragment of membrane HRF. Because of the specific binding reaction observed between HRF and C8 or C9, HRF was tested with anti-human C8 and anti-human C9. A limited immunochemical relationship of HRF to C8 and C9 could be established and solid-phase anti-C9 proved an efficient tool for the isolation of HRF from solubilized EH membranes.

Blood Proteins↗
PubMed1991

Role of human decay-accelerating factor in the evasion of Schistosoma mansoni from the complement-mediated killing in vitro.

Decay-accelerating factor (DAF) is a 70-kD membrane glycoprotein that prevents complement (C)-mediated hemolysis by blocking the assembly or accelerating the decay of C3 convertase. Purified DAF is known to incorporate into the membrane of DAF-deficient cells, inhibiting lysis. Since Schistosoma mansoni is a blood-dwelling parasite, we investigated whether DAF can be transferred from human erythrocytes to the worm and protect it against C-mediated killing in vitro. We have found that schistosomula (schla) incubated with normal human erythrocytes (N-HuE), but not with DAF-deficient erythrocytes, become resistant to C damage in vitro. Protected parasites acquire a 70-kD surface protein which can be immunoprecipitated by anti-DAF antibodies. The acquired resistance is abrogated by treatment of N-HuE-incubated parasites with anti-DAF antibody. These results indicate that, in vitro, N-HuE DAF can be transferred to schla, and suggest its participation in preventing their C-mediated killing. This could represent an important strategy of parasites to evade the host's immune response in vivo.

Animals↗
PubMed1992

Structural properties of the glycoplasmanylinositol anchor phospholipid of the complement membrane attack complex inhibitor CD59.

CD59, the membrane regulator of autologous C5b-9 channel formation, exhibits variable sensitivity to cleavage by phosphatidylinositol-specific phospholipase C (PI-PLC), an enzyme that releases glyco-inositolphospholipid (GPI)-anchored proteins from cell surfaces. To determine whether the GPI-anchor phospholipid of CD59 is similar to that of decay-accelerating factor (DAF) and whether variation in its structure underlies its variable enzyme susceptibility, the GPI anchors of the two proteins expressed on erythrocytes, polymorphonuclear and mononuclear leucocytes were compared in situ and after purification. Flow cytometric analyses of PI-PLC-treated cells showed parallel cell type specific release of both proteins as a function of enzyme concentration. Non-denaturing PAGE analyses of alkaline/hydroxylamine-treated proteins (affinity-purified from [125I]-surface-labelled cells) provided evidence for (i) comparable proportions of GPI-anchor acylation, and (ii) alkali-resistant rather than alkali-sensitive lipid substituents in erythrocytes. These findings argue that the differential C5b-9 sensitivity that distinguishes paroxysmal nocturnal haemoglobinuria II and III erythrocytes does not derive from expression of CD59 molecules with alternative GPI-anchor phospholipid structures.

Antigens, CD↗
PubMed2005

Additive inhibition of complement deposition by pneumolysin and PspA facilitates Streptococcus pneumoniae septicemia.

Streptococcus pneumoniae is a common cause of septicemia in the immunocompetent host. To establish infection, S. pneumoniae has to overcome host innate immune responses, one component of which is the complement system. Using isogenic bacterial mutant strains and complement-deficient immune naive mice, we show that the S. pneumoniae virulence factor pneumolysin prevents complement deposition on S. pneumoniae, mainly through effects on the classical pathway. In addition, using a double pspA-/ply- mutant strain we demonstrate that pneumolysin and the S. pneumoniae surface protein PspA act in concert to affect both classical and alternative complement pathway activity. As a result, the virulence of the pspA-/ply- strain in models of both systemic and pulmonary infection is greatly attenuated in wild-type mice but not complement deficient mice. The sensitivity of the pspA-/ply- strain to complement was exploited to demonstrate that although early innate immunity to S. pneumoniae during pulmonary infection is partially complement-dependent, the main effect of complement is to prevent spread of S. pneumoniae from the lungs to the blood. These data suggest that inhibition of complement deposition on S. pneumoniae by pneumolysin and PspA is essential for S. pneumoniae to successfully cause septicemia. Targeting mechanisms of complement inhibition could be an effective therapeutic strategy for patients with septicemia due to S. pneumoniae or other bacterial pathogens.

Animals↗
PubMed1990

[Changes in the levels of serum proteins in patients with chronic obstructive bronchitis].

A new approach is suggested for evaluation of changes observed in serum levels of immunoglobulins, compliment components and proteinase inhibitors in subjects suffering from chronic obstructive bronchitis (COB). These levels were compared for COB patients (n-15) in remission and under aggravation of the disease. The comparison promoted a significant assessment of the shifts and their pattern for humoral defence factors. There appeared a correlation between concentration of some serum proteins and bronchial obstruction characteristics.

Adult↗
PubMed1991

Molecular basis of the enhanced susceptibility of the erythrocytes of paroxysmal nocturnal hemoglobinuria to hemolysis in acidified serum.

When incubated in acidified serum, the erythrocytes of paroxysmal nocturnal hemoglobinuria (PNH) are hemolyzed through activation of the alternative pathway of complement (APC), but normal erythrocytes are resistant to this process. PNH cells are deficient in decay-accelerating factor (DAF), a complement regulatory protein that inhibits the activity of both the classical and the alternative pathways. However, deficiency of DAF alone does not account entirely for the aberrant effects of acidified serum on PNH cells. Recently, we have shown that PNH erythrocytes are also deficient in another complement control protein called membrane inhibitor of reactive lysis (MIRL) that restricts complement-mediated lysis by blocking formation of the membrane attack complex (MAC). To determine the effects of the DAF and MIRL on susceptibility to acidified serum lysis, PNH cells were repleted with the purified proteins. DAF partially inhibited acidified serum lysis by blocking the activity of the amplification C3 convertase. MIRL inhibited acidified serum lysis both by blocking the activity of the MAC and by inhibiting the activity the C3 convertase. When DAF function was blocked with antibody, normal erythrocytes became partially susceptible to acidified serum lysis. By blocking MIRL, cells were made completely susceptible to lysis, and control of C3 convertase activity was partially lost. When both DAF and MIRL were blocked, the capacity of normal erythrocytes to control the activity of the APC and the MAC was destroyed, and the cells hemolyzed even in unacidified serum. These studies demonstrate that DAF and MIRL act in concert to control susceptibility to acidified serum lysis; of the two proteins, MIRL is the more important. In addition to its regulatory effects on the MAC, MIRL also influences the activity of the C3 convertase of the APC. Further, in the absence of DAF and MIRL, the plasma regulators (factor H and factor I) lack the capacity to control membrane-associated activation of the APC.

Animals↗
PubMed1998

Endothelial cells cultured from human brain microvessels produce complement proteins factor H, factor B, C1 inhibitor, and C4.

The inflammatory mediators, cytokines and complement proteins are believed to regulate the sequential events during the development of lesions secondary to ischaemia and reperfusion. The endothelial cell monolayer of the brain microvasculature is the critical interface between the blood-borne mediators and brain tissue. The involvement of these cells in complement production and regulation has not been well documented. In the present study, expression of complement proteins (C1 inhibitor, factor H, factor B, C4) by cultured endothelial cells obtained from human brain microvessels has been characterized. Interferon gamma upregulates the production of all the complement factors studied. Serine proteases, plasmin and miniplasmin induce the expression of C4, decrease the level of ELISA detectable C1 inhibitor, and do not affect the production of factors H and B. These data indicate that complement proteins are expressed locally by the brain microvessels, and may modulate the inflammatory responses of brain tissue.

Brain↗
PubMedDate not supplied

The role of complement in urticaria and angioedema.

Complement may play a primary or exacerbating factor in the production of urticaria and/or angioedema. As we have seen, the absence of inhibitor proteins, such as ClINH, C3bINA, or Carboxypeptidase N Anaphylatoxin Inactivator) can permit small amounts of active complement fragments, liberated "normally" through the action of nonspecific effector pathways, to produce generalized urticaria or angioedema. Abnormal degrees of complement activation, produced by circulating immune complexes, cryoglobulins, paraproteins, may also cause angioedema and/or urticaria. Autoimmune diseases, lymphoreticular malignancy, infections, drug reactions, and syndromes currently termed idioipathic may be associated with urticaria and angioedema due to pathologic complement activation. Direct effects of complement on blood vessels, either by anaphylatoxins or by the deposition of complement fixing immune complexes, may produce the vascular permeability requisite to these syndromes. Secondary effects, produced by the recruitment of inflammatory cells and/or the liberation of other vasoactive mediators from these cells may also occur. Finally, complement may act in a potent synergistic fashion with mediators such as prostaglandins to produce vascular permeability. Current studies, using antigenic, hemolytic, and immunofluorescent techniques for detecting complement involvement have identified a relatively limited number of syndromes in which complement is involved. It is anticipated that the use of more sensitive assays for anaphylatoxins, such as radioimmunoassay, neutrophil aggregation, and others, coupled with an understanding of the potential synergism between these and other mediators, will lead to the recognition of a wider role for complement in urticaria and angioedema.

Angioedema↗