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PubMed1987

Bactericidal activity for Neisseria meningitidis in properdin-deficient sera.

We investigated serum bactericidal reactions against Neisseria meningitidis (serogroups A, B, C, D, Y, W-135, 29E, X, and Z) in the sera of two healthy adults with properdin deficiency. Bactericidal reactions mediated via the classic complement pathway (unchelated system) were not impaired in properdin-deficient serum. The properdin-deficient sera supported alternative pathway-mediated killing (Mg++EGTA-chelated system) of some, but not all, of the strains investigated. Vaccination of the properdin-deficient individuals with serogroup A and C polysaccharide clearly increased the concentrations of antibody to meningococci. At least some of the antibodies induced by vaccination supported the bactericidal activity of properdin-deficient serum. Some antibodies to meningococci, probably of the IgM class, promoted alternative pathway-mediated bactericidal reactions in the absence of properdin. By contrast, presensitizing meningococci with IgG enhanced the alternative pathway-mediated reactions, but this was strictly a properdin-dependent effect.

Antibodies, Bacterial↗
PubMed1986

Determination of anaphylatoxin concentrations in suction blisters in patients with psoriasis.

Concentrations of C3a and C4a anaphylatoxins in suction blister fluids were determined by radioimmunoassay in patients with psoriasis and normal controls. Comparison of anaphylatoxin levels between serum samples and blister contents in the same subjects revealed that the levels of both C3a and C4a anaphylatoxins were significantly higher in the former than the latter even in those raised on normal skin, suggesting that the classic complement pathway is activated during suction procedure. Therefore we cannot regard suction blister fluid to be simply representative of undisturbed interstitial tissue fluid as far as the complement system is concerned. There was no difference in anaphylatoxin levels between those from uninvolved skin of psoriatic patients and those from normal controls. However, significantly high anaphylatoxin levels were noted in fluids of suction blisters raised on lesional skin as compared with those produced on uninvolved skin in psoriatic patients.

Adolescent↗
PubMed1986

Complement activation in vitro by antiplatelet antibodies in chronic immune thrombocytopenic purpura.

Many chronic ITP patients have increased amounts of platelet-associated IgG, C3, C4 and C9, suggesting in vivo complement activation. In this study, we assessed the ability of various antiplatelet antibodies (APA) to activate and deposit complement proteins and to cause platelet lysis in vitro. Platelet sensitization with rabbit APA, anti-P1A1 antibody (one patient), anti-HLA antibody (two patients) and ITP autoantibodies (four patients) resulted in the deposition of C4 and C3 onto platelets in an amount proportional to the quantity of antibody-containing sera used to sensitize the platelets. Although C9 deposition onto platelets could not be quantitatively demonstrated on platelets sensitized with ITP serum, platelet lysis (51Cr release) was noted after incubation with each of three ITP sera and complement. When compared, ITP autoantibodies, anti-HLA and anti-P1A1 antibodies activated complement to a similar degree. We conclude that some autoantibodies in chronic ITP activate the classical complement pathway. The demonstration of in vitro platelet lysis by autoantibodies and complement suggests that in vivo platelet lysis may occur in some chronic ITP patients.

Autoantibodies↗
PubMed1982

An analysis of the lymphocytotoxic activity found in sera from patients with hypogammaglobulinaemia.

Sera from 59 patients with hypogammaglobulinaemia (hypogamma) were assessed for lymphocytotoxic activity. The activity was compared with that found in sera from patients with systemic lupus erythematosus (SLE) in titre, class of antibody, target cell, and complement requirements. Sera from patients with hypogamma showed cytotoxic activity when compared with sera from normal donors; however, the activity was far less than that in sera from SLE patients, The cytotoxic titre of both hypogamma and SLE sera was greater against T cells than non-T cells. Sera showing activity could be used to sensitize lymphocytes and render them susceptible to subsequent lysis, but IgM was not detectable on the surface of the sensitized cells. Following sucrose density gradient fractionation of the sera the lymphocytotoxic activity was recovered in those fractions that contained IgM. Lymphocytotoxic activity was dependent on classical complement pathway activity. In all the experiments the hypogamma sera showed the same pattern of activity as the SLE sera, but the activity was always far weaker than that found in SLE sera. The evidence does not suggest that lymphocytotoxicity is likely to be more important in the pathogenesis of hypogamma.

Agammaglobulinemia↗
PubMed1979

Chemotaxigenesis by cell surface components of Staphylococcus aureus.

In an attempt to delineate the staphylococcal cell surface components of importance in chemotaxigenesis, we incubated intact Staphylococcus aureus H, crude cell walls, purified cell walls, peptidoglycan, teichoic acid, and cell membranes with human sera. The results reported indicate that both crude cell walls and purified cell walls, as well as peptidoglycan, were potent chemotaxigens. These particles led to the generation in normal human serum of a factor that was chemotactic for human polymorphonuclear leukocytes. Cell wall peptidoglycan and teichoic acid both appeared to play a role in chemotaxigenesis. Kinetic studies employing C2-deficient serum and immunoglobulin-deficient serum revealed that optimal chemotaxigenesis required the presence of an intact classical complement pathway, as well as antibody. Granulocyte aggregometry studies showed that significant levels of C5a were generated in normal serum and that this activated complement component appears to be a major chemotactic factor produced in serum upon interaction with staphylococcal cell wall components.

Cell Membrane↗
PubMed1980

Chemotaxigenesis by encapsulated Staphylococcus aureus M.

Although encapsulated Staphylococcus aureus M is not opsonized by normal human serum, as a chemotaxigen this organism behaved similarly to an unencapsulated variant strain. For optimal chemotaxigenesis, an intact classical complement pathway was required, and C5a appeared to be the major chemotaxin.

Chemotactic Factors↗
PubMed1982

Requirement for an additional serum factor essential for the antibody-independent activation of the classical complement sequence by Gram-negative bacteria.

Killing of Salmonella minnesota and Salmonella typhimurium S and R strains in serum of nonimmune humans and guinea pigs was drastically reduced in the selective absence of C1q, C1r, Ca2+, C4, or C2, the components of the classical complement pathway. Binding of C1 and C1q to the S form and six different core-deficient R mutant strains became stronger the shorter the lipopolysaccharide molecule. C1 and C1q had, under physiological conditions, no affinity to the serum-resistant S forms, whereas these components were bound by the serum-sensitive R forms with high affinity. However, a mixture of the individual complement components C1-C9, which rapidly lysed sensitized erythrocytes, did not kill the serum-sensitive bacteria. Isolated C1 bound to these bacteria cleaved fluid-phase C4 but did not convert C2. C2 turnover could be detected only when serum was used as a source of C1 or C4, indicating that an additional serum component is necessary for the antibody-independent bactericidal effect. Functional tests indicated that this factor is a euglobulin which mediates binding of C4 to the bacteria even in the absence of C1 or after treatment with EDTA. Binding of C4 followed by the generation of C4b sites as acceptors for C2 was a prerequisite for the killing of the bacteria. The factor could not be replaced by immunoglobulin G or immunoglobulin M, nor was it blocked by preincubation with anti-immunoglobulin G or anti-immunoglobulin M.

Animals↗
PubMed1992

Classical complement activation induced by pregnancy: implications for management of connective tissue diseases.

AIMS: To determine the effect of pregnancy on C4d concentrations and to assess whether C4d remains a useful disease activity marker in the management of connective tissue diseases during pregnancy. METHODS: Plasma C3, C4, and C4d concentrations were measured in 83 women at various stages of normal pregnancy and compared with those in 80 non-pregnant controls. RESULTS: C3 concentrations in the pregnant women were significantly raised (p = 0.0001) and the C4 concentrations were reduced (p = 0.0007), and accompanied by a significant increase in C4d (p = 0.0001). The C4d:C4 ratio was higher in the pregnant women (p = 0.0001). CONCLUSIONS: Pregnancy induces activation of the classical complement pathway. C4d concentrations cannot be used to monitor disease activity in patients with connective tissue diseases during pregnancy.

Adolescent↗
PubMed1989

Molecular basis of complement activation in ischemic myocardium: identification of specific molecules of mitochondrial origin that bind human C1q and fix complement.

Mitochondria may be a source of molecules that activate complement during ischemic injury to myocardium, providing therewith a stimulus for infiltration of polymorphonuclear leukocytes. To identify specific molecules that activate the classical complement pathway, detergent lysates of canine cardiac mitochondria were fractionated by polyacrylamide gel electrophoresis and transferred electrophoretically to nitrocellulose paper (NCP). The NCP replicas of the gels were incubated with isolated C1q and fresh sera as a source of complement, washed briefly, and overlaid with sensitized sheep erythrocytes (RBC) in agarose. A cluster of four to six molecules between 45 and 53 kDa as well as four others, 34, 30, 26, and 23 kDa, consumed complement thereby preventing complement-mediated lysis of sensitized sheep RBC in the agarose overlay. Additional molecules reactive with C1 were identified by their ability to bind isolated human C1q and to serve as assembly sites for later acting complement components. Sites of localization of complement were demonstrated by incubating NCP replicas of fractionated mitochondria with antisera specific for C1q, C3, C5, and C9, followed by peroxidase-conjugated anti-immunoglobulin and substrate. A total of 12 C1q binding molecules ranging in size from 67 kDa to 23 kDa, which can fix later acting complement components, were identified. At least two of these reacted with antisera prepared against canine cardiac lymph collected in the first 3-4 hours after a 45-minute coronary artery occlusion. These studies present direct evidence that specific molecules, released from subcellular fractions of myocardial cells rich in mitochondria, can activate the complement cascade.

Animals↗
PubMed1986

Demonstration of modified inactive first component of complement (C1) inhibitor in the plasmas of C1 inhibitor-deficient patients.

The first component of complement (C1) inhibitor plays a critical role in the regulation of the classical complement pathway and the contact system, and the deficiency of C1 inhibitor protein or function is associated with recurrent angioedema. In this study we evaluated the size of the C1 inhibitor antigens present in the plasmas of C1 inhibitor-deficient patients. We found that the C1 inhibitor in the plasmas existed in three forms: high molecular weight forms in complex with proteases, native 110-kD C1 inhibitor, and a modified inactive 94-kD form. The proportion of the total C1 inhibitor in the 94-kD form was 28% in nine hereditary angioedema patients, 92% in five acquired C1 inhibitor-deficiency patients, and 1.2% in five normal controls. In vitro activation of normal plasma with kaolin, but not heat-aggregated gamma-globulin generated 94-kD C1 inhibitor from 110-kD C1 inhibitor. Neither kaolin activation nor heat-aggregated gamma-globulin activation generated 94-kD C1 inhibitor in Hageman factor-deficient plasma. These results suggest that 94-kD C1 inhibitor is generated in vitro by activation of the contact system. The in vivo mechanism of 94-kD C1 inhibitor generation in C1 inhibitor-deficient patients is not known.

Angioedema↗
PubMed1983

C1q and immune complexes in liver cirrhosis sera.

The highest mean value of the serum C1q concentrations among chronic liver diseases was obtained in patients with liver cirrhosis (LC). C1q serum levels seemed to increase along the progression of liver damage. Serum levels of C1q and CH50 in patients with LC and systemic lupus erythematosus (SLE) were simultaneously estimated. No correlation between C1q and CH50 levels was observed in LC sera, while a significant correlation was demonstrated in SLE sera. It could be suggested that the mechanism for the low CH50 in LC sera seemed different from that in SLE sera, and that the activation of classical complement pathway was not the predominant cause in LC sera. Correlations of serum levels between immune complexes and C1q were examined in patients with LC and SLE. It could be deduced from the results of a positive correlation in LC sera and the reverse tendency in SLE sera that the significances of C1q and immune complexes in LC sera differed from those in SLE sera.

Antigen-Antibody Complex↗
PubMed1983

A simplified quantification method of complex-release activity using peroxidase as immune complex antigen.

The complement-mediated solubilization of precipitable immune complexes (complex-release activity) in serum specimens was determined by a simplified method using peroxidase as an immune complex antigen. The results correlated well with the hemolytic activity via the classical complement pathway and that via the alternative complement pathway. This simplified method proved to be reliable and useful.

Antigen-Antibody Complex↗
PubMed1992

Induction of contact sensitivity by cell-associated immunocomplexes requires activation of the early complement components.

Lymph node cells collected from CBA/J mice 4 days after painting the skin with picryl chloride behave like antigen presenting cells and induce contact sensitivity when injected into naive recipient mice. The immunizing capacity of these '4-day' cells is due to T cells which carry on their membrane hapten-IgM immunocomplexes. Incubation of the cells with complement from mouse strains that express high C4 serum levels (C4H), abolishes their immunizing capacity. This effect is related to the activation of the early components of the classical complement pathway, as supported by experiments using C3 and C4-depleted or C5 and C6-genetically deficient mouse sera. The detection of different amounts of C3b and C4b on the surface of 4-day T cells after incubation with C4L and C4H sera supports the possibility that membrane bound activated complement components could modify the immunizing capacity of these cells. Results herein reported suggest that membrane-bound C3b and C4b are not per se inhibitory but interfere with the residual complement activating capacity of 4-day T cells. The role of complement activation by 4-day T cells is pivotal as complement depletion of recipient mice by cobra venom factor (CVF) inhibits the immunizing capacity of untreated 4-day T cells, while 4-day T cells treated with complement in vitro and injected together with C4a anaphylatoxin are able to immunize recipient mice.

Animals↗
PubMed1990

[Complement activation by killed polyvalent bacterial vaccine on the pleurodesis].

Broncasma Berna (B.B.) prepared from killed polyvalent bacterial vaccine is used as a pleural irritant for pleurodesis on patients with spontaneous pneumothorax. The effects of B.B. on the complement system in vivo after injections into pleural spaces were investigated. Five patients with spontaneous pneumothorax underwent intrapleural injections of B.B. Increased body temperatures with positive C-reactive proteins and increased polymorphonuclear leukocyte counts in peripheral blood were observed in all patients. Serum levels of complement components (Clq, Cls, C4, C3 and B), hemolytic activity of complement (CH50) and plasma levels of C3a were gradually elevated after intrapleural injections of B.B. Analysis of pleural fluids from 4 patients showed that levels of C3a and C5a were increased compared with plasma levels, and an accumulation of polymorphonuclear leukocytes were observed. These findings suggest that intrapleural injections of B.B. activate the complement system and cause inflammatory reactions accompanied by an increase of C3a and C5a and an accumulation of polymorphonuclear leukocytes. Such inflammatory reactions might inversely induce the synthesis of complement components and promote the migration of polymorphonuclear leukocytes from bone marrow. The deposit of fibrin during these inflammatory processes might contribute to the development of pleurodesis. These inflammatory reactions might be mediated through the activation of the classical complement pathway by B.B.

Adult↗
PubMed1990

[Fatal pneumococcal meningitis in a 1-year-old child with homozygous C2 deficiency].

The 1-year old girl died of recurrent bacterial meningitis. Streptococcus pneumoniae was isolated from the cerebrospinal fluid. The analysis of the immune system revealed only a defect of the complement system. The following results were obtained: 1. No function of the classical complement pathway. 2. Reduced function of the alternative complement pathway. 3. No functional C2 activity. 4. No C2 protein. The parents had half normal C2 titers. HLA typing was only possible for the parents with the following results: A1, A32(w19), B18, DR2, DRw11(5) (father) and A3, A10, B18, B7, DR2 (mother). These data are compatible with a B18, DR2 haplotype of the child which is found in most cases of homozygous C2 deficiency. Our patient list another example for the high risk of recurrent severe infectious diseases in persons with a total complement defect.

Complement C2↗
PubMed1989

Murine membrane inhibitor of complement which accelerates decay of human C3 convertase.

A membrane protein of MW 60,000 was purified from mouse erythrocytes. This protein inhibits generation of mouse complement C3/C5 convertases on antibody-sensitized rabbit erythrocytes, in a haemolytic assay system using guinea-pig serum diluted in EDTA as the source of C3 to C9. This protein also has the capacity to accelerate the decay of human C3 convertase of the classical complement pathway. Antibody to this membrane protein also reacted with peripheral blood mononuclear cells and spleen cells, as observed by fluorescent flow cytometry analysis. Since the reactivity of these cells to the antibody was reduced by treatment with phosphatidyl inositol-specific phospholipase C (PIPLC), it is suggested that the protein is attached to the membrane via a glycophospholipid anchor. Based on these results, we conclude that this membrane protein is a murine homologue of human decay-accelerating factor (DAF).

Animals↗
PubMed1987

Deficiency of C2, the second complement component, in the family of a patient with SLE-like syndrome: the first case of hereditary C2 deficiency in Czechoslovakia.

A family with hereditary C2 deficiency was discovered in Czechoslovakia. The proband is a 47-year-old female with a SLE-like syndrome and zero activity of the classical complement pathway. Functional CH50, C1, C2, and C4 estimations for all family members revealed a homozygous C2 deficiency in both the proband and her elder sister, and several heterozygotic C2-deficient individuals. The defect segregates with haplo-type HLA A25, B18, DR2.

Adult↗
PubMed1979

Neonatal cellular and humoral immunity to group B streptococci.

The mechanisms of host resistance to group B streptococci have not been defined precisely. In the studies reported here we have assessed the contributions of both humoral and cellular factors in protection against strains of this group. With assays of specific opsonic activity based upon the production of polymorphonuclear leukocyte chemiluminescence and radiolabeled bacterial uptake, we have demonstrated that specific heat-stable antibody and the classic complement pathway are major factors in opsonization of these organisms. In the absence of specific antibody, fresh serum resulted in markedly reduced bacterial uptake indicating, at best, a minor role for the alternative complement pathway. Additional studies have indicated that strain-specific antiphagocytic factors as well as type-specific ones may play a role in the virulence of these organisms. Neonates who developed group B streptococcal sepsis usually lacked opsonic activity in their infecting strain. In addition, polymorphonuclear leukocytes from normal term and stressed neonates showed impaired metabolic activation as measured in the chemiluminescence assay following exposure to opsonized group B streptococci. These results suggest that neonates who develop group B streptococcal disease may have defects in both the humoral and cellular aspects of their acute inflammatory response which may contribute to the high mortality observed in this most fulminant of bacterial infections.

Antibody Formation↗