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PubMed1994

Is partial deletion of the complement C4 genes associated with sudden infant death?

The two C4 loci C4A and C4B in 61 cases of sudden infant death (SID), 93 living controls and 7 cases of infectious death were studied. In the SID group 13.1% showed deletion of the C4A gene, while 2.5% of the cases showed deletion of the C4B gene. This was not significantly different from neither the controls nor the infectious death group. We were not able to confirm that deletion of the C4B gene is associated with SID. However, in the SID group deletion of either the C4A or the C4B gene was associated with signs of infections prior to death (P = 0.035). This observation may indicate that a proportion of SID victims are more vulnerable to infections than other infants.

Adult↗
PubMed1988

Complement activation by vascular prostheses and its role in progression of arteriosclerotic lesions.

This study, using C3a, C4a, and C5a assay and crossed immunoelectrophoresis in vitro and in vivo, was designed to determine whether vascular prostheses activate the complement system. The degree of complement activation and the pathway of activation were also studied. The complement levels (C3, C4, CH50) in different arterial diseases were measured, and the relationship of complement levels to serum lipids in patients with arteriosclerosis obliterans (ASO) was also investigated, in order to clarify a relationship between the complement system and arteriosclerosis or other arterial diseases. Bovine graft, dacron, and PTFE activated the complement system in vitro. In order of the degree of complement activation, bovine graft ranked first, followed by dacron and PTFE. The patient group with acute arterial occlusion showed high C3 and C4 levels. The healthy elderly group showed higher C3 and C4 levels than the healthy persons in their twenties. In ASO patients, C3 levels correlated with serum lipid levels. Judged from the relation of complement activation by vascular prostheses to the progression of arteriosclerotic changes, vascular prostheses should be assessed with regard to complement activation.

Arterial Occlusive Diseases↗
PubMed1997

Quantitative analysis of C4Ab and C4Bb binding to the C3b/C4b receptor (CR1, CD35).

Complement-dependent clearance of immune complexes in humans is dependent on the activation and binding of the early components of the classical complement cascade. This prevents immune complex precipitation and promotes binding of the complexes by the C4b/C3b complement receptor CR1 (CD35) found on erythrocytes. The fourth component of human complement is encoded by two closely linked genes within the MHC. These genes give rise to the isotypic forms C4A and C4B, and recent studies suggest that CR1 binds activated C4A (C4Ab) to a greater extent than activated C4B (C4Bb). To study this difference in a more quantitative way the binding reactions between CR1 and C4Ab- and C4Bb-coated immune complexes and between CR1 and soluble dimers of C4Ab (C4Ab2) and C4Bb (C4Bb2) were analysed using the native receptor on human erythrocytes. The binding reaction between immune complexes with equivalent amounts of covalently bound C4Ab or C4Bb and erythrocyte CR1 showed a two-fold higher binding of complexes coated with C4A. Furthermore, erythrocyte CR1 bound C4Ab2 with an apparent four-fold higher affinity (Kd approximately 1.4 x 10(-7) M) than C4Bb2 (Kd approximately 4.8 x 10(-7) M), indicating a preferential binding of CR1 for C4A.

Antigen-Antibody Complex↗
PubMed1979

The isolation and characterization of bovine C4a, an activation fragment of the fourth component of complement.

The fourth component of bovine complement, C4, was cleaved specifically by subcomponent C1s to produce two fragments, C4a and C4b. The smaller, C4a, was isolated in pure form and is a peptide of 9500 mol.wt. containing approx. 84 amino acids and no detectable carbohydrate. C4a has an amino acid composition that is comparable with the anaphylatoxins C3a and C5a, containing six cysteine residues/mol and a high proportion of basic residues. The amino acid sequence of the first thirteen residues shows four identities with the porcine C3a sequence. There is almost complete identity between the C4a sequence and that of the alpha-chain of human C4, indicating that this region is highly conserved. This evidence also clearly establishes that C4a is cleaved from the N-terminal of the alpha-chain of C4.

Amino Acid Sequence↗
PubMedDate not supplied

The suppression effect of DNA sequences within the C4A region on the transcription activity of human CYP21.

Two CYP21 genes, the active CYP21 and the pseudogene, CYP21P, also pairs of duplicated genes including the XA, XB, XB-S; YA, YB; and ZA, ZB are arranged in tandem next to the serum complement C4 genes (C4A and C4B). In this report, we have analyzed the influence of some DNA sequences within the C4A/CYP21P region on the transcription activity of the human CYP21. After transiently transfecting the plasmid constructs into mouse adrenocarcinoma Y1 cells, mouse testis Leydig tumor MA10 cells and human liver tumor HepG2 cells, our results showed that sequences located within the -13943/-13174 and -3278/-2586 regions upstream from the CYP21P had suppression effects on the promoter activity of human CYP21. However, the short sequences spanning from -8415/-8373 and -4511/-4140 upstream from the CYP21P did not alter the basal transcription activity of the CYP21 gene. Our results indicated that specific sequences within the C4A region might function as suppressor-like elements for the transcription of human CYP21.

Adrenal Cortex↗
PubMed1986

Molecular genetics of the fourth component of human complement.

The fourth component of human complement is encoded by two separate, but closely linked, loci, C4A and C4B, that have been positioned within the class III region of the HLA complex. While the two isotypes vary by only six amino acid residues, they differ significantly in haemolytic activity. Both loci are considerably polymorphic and this may be biologically relevant to ensure interaction with a wide range of pathogens. The number of C4 genes expressed is polymorphic as null alleles, total deficiency and duplication has been shown based on protein studies. Southern analysis of 24 different haplotypes with either C4A or C4B null alleles using the C4 probes showed that three of the null alleles were due to deleted genes but the majority appeared normal. A cosmid library was prepared from DNA of one of the deleted haplotypes and the region of deletion analysed by restriction mapping.

Alleles↗
PubMed1989

Factor B activation products in patients with systemic lupus erythematosus. A marker of severe disease activity.

Complement activation patterns were determined in a group of 51 patients with systemic lupus erythematosus (SLE), and the clinical outcomes of these patients at 2 years were correlated with the complement activation patterns. Activation of the classical pathway was monitored by analysis of C4a desArg levels and total C4 levels, and activation of the alternative pathway was monitored by isoelectric focusing/immunofixation and quantitative analyses of Factor B. Activation of C3 (a general measure of complement activation) was determined by an enzyme-linked immunosorbent assay for C3d and by quantitative analysis of C3. Patients were stratified into 3 groups: those with C4 but not C3 activation; those with C4 and C3 but not Factor B activation; and those with C4, C3, and Factor B activation. At the end of 2 years, there was a statistically significant difference in the morbidity and mortality rates of the third group of SLE patients compared with those in the other 2 groups. There was also a statistically significant association between the presence of Ba and cutaneous vasculitis. Unlike the patterns seen with in vitro-activated serum or with membrane-activated plasma, the Bb activation fragment was not present in the activated plasma samples from the SLE patients. These data suggest that activation of the alternative complement pathway may be a marker for severe SLE and that the Bb fragment may be playing a role in the development of this more serious pathologic condition.

Biomarkers↗
PubMed1994

Complete inherited deficiency of the fourth complement component in a child with systemic lupus erythematosus and his disease-free brother in a north African family.

Although null alleles of complement C4 genes (C4A*Q0 and C4B*Q0) are frequent in the normal population, the occurrence of two null alleles on the same chromosome is very rare and therefore complete C4 deficiency is exceptional. We describe a 16-year-old North African boy who presented with systemic lupus erythematosus with renal involvement and persistent undetectable classical pathway activity and C4 protein and hemolytic activity in plasma, with normal C3 levels. Similar complement abnormalities were observed in his healthy 12-year-old brother. Complete C4 deficiency was documented in the two brothers by investigation of the family and the lack of C4A and C4B bands upon phenotyping of C4. Southern blot analysis of the C4/CYP21 gene organization in the family indicated that the deficiency resulted from a deletion of the C4B/CYP21A genes associated with nonexpression of a C4A gene. The double-null haplotype was found to be associated with homozygous A2 B17 C2C BFF C4 AQ0 BQ0 DR7 HLA haplotype. Thus, similar C4 deficiencies with HLA identity may lead to different clinical presentations.

Adolescent↗
PubMed2005

Increased concentration of the complement split product C5a in acute pyelonephritis during pregnancy.

OBJECTIVE: Pregnant women with acute pyelonephritis develop acute respiratory distress syndrome (ARDS) more frequently than non-pregnant women. The reasons for this remain unknown. The complement system is a complex set of self-assembling proteins that have been implicated in the pathophysiology of ARDS and sepsis. The purpose of this study was to determine if activation of the complement system occurs in pregnant women with acute pyelonephritis. METHODS: A cross-sectional study was conducted to determine the plasma concentrations of C3a, C4a and C5a (i.e., complement split products) in pregnant patients with acute pyelonephritis (n=38) and normal pregnant women (n=38). The complement split products C3a, C4a and C5a were measured using ELISA. Data were analyzed using non-parametric statistics. RESULTS: 1) The median plasma concentration of C5a in pregnant patients with acute pyelonephritis was significantly higher than that in normal pregnant women (p<0.001); 2) there was no statistical difference in the median plasma concentration of C3a and C4a between the two groups (p>0.05); and 3) concentrations of C3a, C4a and C5a were not different among patients with acute pyelonephritis with and without bacteremia. CONCLUSIONS: 1) Pyelonephritis in pregnant women is associated with an increased plasma concentration of C5a, but not C3a and C4a; and 2) an excess of C5a can predispose pregnant women to develop ARDS and multi-organ failure in pyelonephritis. This finding may have clinical implications since blocking C5a improves ARDS in experimental sepsis.

Acute Disease↗
PubMed1990

The effect of FUT-175 (Nafamstat Mesilate) on C3a, C4a and C5a generation in vitro and inflammatory reactions in vivo.

FUT-175 is a synthetic protease inhibitor and an inhibitor of the classical and alternate pathways of complement activation. In human serum, FUT-175 inhibited C3a, C4a and C5a generation induced by heat aggregated IgG, zymosan and Cobra venom factor with IC50 values in the range of 3-43 microM depending on the stimulus and the fragments. To assess in vivo anti-inflammatory activity, inflammatory reactions induced in the skin of rabbits were quantitated by using 125I-albumin extravasation, 51Cr-labelled leukocyte accumulation and 86RbCl accumulation as a measure of hyperemia. Infusion of FUT-175 at 2 mg/kg/h inhibited all three parameters by 50-80% in dermal reactions induced by killed E. coli, zymosan, immune complexes, the reversed Arthus reaction, zymosan activated plasma (ZAP), f-norleu-leu-phe (FNLP) and LTB4. In contrast, the response to endotoxin (0.1 microgram) was not effected by FUT-175 treatment. The effect of FUT-175 was comparable to that of local or systemic therapy with indomethacin, but unlike indomethacin, the effect of FUT-175 was not reversed by local PGE2 administration. Furthermore, indomethacin and FUT-175 had additive anti-inflammatory effects. These results suggest that although FUT-175 is a potent inhibitor of C3a, C4a and C5a generation, it has novel and broad anti-inflammatory effects, possibly through actions in addition to complement inhibition as indicated by inhibition of FNLP-, LTB4- and ZAP-induced reactions.

Animals↗
PubMed2001

Genetics of human complement component C4 and evolution the central MHC.

The two classes of human complement component C4 proteins C4A and C4B manifest differential chemical reactivities and binding affinities towards target surfaces and complement receptor CR1. There are multiple, polymorphic allotypes of C4A and C4B proteins. A complex multiplication pattern of C4A and C4B genes with variations in gene size, gene dosage and flanking genes exists in the population. This is probably driven by the selection pressure to respond to a great variety of parasites efficiently and effectively, which the bony fish achieved through the multiplication and diversification of the related complement C3 proteins. Complement C4, C3 and C5 belong to the alpha2 macroglobulin protein family but acquired specific features that include an anaphylatoxin domain, a netrin (NTR) domain, and stretches of basic residues for proteolytic processings to form multiple chain structures. Complement C3 and C4 are important in the innate immune response as they opsonize parasites for phagocytosis. The emergence of complement C3 predates proteins involved in the adaptive immune response as C3 is present in deuterostome invertebrates such as echinoderms. The human C4 genes are located in the central MHC at chromosome 6p21.3. C3 and C5 are located at chromosome 19 and 9, respectively, with representatives of the other groups of genes paralogous to the MHC at 19p13.1-p13.3, 1q21-25, and 9q33-34. The central MHC also contains genes for complement components C2 and Bf. These genes appear to have similar evolutionary histories to C3/C4/C5 and are used here to illustrate stepwise processes resulting in co-location of diverse domains, chromosomal duplication, local segmental duplication and divergence of sequence and function. This model of evolution is useful in the investigation of innate and acquired immunity and in seeking explanations for diseases associated with MHC ancestral haplotypes.

Amino Acid Sequence↗
PubMed1987

Familial systemic lupus erythematosus: evidence for separate loci controlling C4 deficiency and formation of antibodies to DNA, nRNP, Ro and La.

A family has been identified in the Canadian province of Prince Edward Island in which 2 sisters have systemic lupus erythematosus in a sibship of 14. Studies are reported on 11 of the siblings and 16 other family members. The affected siblings, and 4 other members of their sibship, are halfnull homozygotes for the C4A component of complement. We studied the distribution in family members of antibodies to ss and dsDNA, and to Ro(SSA), La(SSB), Sm and nRNP. Eight of 11 members of the affected sibship are antibody producers, compared to only 3 of 13 members of the parental generation. Our study provides further evidence for an association between null genes for C4A and familial lupus, and suggests, in an unusually large kindred, that several other genetic factors are involved in the production of antinuclear antibodies.

Adult↗
PubMed1995

HLA complement gene polymorphisms in multiple sclerosis. A study on 80 Italian patients.

We studied C4A, C4B, and Bf complement gene polymorphisms in 80 Italian patients with multiple sclerosis (MS). We observed a significantly higher frequency of C4AQ0 allele in patients with the relapsing-remitting form of MS than in ethnically homogeneous controls. Restriction fragment length polymorphism analysis by Southern blotting of the C4/CYP21 gene complex showed that a structural gene deletion was present in 45% of patients with the C4AQ0 allele. Our data support the hypothesis that relapsing-remitting MS and primarily chronic progressive MS are immunogenetically distinct diseases; further, complement factor abnormalities typical of autoimmune diseases could influence the pathogenesis of MS.

Case-Control Studies↗
PubMed1994

Complement activation during storage of single-donor platelet concentrates.

Single-donor platelets are stored up to 5 days prior to transfusion. Since contact of plasma to plastic surfaces may lead to complement activation, we investigated whether there is any increase in the complement factors C3a, C4a and C5a in routinely stored single-donor platelet concentrates. C3a levels increased about 40-fold during a 7-day storage. C4a levels also increased with storage time but to a lesser extent. By contrast, C5a levels remained stable throughout this period. ADP- and collagen-induced aggregation was impaired after storage of platelets, indicating severe functional injury. In platelet-poor plasma stored under identical conditions a comparable increase in C3a and C4a concentrations was observed. The loss of platelet function during storage might at least in part be due to the excessive anaphylatoxin concentrations observed.

Blood Donors↗
PubMed1984

Anaphylatoxin generation in multisystem organ failure.

Complement components were studied in 44 patients with extensive injuries or infections. The concentrations of anaphylatoxins (C4a, C3a, and C5a) and other complement components (C1INH, C4, C3, and C5) were determined in plasma using radioimmunoassay and rocket immunoelectrophoresis techniques. The results were correlated with the development of multisystem organ failure (MSOF). In particular, plasma concentrations of C3a and C4a were found elevated in trauma patients. These elevated anaphylatoxin levels were correlated with severity of the injury. As reported in other types of patients, the apparent C5a plasma levels were not elevated. Therapy reduced the plasma levels of C3a with great predictability. It appears that plasma C3a and C4a levels may relate not only to severity of the injury but may signal onset of secondary events such as bacteremia. Consequently, longitudinal monitoring of anaphylatoxin levels may prove helpful in diagnosing the status of trauma patients.

Adolescent↗
PubMed1988

Effects of cardiopulmonary bypass on pulmonary leukostasis and complement activation.

We measured white blood cell counts and complement component (C3a, C4a, and C5a) and prostacyclin levels, and studied lung biopsy specimens, in 16 patients undergoing cardiopulmonary bypass and compared them with four patients undergoing other pulmonary procedures. Bypass caused no significant elevation in peripheral venous white blood cell counts. Higher counts were present in the right atrium compared with the left atrium. Patients who underwent bypass had elevated complement component and prostacyclin concentrations before operation and these levels increased further during operation. Trapping of polymorphonuclear leukocytes occurred in pulmonary alveolar capillaries and venules after bypass. We conclude that bypass activates complement components primarily of the alternative pathway and leads to increased blood prostacyclin levels. These changes are accompanied by polymorphonuclear leukocyte accumulation in the lungs and may be important in initiation of the adult respiratory distress syndrome in these patients.

6-Ketoprostaglandin F1 alpha↗
PubMed2005

Structural comparison of human C4A3 and C4B1 after proteolytic activation by C1s.

The fourth component of human complement is an essential part of the classical and lectin pathways performing multifunctional roles in both host defense and immune regulation. C4 is the most polymorphic member of the complement proteins, and complete deficiency is strongly associated with autoimmune disease, especially, systemic lupus erythematosus (SLE). Of the two C4 genes C4A, but not C4B, null alleles have been implicated as important independent disease susceptibility genes occurring in more than half of SLE patients. Whether and how this deficiency contributes to the development or pathology remains unclear. We do know that activation of C4 by C1s cleaves the thioester bond, thus inducing a conformational change that exposes numerous ligand-binding sites involved in functional activity. Structural comparison, among many other tools, plays an important role in predicting function. In this report, the tertiary structures of C4A and C4B were compared using near and far-UV circular dichroism, ANS fluorescence, site-specific monoclonal antibodies and isoelectric focusing. Negligible differences in the native proteins were found. However, the activated proteins were dissimilar in secondary and tertiary structure that was accompanied by significant differences in charge distribution and surface hydrophobicity. These conformational differences, together with known acceptor preferences, have functional implications for the association between C4A null alleles and SLE.

Alleles↗