[C4 component of complement, rheumatoid factors and circulating immunocomplexes in rheumatoid-arthritis and reactive synovitides of local origin; serum synovial fluid].
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Adult↗
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Results for “Complement C4”
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[The significance of C3 and C4 of serum complement in systemic lupus erythematosus (SLE)].
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Adolescent↗
Serum immunoglobulins, complement levels and lymphocyte subpopulations in phenytoin-treated epileptic patients.
The peripheral blood lymphocytes, serum immunoglobulins, C3 and C4 complement protein concentrations of 20 patients with idiopathic epilepsy who were receiving phenytoin were examined and compared with 30 healthy controls in order to obtain a detailed profile of the effects of the drug on the humoral and cellular immune systems. The T-lymphocyte subsets were identified using monoclonal antibodies. A significant decrease in suppressor T-cells (p less than 0.05) and an increase in the ratio of T-helper to T-suppressor lymphocytes (p less than 0.01) have been found. Furthermore, an increase in B-lymphocytes (p less than 0.01) and a significant rise in serum Ig M concentrations (p less than 0.05) have been observed. No significant changes in serum concentrations of Ig G, Ig A and complement proteins were detected.
Adolescent↗
DNase I hypersensitivity mapping and promoter polymorphism analysis of human C4.
Human complement component C4 is encoded by two structurally distinct loci in the major histocompatibility complex (MHC) class III region. The two isotypes, C4A and C4B, differ at only four residues in the C4d fragment, but C4 constitutes the most polymorphic of the complement components. It is not known, however, whether the regions involved in the regulation of C4 expression also display polymorphic variation. By using the technique of DNase I hypersensitivity mapping, we established that the only area of transcriptional activity for C4 in the hepatocyte cell line, HepG2, occurs approximately 500 base pairs upstream of the transcriptional start site. This region was found to be remarkably constant in sequence when analyzed in the context of differing MHC haplotypes including HLA B57, C4A6, C4B1, DR7, which has been correlated with reduced expression of the C4A isotype. Similarly, polymerase chain reaction followed by single-strand conformation polymorphism analysis failed to demonstrate any promoter polymorphisms in 103 individuals comprising 52 systemic lupus erythematosus patients and 51 healthy controls.
Base Sequence↗
Administration of C1-esterase inhibitor during emergency coronary artery bypass surgery in acute ST-elevation myocardial infarction.
OBJECTIVE: Myocardial inflammatory response including complement activation was demonstrated as an important mechanism of ischemia-reperfusion injury and complement inhibition by C1-esterase inhibitor (C1-INH) has recently shown to have cardioprotective effects in experimental and clinical settings. METHODS: The effects of C1-INH on complement activation, myocardial cell injury, and clinical outcome were studied in patients undergoing emergency CABG due to acute ST-elevation myocardial infarction (STEMI) with (group 1, CABG+STEMI+C1-INH, n=28) and without (group 2, CABG+STEMI, n=29) bolus administration of C1-INH (40 IU kg(-1)) during reperfusion and 6 h postoperatively (20 IU kg(-1)) besides the same study protocol. C1-INH activity, C3c and C4 complement activation fragments, and cardiac troponin I (cTnI) were measured preoperatively and up to 48 h postoperatively and compared to another elective set of CABG patients without STEMI as controls (group 3, CABG-STEMI, n=10). Clinical data, adverse events, and patient outcome were recorded prospectively. RESULTS: Patient characteristics were not different between groups 1 and 2. No drug-related adverse events were observed. Constant plasma levels of C1-INH were found in group 1, but not in groups 2 and 3. Plasma levels of C3c and C4 complement fragments were reduced in all three groups after surgery throughout the observation time, but tended to be lower in groups 1 and 2 compared with group 3. Preoperative cTnI levels were elevated but not different between the groups 1 and 2. The area under curve (AUC), as well as the postoperative cTnI serum levels, was significantly lower (P<0.05) in group 1 with a treatment delay < or = 6 h between reperfusion and symptom onset compared to group 2 at 36 h (47.9+/-11.1 ng/ml vs 97.7+/-17.2 ng/ml; mean+/-SEM), and 48 h (33.5+/-5.8 ng/ml vs 86.5+/-19.2 ng/ml) after surgery, but remained unchanged between groups among patients with a treatment delay of more than 6-24 h. In-hospital adverse events and postoperative complications, ICU and hospital stay, as well as in-hospital mortality (14.3% vs 13.8%; P=NS) were not different between groups 1 and 2. CONCLUSIONS: C1-INH administration in emergency CABG with acute STEMI is safe and effective to inhibit complement activation and may reduce myocardial ischemia-reperfusion injury as measured by cTnI.
Aged↗
Role of complement in host defense against experimental disseminated candidiasis.
The role of complement in experimental disseminated candidiasis was studied in normal guinea pigs, animals congenitally deficient in the fourth component of complement (C4), and animals depleted of alternative pathway activity by cobra venom factor (CVF). Animals pretreated with CVF and challenged with Candida albicans had a high rate of mortality. Results of quantitative organ cultures corroborated prior reports that the kidney was the major target organ of infection. Infection of the kidney was markedly enhanced by CVF-induced depletion of the alternative pathway but not by classical pathway deficiency (deficiency in C4). There were differences among organs (kidney, liver, and spleen) in their requirement for complement to mount an effective host defense response. Ultimately, the integrity of the alternative pathway and late components of complement appears necessary for the limitation of and survival from sepsis due to C. albicans in nonimmune animals.
Animals↗
Urinary C4 excretion in systemic lupus erythematosus.
The fourth component of complement (C4) in urine was measured in 19 patients with systemic lupus erythematosus (SLE). Urinary C4 was detectable in all SLE patients using an enzyme linked immunosorbent assay. In 11 of 13 patients whose urinary C4 was serially measured, a decrease of urinary C4 was found in parallel with a decrease of disease activity of SLE. In the remaining 2 patients, the amount of C4 increased preceding a flare-up of the disease. The measurement of urinary C4 may be useful in evaluating the disease activity of SLE in individual patients and sometimes in predicting the flare-up of the disease. The specific hemolytic activity of excreted C4 and Western blotting analysis showed that urinary C4 consisted mainly of degraded fragments of C4. In two cases, camostat, a serine protease inhibitor, rapidly decreased the urinary C4 excretion, suggesting that the complement activation occurred in the glomerulus in lupus nephritis.
Adolescent↗
Reactive arthritis and serum levels of mannose binding lectin -- lack of association.
The purpose was to evaluate the possible association of serum mannose binding lectin (s-MBL) levels on type of triggering microbe, duration of diarrhoea, incidence and course of reactive arthritis (ReA) caused by Salmonella, Yersinia and Campylobacter. Sixty patients with ReA of 1-228 months duration, 173 patients with ReA or uncomplicated enterocolitis caused by Campylobacter, 226 sera from patients with elevated antibody levels against Salmonella, Yersinia or Campylobacter, and 114 blood donors were tested for s-MBL using ELISA technique, both direct mannan binding assay and sandwich ELISA. s-MBL was compared with C-reactive protein (CRP) levels and with the ability of activating complement C4. Among the 114 donors 9% had s-MBL <50 microg/l, 16% had from 50-500 microg/l and 75% had >500 microg/l. The distribution of s-MBL levels in the three-patient groups did not differ significantly from the controls. There were no indications that low s-MBL was associated with prolonged duration of arthritis, diarrhoea or individual bacterial infections. The two MBL assays were comparable with respect to serum concentrations, indicating that the actual circulating MBL was also functionally active. s-MBL exhibited acute phase reactant behaviour and correlated to CRP level, but only in patients with s-MBL concentrations exceeding 1000 microg/l. MBL in 10 randomly selected ReA sera were tested for the ability to activate complement C4. The results did not differ from those of donor controls. This study demonstrates that the distributions of s-MBL levels in serum among patients with ReA are not different from donor controls. The course, outcome or triggering bacteria are not associated with a particular level of s-MBL.
Adolescent↗
Amino acid residues 1101-1105 of the isotypic region of human C4B is important to the covalent binding activity of complement component C4.
The C4A and C4B isotypes of human C4 show certain functional differences that stem from their relative preference for transacylation to amino (-NH2) vs hydroxyl (-OH) nucleophiles, respectively, on complement-activating surfaces. Comparison of amino acid sequences of the alpha-chain fragment of C4, C4d, has shown C4A- and C4B-specific sequences at residues 1101-1106 are the only consistent structural difference between isotype, i.e., Pro, Cys, Pro, Val, Leu, Asp in C4A and Leu, Ser, Pro, Val Ile, His in C4B. These residues may be responsible either in part or entirely for properties associated with isotype. To examine the functional role of residues 1101-1106 in C4B-mediated hemolysis, whole serum or immunopurified human C4 with allotypes, A3B1, A3, B2B1, or B1 were preincubated in the presence or absence of an antipeptide mAb (BII-1) specific for amino acid residues 1101-1105 of C4B. Sensitized sheep E and C4-deficient guinea pig serum was then added and lysis measured by absorbance at 415 nm. Our results show lysis of antibody-sensitized sheep E is inhibited by antibody and C4B2B1, C4B1, or C4A3B1 but not antibody and C4A3. The interference of hemolysis by BII-1 could not be explained by inhibition of activation of C4B or inhibition of C3 or C5 convertase activity. Furthermore, results from uptake experiments show that BII-1 interferes with the covalent binding activity of C4B, indicating residues 1101-1105 play a role in the covalent binding reaction of C4B to the target E-antibody complex.
Amino Acid Sequence↗
Constitutive expression of Slp genes in mouse strain B10.WR directed by C4 regulatory sequences.
The murine fourth component of complement (C4) and sex-limited protein (Slp) are two closely related serum proteins that exhibit very disparate patterns of gene expression: all mice constitutively express C4, whereas only adult male mice from a limited number of standard inbred strains express Slp. Several exceptional strains exhibit constitutive (C4-like) Slp expression, a phenotype that correlates with multiple copies of the Slp gene. To determine the molecular basis for constitutive Slp expression we have isolated genomic clones and compared the sequences of 1.5 kb of 5' flanking DNA from 1 C4 gene and three different Slp genes from the Slp-constitutive strain B10.WR. These sequence comparisons demonstrate C4-like regulatory sequences adjacent to two of the Slp genes. By analysis of cDNA clones isolated from a B10.WR liver library we demonstrate that the constitutive Slp phenotype is due primarily to expression of one of these C4/Slp hybrid genes. It appears likely that Slp gene duplication in strain B10.WR came about via homologous unequal crossover events between C4 and Slp genes; this would accommodate both the gene sequence data and the pattern of C4-like Slp expression in mouse strain B10.WR.
Animals↗
Functional properties of heterogeneous human asialo-C4 and its isotypes C4A and C4B.
The fourth component of human complement (C4) is encoded at two separate but closely linked loci within the MHC on the short arm of chromosome 6. Thus, there are two types of C4 protein in most individual and pooled normal human sera (NHS): C4A and C4B. Incubation of individual sera, pooled NHS, or purified heterogeneous C4 (C4A/C4B) with bacterial sialidase at 37 degrees C increased C-mediated hemolysis of antibody-sensitized sheep erythrocytes 1.54- to 1.93-fold. Comparative studies of Tmax of human C2, using asialo-C4 or buffer-treated C4 on EAC1gp and extrapolation to time 0 indicated a z value 4-fold higher with asialo-C4. This indicated that more hemolytically active C42 complexes are available with sialidase-treated C4 compared to untreated C4. There was no appreciable difference in the % 125I-C4 bound to EAC1gp (sialidase- or buffer-treated). Sera from two different blood donors with C4A3 phenotype (C4BQ0), two different donors with C4B1 phenotype (C4AQ0), and serum from an individual heterozygous deficient at both C4A3 and C4B1 regions (A3, AQ0; B1, BQ0) were investigated. The C4 allotypes, purified from these sera, were treated with sialidase; the C4A3 was enhanced in hemolytic assays by sialidase-treatment (1.52- to 2.3-fold), whereas the C4B1 allotype was not enhanced. Fluorometric determinations revealed that approximately the same percentage of sialic acid was released from sialidase-treated C4A3 and C4B1. Therefore, the increase in hemolytic titer observed after treatment of NHS or purified heterogeneous C4 with sialidase is a property of C4A3 but not a property of C4B1.
Asialoglycoproteins↗
Familial discoid lupus erythematosus associated with heterozygous C4 deficiency.
Low levels of the fourth component of complement (C4) were found functionally and immunochemically in two sisters (17 and 22 years of age) suffering both from discoid lupus erythematosus. C4-typing of the family revealed that the two sisters and the mother had only two, and the father three of the four genes coding for C4 expressed. All carried the null allele C4B*QO. This observation adds to the increasing evidence that not only complete but also partial genetic complement deficiencies may predispose to lupus erythematosus.
Adolescent↗
Involvement of dipeptidyl peptidase IV in immune complex-mediated glomerulonephritis.
Dipeptidyl peptidase IV (DPPIV) is widely expressed in many tissues; however, its precise biological function is poorly understood. One of its possible physiologic roles is an involvement in the immune system, which plays a pivotal role in the pathogenesis of glomerulonephritis. The present study focused on the involvement of DPPIV in immune complex-mediated glomerulonephritis. Experimental nephritis was induced by anti-Thy-1.1 monoclonal antibody E30 using Wistar or F344 rats. The application of a new monoclonal antibody against DPPIV, F16, completely suppressed E30-induced proteinuria and mesangial proliferation in Wistar rats, whereas these preventive effects of F16 were not observed in F344 rats, which spontaneously lack DPPIV protein. Treatment with F16 inhibited glomerular deposition of complement C3 and complement C4 after the binding of E30 to the mesangial cell surface. Because the preventive effect of F16 was attributable to suppression of the complement cascade, we examined its influences on complement-dependent mesangial cell lysis in vitro. We discovered that the complement cascade was markedly inactivated in F16-treated Wistar rat serum but not in F16-treated F344 rats. These results indicate that DPPIV may play a somewhat crucial role in regulating the complement cascade and that inhibition of DPPIV may serve as a new target for preventing complement-dependent tissue injury.
Animals↗
Associations between restriction fragment length polymorphisms detected with a probe for human C4 and allotype of C4B5 allele.
We studied the fourth component of human complement (C4) allotypes in 58 Japanese individuals. The technique of Southern, with C4 and 21-OH cDNA probes, was used to examine the genomic DNA of 45 individuals typed for C4 by protein electrophoresis. Novel HindIII C4 10- and 5-kb and EcoRI C4 13-Kb restriction fragments were identified in each of nine Japanese individuals. The novel fragments were different from the previously described C4B long (HindIII 31-kb, TaqI 6-kb, BamHI 4.3-kb, and EcoRI 12-kb) and C4B short (HindIII 25-kb, TaqI 5.4-kb, BamHI 3.5-kb, and EcoRI 15-kb) fragments. All novel HindIII- and EcoRI-positive individuals carried C4B5, BfS, and HLA-Bw54. Therefore, the fragments were characteristic for the C4B5 allele. The C4 region was analyzed to determine the restriction sites by single and double digests of uncloned genomic DNA with several restriction endonucleases. It is speculated that an insertion gene lies between the 3' end of the 21-OH and the 5' end of the C4B genes.
Adult↗
Effects of the rate of acetylcholine receptor synthesis on the severity of experimental autoimmune myasthenia gravis.
The effect of target organ manipulation by means of denervation and treatment with anabolic steroids on the severity of disease in EAMG was assessed in inbred rats. Unilateral limb denervation, a procedure known to increase the AChR content of muscle, 'protected' the denervated leg against antibody-mediated AChr loss in acute EAMG induced by passive transfer of mAb 35 directed against the main immunogenic region. Also in chronic EAMG, brought about by immunizing rats with AChR in complete Freund's adjuvant, the AChR loss of the denervated leg was about one fourth (13.5 vs. 53%) of the control leg. In both acute and chronic EAMG the amount of AChR complexed with antibody was lower in the denervated leg. This lower AChR occupancy with antibody in the denervated leg occurred also in conditions of marked antibody excess and was therefore due to enhanced AChR synthesis. Next the effect of treatment with a weakly virilizing anabolic steroid nandrolone in chronic and acute EAMG was examined in order to examine whether a hypothesized enhanced synthesis of AChR would protect animals from disease. In the absence of an immunosuppressive effect, in terms of concentration of antibodies to AChR, nandrolone treatment protected the rats from severe disease in the chronic EAMG model as shown by the fact that of the 9 rats 6 showed mild (1+) disease and 3 no disease at all; conversely 6 out of 9 control rats showed severe (3+) disease. Rats treated with nandrolone showed a 48 +/- 1.7% loss of AChR compared to a loss of 58 +/- 3.6% in the control rats, suggesting enhanced AChR synthesis. When nandrolone-pretreated rats were given acute EAMG by passive transfer of mAb 35 a paradoxical effect was seen. In contrast to the controls all of the rats pretreated with nandrolone showed severe signs of EAMG; this was associated with a higher loss of AChR and increased consumption of complement C4 as suggested by decreased concentrations of C4 in the serum. Results show increased AChR synthesis to protect against chronic EAMG both in terms of clinical disease (nandrolone) as well as AChR loss (nandrolone, denervation). In addition it was shown that nandrolone increases serum C4 consumption which in the complement-dependent acute EAMG model causes enhancement of the severity of clinical disease and increased AChR loss.
Acute Disease↗
An improved method for separation of the fourth component of complement and C4 inactivating substance.
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Benzyl Compounds↗
Clinical evolution, and morbidity and mortality of primary Sjögren's syndrome.
OBJECTIVES: To study the clinical and laboratory profile evolution, as well as morbidity and mortality impact, of primary Sjögren's syndrome (pSS), in a large cohort of patients followed-up longitudinally. METHODS: We studied the evolution of the clinical picture and laboratory profile of pSS, the incidence and predictors for systemic sequelae, and the impact of pSS on overall survival in a prospective cohort study of 261 patients with pSS. Analyses included calculation of incidence rates, Cox proportional hazards predictive models, and estimation of standardized mortality ratios (SMRs) compared with the general Greek population, adjusting for age and sex. RESULTS: Glandular manifestations of the syndrome were typically present at the time of diagnosis. Systemic manifestations such as arthritis, Raynaud's phenomenon, purpura, interstitial nephritis, and liver involvement, as well as the serological profile, also did not change substantially during subsequent follow-up. Incidence rates for peripheral neuropathy, glomerulonephritis, and lymphoproliferative disorders were 3.3, 6.6, and 12.2 per 1,000 person-years, respectively. Glomerulonephritis and lymphoma tended to co-exist in the same patients (relative risk, 34.0; P < .0001). The development of lymphoproliferative disorders was associated with low levels of C4 complement (relative risk, 7.5; P = .0016), the presence of mixed monoclonal cryoglobulins (relative risk, 7.9; P = .0012), and purpura (relative risk, 3.9; P = .037). Low levels of C4 was the strongest predictor for mortality after adjusting for age (relative risk, 6.5; P =.0041). Patients with pSS had an SMR of 2.07 (95% CI, 1.03 to 3.71). However, when patients with adverse predictors were excluded, the mortality rate was identical to that of the general population (SMR 1.02). CONCLUSIONS: The initial presentation of pSS determines subsequent outcome. Purpura, decreased C4 complement levels, and mixed monoclonal cryoglobulinemia are adverse prognostic factors. The overall mortality of patients with pSS compared with the general population is increased only in patients with adverse predictors.
Adolescent↗
Selective deficiency of the fourth component of complement in a patient with systemic lupus erythematosus (SLE): immunochemical and biological studies.
A 45-year-old female (J.B.) with clinically inactive systemic lupus erythematosus was devoid of haemolytic serum complement activity. Functional and immunoprecipitin assays showed that the complement defect was due to lack of the fourth component of complement (C4). The patient's serum and red cells were Chido-negative, Rodgers-negative. In J.B.'s serum there was marked impairment of opsonization of Staphylococcus aureus and of the formation of chemotactic activity in the presence of zymosan. The chemotactic defect was not due to the presence of inhibitory factors: the activity was increased by the addition of C4. These findings suggest that an intact classical pathway is necessary for the optimal generation of serum chemotactic factors by zymosan via the alternative pathway of the complement system.
Adolescent↗