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PubMedDate not supplied

Complement polymorphism in Greece.

The polymorphisms of the complement components C2, C3, C4 and BF have been studied in a sample of 166 unrelated individuals from Northern Greece. The C3*F and BF*F allele frequencies of Greeks are within the range of frequencies reported from Europe. A single individual with a rare heterozygote variant C2C/C2A was found in Greeks. This C2*A allele was found for the first time in European Caucasoids. For the C4 system six different alleles were found at both C4A and C4B loci. There were a low frequency of the null alleles at the C4A locus and a relatively high incidence of gene duplications in this system.

Complement C2↗
PubMed1985

Complement levels and C3 breakdown products in open-heart surgery: association of C3 conversion with the postpericardiotomy syndrome.

The role of the complement system in the pathogenesis of the post-pericardiotomy syndrome (PPS) was evaluated in a prospective study by measuring the levels of complement (C) components, total haemolytic complement activity and circulating C3 breakdown products in serial plasma and serum samples of 45 patients undergoing open-heart surgery. A consistent reduction in the levels of C3 and C4 but not of factor B was seen on the second post-operative day. During the second post-operative week the antigenic levels of each C component increased significantly. At this time six patients developed the post-pericardiotomy syndrome. Circulating C3 conversion products (C3bi and C3c) were demonstrated in the plasma samples from five of these patients by the immunofixation technique, the mean conversion percentage being 14.3 +/- 10.6. The samples from 15 of the 39 other patients also showed C3 conversion, but the mean percentage was significantly lower (4.5 +/- 6.1%, P less than 0.05). Before the second post-operative week C3 conversion was rare in both groups. The C3d levels of plasma samples, as detected by rocket immunoelectrophoresis, followed a similar pattern. Reduced total haemolytic complement activity was found in three patients suffering from the PPS. These results suggest a role for complement in the non-infectious, inflammatory response during the late post-operative period after open heart surgery, and especially in the post-pericardiotomy syndrome.

Adolescent↗
PubMed1985

Renal filtration and catabolism of complement protein D.

Complement protein D, a serine protease participating in the formation of the C3 convertase of the alternative complement pathway, has the lowest molecular weight (23,750) and serum concentration of all complement proteins. In normal serum, D is the rate-limiting protease of the alternative pathway of complement activation. We report that the serum concentrations of D in 20 patients with chronic renal failure (mean +/- S.D., 0.42 +/- 0.28 mg per deciliter) and in 16 patients on long-term dialysis (1.53 +/- 0.39 mg per deciliter) were significantly higher (P less than 0.001) than in 22 healthy adults (0.18 +/- 0.04 mg per deciliter). In chronic renal failure the serum concentration of D correlated with that of creatinine (r = 0.75, P less than 0.001). The serum concentrations of D found in patients with renal failure reached and in some cases exceeded those at which the protease is no longer rate-limiting. Thus, enhanced activity of the alternative pathway of complement should be expected in patients with advanced renal failure. Urinary D was undetectable (less than 0.2 micrograms per deciliter) in 17 normal adults and either undetectable or below the concentration expected from the degree of proteinuria in 10 patients with nephrotic syndrome. However, in a patient with Fanconi's syndrome the urinary concentration of D (1.3 mg per deciliter) was an order of magnitude higher than the serum concentration, representing 0.5 per cent of the total protein. The urinary D in this patient had normal hemolytic activity, antigenicity, and size. These results indicate that D is filtered through the glomerular membrane and is probably catabolized in the proximal renal tubules.

Adult↗
PubMed1978

Binding of activated properdin to untreated erythrocytes: a new function of activated properdin.

Activated human properdin was found to be capable of binding to rabbit and sheep erythrocytes to form new intermediate cells of the alternative pathway of the complement system. The intermediate cells, termed EP, can react with B, D and C3 to form other intermediate cells, tentatively termed EPB(D)C3, which can be lysed by the subsequent action of six late-acting complement components, C3 to C9. The possibility of participation of C3, B, D or immunoglobulin in the formation of EP cells was neglected by the experiments in which the inhibition of the reactivities of P or EP by antisera to P, C3, B, D or immunoglobulins were investigated. The reduction in reactivities of P to E, or of EP to B, D and C3 was observed only when pretreated with antiserum to P. Furthermore, EP cells were agglutinated only by anti-P, not by antisera to C3 or IgG. The other possibility of participation of the classical complement components such as antibody, C1, C4 and C2 in the formation of EPB(D)C3 was excluded by the non-reactivities of EP with C4 and C2 and of EAC1 with B, D and C3. Thus, activated properdin is likely to function not only as modulator of preformed enzyme such as C3bBb but also as one of early-acting components of the alternative pathway.

Agglutination↗
PubMed1987

Concentrations of C1q, factor B, factor D and properdin in healthy children, and the age-related presence of circulating C1r-C1s complexes.

The concentrations of C1q, factor B, factor D and properdin were determined in healthy children belonging to various age groups of one through five years of age. All concentrations were found to be age-dependent, though they varied from one component to another with regard to ontogenetic pattern. Thus, the concentrations of factor B were high, and those of factor D low throughout the age range studied. C1q and properdin levels were lowest in the younger children, who also showed a fairly high incidence of C1r-C1s complexes in excess of C1q. Since the concentrations of C1q are influenced by those of IgG, the presence of C1r-C1s complexes might partly have reflected maturation of immunoglobulin synthesis during ontogeny.

Age Factors↗
PubMed1979

Relationships between the haemolytic activities of the human complement system and complement components.

The relationships between the haemolytic activities of complement and its components were studied. The activities studied included CH50 (classical pathway), AP50 (alternative pathway), CV50 (early part of alternative pathway) and C(3--9)H50 ((the late part of both pathways). The components included C3, C4, C5, C9, B and D. There was a good correlation between CH50 and AP50. AP50 had a good correlation with B and CV50. There was no correlation between AP50 and C(3--9)H50, and none between C(3--9)H50 and C5 or C9. AP50 may primarily represent changes in the early part of the alternative pathway. C(3--9)H50 is not influenced by respective changes in the amounts of C5 or C9. Since cell lesion is now considered to be caused by a unit of C5b to C9, a change in each component of C5 to C9 may not influence haemolytic activity.

Adult↗
PubMed1987

Effects of lysine and glutamic acid or [corrected] Mg++ on the conformations of C3 and B, and the activation of the alternative complement pathway.

The conversion of C3 and B in the mixture of C3, B, D and Mg++ ions was inhibited in the presence of arginine and lysine, but not in the presence of glutamic acid and aspartic acid among other amino acids. Application of dialyzed plasma to a lysine-Sepharose column resulted in elution of B and a part of D in pass-through fractions, and C3 and the other part of D were retained in the column, subsequently eluted by increase in salt concentrations. C3, B and a part of D were eluted in pass-through fractions, and C3 and the other part of D were retained in the column, subsequently eluted by increase in salt concentrations. C3, B and a part of D were eluted in pass-through fractions when applied to glutamic acid-Sepharose. A highly purified D preparation appeared in the pass-through fraction of the lysine-Sepharose column, suggesting that D may form a complex in plasma. The intensity of intrinsic fluorescence of C3 decreased in the presence of arginine to the largest extent. Lysine affected the intensity less than arginine. Kd was calculated to be 0.42 mM for arginine and 0.55 mM for lysine in the interaction with C3. The intensity of intrinsic fluorescence of B decreased in the presence of aspartic acid and glutamic acid (Kd = 0.48 mM for aspartic acid and 0.24 mM for glutamic acid). Arginine or lysine affected the intensity of B less than those anionic amino acids. The presence of Mg++ ions resulted in a decrease in the fluorescence intensity of C3 and B.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗
PubMed1990

Effects of sulindac and naproxen on prostaglandin excretion in patients with impaired renal function and rheumatoid arthritis.

PURPOSE: The purpose of the current investigation was to study the influence of sulindac and naproxen on renal function and urinary excretion of the stable hydration product of prostacyclin, 6-keto-PGF1 alpha, in patients with arthritis and impaired renal function. PATIENTS AND METHODS: In a placebo-controlled, double-blind, cross-over design, the effects of 7 days of oral sulindac 200 mg twice a day were compared with naproxen 500 mg in the morning and 250 mg in the evening in 10 patients with polyarthritis and stable impaired renal function. Inulin and para-amino-hippurate sodium were used to calculate glomerular filtration rate and renal plasma flow. The excretion rate of 6-keto-PGF1 alpha was measured in urine collected overnight. After patients ingested drugs in the morning, urine was collected in fractions by spontaneous voiding. Venous blood samples were drawn repeatedly for assay of electrolytes, creatinine, proteins, hormones, and drugs. Grip strength and Ritchie articular index were recorded as indicators of symptomatic antiarthritic effectiveness. RESULTS: Naproxen decreased urine levels of 6-keto PGF1 alpha by 59% (p less than 0.01). Sulindac had no effect on renal prostaglandin excretion. Naproxen reduced the glomerular filtration rate and renal plasma flow by 18% (p less than 0.05) and 13% (p less than 0.05), respectively, while no significant change was observed during the sulindac treatment periods. Serum levels of creatinine and complement factor D were unaffected by either drug. Plasma renin activity decreased during naproxen and sulindac treatments by 38% (p less than 0.05) and 22% (p less than 0.05). No significant change in plasma aldosterone was observed during the two drug treatments, but urinary aldosterone declined significantly (p less than 0.05) by 34% with naproxen. Albuminuria decreased (p less than 0.05) during both naproxen (41%) and sulindac treatment (72%), while the albumin/creatinine clearance ratio decreased by 59% (p less than 0.05) only during treatment with sulindac. N-acetyl-beta-D-glucosaminidase in urine was not changed by either drug. Sulindac and naproxen had no discernible effects on base excess, excretion of water, sodium, or potassium, or on osmolal clearance. However, serum potassium increased slightly but significantly (p less than 0.01) during treatment with naproxen. Sulindac sulfide, the active metabolite of sulindac, could not be traced in the urine from any of the patients. Mean arterial blood pressure declined significantly (p less than 0.05) during sulindac treatment but did not change during treatment with naproxen. Both drugs produced equal clinical improvement as measured by grip strength and the Ritchie articular index. CONCLUSION: The results suggest that when sulindac and naproxen are given in clinical equipotent doses to patients with impaired renal function, sulindac does not affect renal prostaglandin synthesis or renal function, whereas naproxen induces suppression of renal prostaglandin synthesis and a further decrease in renal function.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Activation of complement pathways by univalent antibody derivatives with intact Fc zones.

The ability of two univalent antibody derivatives to invoke complement-mediated lysis of guinea-pig L2C leukemic lymphocytes was investigated. The derivatives were Fab/c from rabbit IgG antibody, in which only one Fab arm is removed from the parent molecule and FabFc in which Fab gamma, from peptic digestion of sheep IgG antibody, is disulfide-bonded to the Fc gamma yielded by papain digestion of an arbitrary IgG. Antibody activity was directed against surface IgM on the target cells. Both derivatives could invoke lysis via the classical pathway in the presence of rabbit complement. Exposure of the cells to the derivatives at 37 degrees C before introducing complement yielded no protective antigenic modulation. At low complement concns the derivatives were more efficient than the parent antibodies at invoking lysis, apparently due to the fact that the derivatives do not cause modulation: it appears that cells can undergo a useful degree of modulation when confronted simultaneously by bivalent antibody and low levels of complement. The Fab/c preparations were also able to invoke lysis by guinea-pig complement. Lysis occurred under conditions where activation took place only via the classical pathway (in dilute complement) or only via the alternative pathway (in the absence of calcium ions, or in C4-deficient guinea-pig serum). The results demonstrate that there is no need for two antigen-binding Fab arms in antibody activation of either the classical or alternative complement pathways. They favour models requiring clustering of Fc regions rather than steric changes which might follow binding of antigen.

Animals↗
PubMed1989

Complement abnormalities in multiple myeloma.

PURPOSE: Patients with multiple myeloma have been shown to have defective opsonization and C3 deposition. Previous studies have suggested that defective C3 deposition may be related to a failure of C3 activation in myeloma serum, the mechanism of which is unknown. We therefore decided to investigate the underlying mechanism responsible for the failure in C3 activation and deposition. PATIENTS AND METHODS: The study consisted of 10 patients from whom a total of 12 serum specimens were obtained. Normal serum was prepared from a pool of serum specimens in four healthy male donors. We evaluated, in vitro, the kinetics of C3 deposition onto zymosan using radiolabeled C3 under various conditions. We also measured the serum levels of a variety of complement components using standard methods. RESULTS: Five of 10 patients' sera demonstrated poor C3 deposition onto zymosan at all time points, whereas an additional two showed poor C3 deposition at early time points but a rebound to normal by 30 minutes. Multiple components of the classical and alternative complement pathways were decreased in many patients, with the most striking abnormalities occurring in those with the poorest C3 deposition. No single complement component abnormality was found to be common to the group. Elevations in Bb fragment concentration strongly suggest in vivo activation as the likely mechanism for depletion of alternative pathway components; the mechanism for classical pathway abnormalities is less clear. There was an inverse correlation between paraprotein concentration and abnormal C3 deposition (p less than 0.0001) and C3 (p less than 0.0005) and C4 (p less than 0.0001) concentrations. However, no consistent evidence of fluid-phase complement consumption was present. CONCLUSION: The defect in C3 activation and deposition in multiple myeloma cannot be explained on the basis of a single complement component abnormality but rather is due to a heterogeneous group of complement abnormalities. Although no correlation between in vitro abnormalities and clinical status was identified in this small group of patients, it is likely that the described complement defects play an important role in defective host defense in multiple myeloma.

Complement Activation↗
PubMed1991

Elevated plasma levels of the immunosuppressive complement fragment Ba in renal failure.

The complement fragment Ba is a 33 kD activation product of factor B which suppresses human B-lymphocyte functions in vitro. We report that plasma levels of Ba are highly elevated in patients with chronic renal failure (4.84 +/- 3.58 micrograms/ml) and in patients with end-stage renal disease undergoing regular hemodialysis (16.1 +/- 6.1 micrograms/ml) as compared to normals (1.01 +/- 0.30 micrograms/ml). Ba levels were strictly correlated with the creatinine clearance. The urinary excretion of Ba was 165-fold higher in patients with tubular proteinuria than in normals. These results indicate that the kidney is the major catabolic site for Ba. In addition, direct evidence was obtained for an enhanced turnover of the alternative pathway of complement in renal failure that, although it appears to be less important than the renal retention of Ba, contributes to elevated Ba plasma levels in these patients. Ba concentrations in dialysis patients who responded to hepatitis B vaccination were significantly lower than in non-responders. Furthermore, the in vitro IgM synthesis by purified mononuclear cells was negatively correlated with Ba concentrations determined in the plasma of these patients. These results suggest that the accumulation of Ba contributes to the defective immune response in patients with renal failure.

Adult↗
PubMed2025

Transcriptome-wide analysis reveals potential roles of CFD and ANGPTL4 in fibroblasts regulating B cell lineage for extracellular matrix-driven clustering and novel avenues for immunotherapy in breast cancer.

BACKGROUND: The remodeling of the extracellular matrix (ECM) plays a pivotal role in tumor progression and drug resistance. However, the compositional patterns of ECM in breast cancer and their underlying biological functions remain elusive. METHODS: Transcriptome and genome data of breast cancer patients from TCGA database was downloaded. Patients were classified into different clusters by using non-negative matrix factorization (NMF) based on signatures of ECM components and regulators. Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify core genes related to ECM clusters. Additional 10 independent public cohorts including Metabric, SCAN_B, GSE12276, GSE16446, GSE19615, GSE20685, GSE21653, GSE58644, GSE58812, and GSE88770 were collected to construct Training or Testing cohort, following machine learning calculating ECM correlated index (ECI) for survival analysis. Pathway enrichment and correlation analysis were used to explore the relationship among ECM clusters, ECI and TME. Single-cell transcriptome data from GSE161529 was processed for uncovering the differences among ECM clusters. RESULTS: Using NMF, we identified three ECM clusters in the TCGA database: C1 (Neuron), C2 (ECM), and C3 (Immune). Subsequently, WGCNA was employed to pinpoint cluster-specific genes and develop a prognostic model. This model demonstrated robust predictive power for breast cancer patient survival in both the Training cohort (n = 5,392, AUC = 0.861) and the Testing cohort (n = 1,344, AUC = 0.711). Upon analyzing the tumor microenvironment (TME), we discovered that fibroblasts and B cell lineage were the core cell types associated with the ECM cluster phenotypes. Single-cell RNA sequencing data further revealed that angiopoietin like 4 (ANGPTL4)+ fibroblasts were specifically linked to the C2 phenotype, while complement factor D (CFD)+ fibroblasts characterized the other ECM clusters. CellChat analysis indicated that ANGPTL4+ and CFD+ fibroblasts regulate B cell lineage via distinct signaling pathways. Additionally, analysis using the Kaplan-Meier Plotter website showed that CFD was favorable for immunotherapy response, whereas ANGPTL4 negatively impacted the outcomes of cancer patients receiving immunotherapy. CONCLUSION: We identified distinct ECM clusters in breast cancer patients, irrespective of molecular subtypes. Additionally, we constructed an effective prognostic model based on these ECM clusters and recognized ANGPTL4+ and CFD+ fibroblasts as potential biomarkers for immunotherapy in breast cancer.

Humans↗
PubMed1991

Genomic organization and subchromosomal in situ localization of the murine granzyme F, a serine protease expressed in CD8+ T cells.

Granzyme F belongs to a closely related family of seven murine serine proteases stored in cytoplasmic granules of lymphoid cell populations. In contrast to the murine granzymes A to E and G, granzyme F is exclusively expressed in the CD4-CD8+ subset of peripheral T cells. To characterize the genomic sequences responsible for its highly restricted expression, we isolated a cosmid clone and sequenced a 7.5-kb genomic fragment that contains the promoter region and all five exons of the murine granzyme F gene. A TATA box sequence is located at position -25 relative to the transcription initiation site, which was determined by RNase protection. The genomic organization of granzyme F is similar to that of granzyme B and granzyme C, leukocyte elastase, cathepsin G, rat mast cell protease II, and complement factor D (adipsin). By the use of two fluorochromes for simultaneous high resolution in situ hybridization, the granzyme F gene was localized in close proximity distally from the TCR alpha-chain locus on mouse chromosome 14.

Amino Acid Sequence↗
PubMed1978

Plasma levels of complement components and complement haemolytic activity in protein-energy malnutrition.

The plasma levels of complement haemolytic activity (CH50) of some complement components and of C3d, a C3 breakdown product, were measured in fifty-nine African children with various types of protein-energy malnutrition (PEM) including kwashiorkor, before and during recovery. A significant decrease of CH50, C3, C9 and factor B was observed in PEM without a concomitant decrease of C4 and C5. Increased plasma levels of C3d were also found in PEM patients. Two mechanisms seem to be involved in the impairment of the complement system in PEM: (1) a decreased synthesis of at least C3 and C9 as suggested by a significant correlation between C3 or C9, levels and those of albumin and cholinesterase; (2) an increased catabolism of C3 possibly due to an activation of the alternative complement pathway, as suggested by the increased level of C3d and the decreased level of factor B which are significantly correlated with C3 levels but not with albumin levels. These data support the possible role of a relative complement deficiency upon the decreased resistance to infections observed in malnourished children.

Child, Preschool↗