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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↗
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↗
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↗
PubMed1979

Requirements of immunoglobulin and the classical and alternative complement pathways for phagocytosis and intracellular killing of multiple strains of Gram-negative aerobic bacilli.

The requirements for immunoglobulin and the alternative and classical complement pathways for phagocytosis and intracellular killing of clinical isolates of Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, and Serratia marcescens by normal human polymorphonuclear leukocytes were determined. Human sera deficient in immunoglobulin or classical pathway activity, or both, were compared for their ability to promote phagocytosis os and killing of 13 bacterial strains by the polymorphonuclear leukocytes. Seven of the thirteen microorganisms required immunoglobulin for phagocytosis and killing and utilized only the classical complement pathway. Three required immunoglobulin and utilized both the classical and alternative pathways. The other three microorganisms required minimal immunoglobulin and utilized the alternative or classical pathway, or both. None of the microorganisms utilized the alternative pathway in immunoglobulin-deficient sera or could be forced to utilize this pathway in sera deficient in both immunoglobulin and classical pathway activity. These results demonstrated a heterogeneity in the requirements for immunoglobulin and the alternative and classical complement pathways for phagocytosis and intracellular killing by polymorphonuclear leukocytes among various genera of gram-negative aerobic bacilli, as well as among strains of the same species. In addition, the results suggested that a mechanism of classical pathway activation dependent upon minimal immunoglobulin participates in phagocytosis and intracellular killing of certain gram-negative aerobic bacilli.

Complement Activation↗
PubMed1991

The role of immunoglobulin and complement in enhancing the respiratory burst of neutrophils against Trichomonas vaginalis.

Human neutrophils, alone, did not kill Trichomonas vaginalis. More than 90% of T. vaginalis (10(5)/ml) survived in the presence of 10% normal human serum (NHS) while 90% of these organisms were killed in the presence of a combination of neutrophils (10(6)/ml) and 10% NHS. Mechanisms responsible for this serum-mediated neutrophil killing of T. vaginalis were demonstrated through a process of lucigenin-amplified neutrophil chemiluminescence. As evidenced by indirect immunofluorescence, NHS showed specific immunoglobulin G (IgG) titre of 1:8 for T. vaginalis. Purified IgG, at 1.6 mg/ml, showed no direct opsonizing or lytic effect on this organism. Formalin-fixed trichomonads opsonized by C2 deficient human serum promote 4 times more neutrophil chemiluminescence than those opsonized by Factor B deficient human serum. With the addition of purified IgG (5 mg/ml) neutrophil chemiluminescence was increased by 4 times and further improved trichomonal killing by neutrophils (from 5 +/- 4% to 78 +/- 16%) via activation of the classical complement pathway, but did not alter that due to activation of the alternative complement pathway. These studies indicate that both an IgG-enhanced classical complement pathway activation and an antibody-independent alternative complement pathway activation provide opsonin (C3) for T. vaginalis to facilitate the neutrophil killing mechanism.

Adult↗
PubMed1979

The quantitation of alternative pathway complement function by timed lysis assay.

A simple timed lysis assay is described for quantifying haemolytic complement activity in human serum. Classical pathway complement function was determined by measuring the time taken to lyse 50% of a standard suspension of antibody-coated sheep erythrocytes; the time required for 50% lysis of a standard rabbit erythrocyte suspension was similarly used to evaluate alternative pathway function. Because target erythrocytes prepared on different days gave slightly different 50% lysis times, it was necessary first to construct a series of calibration curves for converting 50% lysis times into CH50 U/ml. For this purpose, a range of dilutions of the standard human serum, of known haemolytic activity, was tested against erythrocytes prepared on 10 separate occasions. The standard serum was subsequently included with each batch of unknown sera and used to select the appropriate calibration curve for direct conversion of the 50% lysis time into CH50 U/ml. Eleven samples of normal human serum were tested by both the timed lysis assay and by the dilution methods of Mayer (1971) (classical) and Platts-Mills and Ishizaka (1974) (alternative pathway). Comparable results were obtained in all cases.

Animals↗
PubMed1978

Host defense against opportunist microorganisms following trauma. II. Changes in complement and immunoglobulins in patients with abdominal trauma and in septic patients without trauma.

Total hemolytic complement (CH50), conversion of C3 by inulin and cobra venom factor (CoVF), and immunochemical levels of Clq, C4, C2, C3, C5, factor B, properdin, C3b inactivator (KAF), and immunoglobulins (Igs) G, A, and M were measured in the sera of ten patients with abdominal trauma and ten medical patients with septicemia without trauma. Reduction in C3 conversion by CoVF and decrease in the levels of properdin and KAF were demonstrated in the trauma sera. CH50 and the level of C5 were also decreased. Conversion of C3 by inulin and levels of factor B, Clq, C4, C2, and C3 were found to be normal in the patients' sera. Complement levels and activities were found to be normal in the sera of the septic non-trauma patients. A decrease in serum IgM was observed in both patient groups; levels of IgG and IgA were normal. These results indicated that abnormalities of immunoglobulin and of the alternative and classical complement pathways were associated with nonburn trauma. Moreover, the data suggested that consumption of the classical complement pathway associated with septicemia in the thermally injured patient resulted from synergism between the trauma and infection rather than from septicemia per se.

Abdominal Injuries↗
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↗
PubMed1979

Complement in tears from normal humans.

Tears from ten normal persons were used in hemolytic assays to test for activity of total hemolytic complement (tested in all ten subjects), activities of each of the nine complement components (tested in two subjects), and activity of the alternate pathway (tested in two subjects). A modified radial-immunodiffusion method was used to confirm the presence of C3 and C4 complement proteins in the tear samples from all ten subjects. Factor B protein was detected in tears from two of four normal subjects tested. In dilutions up to 1:4, hemolytic activity was observed in tears from five of the ten subjects. Samples from the remaining five subjects had CH50 activity at dilutions up to 1:2. In control tests, human serum had CH50 activity at 1:32. No lysis occurred in Veronal-buffered saline or in serum and tears heated to 56 degrees C for 30 minutes. Complement proteins C3 through C9 displayed hemolytic activity in tears from each of two subjects tested for complement components. The classic and alternate complement pathways in tears can be included among the defense mechanisms of the ocular surfaces.

Complement C3↗
PubMed2025

Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer's disease.

BACKGROUND: Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer's Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer's disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. RESULTS: We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). We additionally identify three population-specific loci with genome-wide significance at/near PTPRK and GRB14 in HIS and KIAA0825 in NHW. Pathway analysis implicates multiple amyloid regulation pathways and the classical complement pathway. Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14). CONCLUSIONS: Using cross-population GWAS meta-analyses, we identify novel LOAD susceptibility loci in/near LRRC4C and LHX5-AS1, both with known roles in neuronal development, as well as several novel population-unique loci. Reflecting the power of diverse ancestry in GWAS, we detect the SHARPIN locus with only 13.7% of the sample size of the NHW GWAS study (n = 409,589) in which this locus was first observed. Continued expansion into larger multi-ancestry studies will provide even more power for further elucidating the genomics of late-onset Alzheimer's disease.

Humans↗
PubMed1979

Consumption of C3 via the classical and alternative complement pathways by sera and synovial fluids from patients with rheumatoid arthritis.

Five sera and four synovial fluids from patients with rheumatoid arthritis were found to contain substances which consumed hemolytic C3 in normal human serum (NHS) and in normal guinea pig serum (NGPS). These fluids were then tested for ability to activate the alternative pathway by incubating them with NHS containing MgEGTA and C4 deficient GPS. All sera and two synovial fluids depleted C3 in these reagents, indicating direct activation by the alternative pathway. Density gradient ultracentrifugation demonstrated C3 fixing activity in some specimens in the greater than 19s regions. These substances may also activate complement similarly in vivo and participate in the development of inflammatory processes associated with this disease.

Adult↗
PubMed1992

Inhibition of the classical activation pathway of complement-mediated lysis by monoclonal antibodies to complement components C3c and C3d.

Eight epitope-mapped monoclonal antibodies (MoAbs) to complement component C3d and five to complement component C3c were investigated to determine whether they could inhibit the classical activation pathway of complement-mediated lysis (CML) by using blood group AB red cells sensitized by A or B MoAbs. Three IgM C3d MoAbs and one IgG1 C3c MoAb were able to inhibit CML in a dose-dependent manner. In the presence of excess complement, no inhibition was observed. The greatest inhibition was observed with two high-affinity IgM antibodies that were specific for epitope 1 on the C3d component. Some inhibition was observed with a high-affinity IgM antibody specific for epitope 3 of the C3d component and also with a lower-affinity IgG antibody specific for epitope 1 of the C3c component. The results indicate that some complement MoAbs have the capacity to distinguish between conformationally and/or functionally different forms of red cell-bound C3.

Antibodies, Monoclonal↗
PubMed1992

The role of complement in the host's defense against Haemophilus influenzae.

In vitro studies have shown that Haemophilus influenzae type b (Hib) can activate both the classical and alternative pathways of complement and generate complement-dependent opsonic and bactericidal activities. In vivo studies and observations in complement-deficient patients have established the biologic significance of complement in the host's defense against H. influenzae. The complement system plays a significant role in the host's defense against Hib and against other encapsulated and unencapsulated H. influenzae, mainly by enhancing clearance from the bloodstream through its action as an opsonin in both nonimmune and immune hosts. Patients with genetically determined deficiencies of C3 or of the complement components involved in C3 activation have an increased susceptibility to H. influenzae. More recently, a relatively common deficiency of one isotype of C4 (C4B) has been shown to be associated with invasive Hib disease, suggesting that defects in complement-mediated host defense may be more common in systemic Hib infections than previously appreciated.

Animals↗
PubMed1979

Complement abnormalities in diffuse plane xanthomatosis with paraproteinaemia.

Paraproteinaemia may be associated with xanthomatous skin deposits and these can arise in the absence of elevated lipid levels. Two cases of benign monoclonal gammopathy with diffuse plane xanthomatosis are reported. Case 1 exhibited hypolipidaemia and a functional deficiency of C1 esterase inhibitor. Case 2 showed a normal lipoprotein profile, abnormal platelet aggregation, and a cutaneous vasculitis with evidence of complement consumption via the classical pathway. The significance of these abnormalities is discussed.

Aged↗
PubMedDate not supplied

[The effect of plasmin on complement in human blood serum].

Plasma exhibited the dose-dependent inactivating effect on human blood serum hemolytic complement both in classic and alternative pathways. Negative correlation (r = -0.8) was found between the rate of complement inactivation and content of C3 component. Plasmin appears to hydrolyze mainly the C3 component of complement as a result of which hemolytic activity of complement is decreased.

Blood↗
PubMed1979

C142 complement activity and conglutinogen in bovine milk.

Bovine milk, derived from uninflamed glands in mid-lactation, is shown to contain the complement components of the classical pathway up to C3. Using functional tests, C142 activity and conglutinogenic activity can be demonstrated in undiluted whey. Conglutinin is rarely found in normal milk.

Animals↗