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At least 163 records · Page 9Linked to original sources
PubMed1978

Hereditary C2 deficiency associated with immune complex disease.

A patient presenting with a syndrome probably due to immune complex deposition was investigated and found to possess an inherited C2 complement deficiency. Family studies indicated that the deficiency was transmitted as an autosomal recessive trait. HLA typing for the HLA-A and HLA-B specificities and HLA-D specificities indicated a close linkage between the HLA and C2 genes, as has been described elsewhere. The HLA-A and B locus specificities HLA-AW25 and HLA-B18 were coded for by each of the two chromosomes carrying the C2(0) gene. However, the two chromosomes differed at the HLA-D locus, as one coded for HLA-DW2 whilst the other did not. This case, therefore, provides a unique haplotype and may be of importance in mapping the C2(0) locus, as it suggests that the gene order on chromosome 6 is HLA-D, C2(0), HLA-B, HLA-A. Extensive complement component assays indicated that utilization of complement in the patient was occurring via the alternate complement pathway. It is suggested that, as a result of the C2 deficiency, infections with viruses and other agents could lead to an immune complex disease due to an impaired capacity to effectively eliminate circulating complexes.

Adult↗
PubMed1986

Simple method for preparing the cellular intermediate EAC14, and its use for estimation of the second component of complement.

Sensitized erythrocytes carrying the first and fourth components of complement (EAC14) were prepared by incubating optimally sensitized sheep erythrocytes with normal serum appropriately diluted in Mg2+-free diethylbarbiturate buffer containing Ca2+. EAC14 cells so prepared were found to be suitable for use in estimating the second component of complement (C2) in human serum, and the method is described here.

Animals↗
PubMed1981

Level of complement activity and components C1, C4, C2, and C3 in complement response to bacterial challenge in malnourished rats.

In experimentally induced malnutrition in rats, there was no significant difference between the measured level of complement activity of the classical pathway (50% hemolytic complement [CH50]) and that of the alternative pathway (ACH50), although the levels of complement components C1, C4, C2, and C3 were depressed significantly. The complement activity showed a temporary elevation with a peak at 2 or 3 days after bacterial challenge with Staphylococcus aureus in rats, and we call this the complement response. After 3 days, CH50 and C3 in the malnourished rats and ACH50, CH50, and C3 in the well-nourished rats showed a significant increase, and C1, C4, and C2 in both groups tended to elevate. On the basis of these observations, the significance of the elevation of C3 in the complement response to bacterial infection showed a strong influence by enhancing the activation of both the classical and the alternative pathways, since C3 is known to be the junction of both complement pathways. In this way, C3 responded to an earlier stage than did the other components and may contribute to maintaining the body defense system against infection.

Animals↗
PubMed1980

Deficiency of the second component of complement. Its occurrence with membranoproliferative glomerulonephritis.

We studied glomerulonephritis in a child with a deficiency of the second component of complement (C2) who was without clinical or serologic evidence of systemic disease. The clinical course was severe, with malignant hypertension and terminal renal failure when the child was 14 years old. Results of histologic studies were typical of membranoproliferative glomerulonephritis with subendothelial deposits. Immunofluorescence microscopy showed diffuse and intense localization of IgG, C1q, and C4 as granular deposits along the glomerular capillary walls and within the mesanguim. Diffuse deposits of C3 were also found along the capillary walls. Nine months after transplantation, the graft biopsy specimen showed glomerular lesions with IgG, C1q, C4, and C3 deposits, which suggests the possibility of a recurrence. The analysis of the previously reported cases of glomerulonephritis with C2 deficiency showed variable, but generally mild, glomerular lesions. Progression of the glomerulonephritis to severe renal insufficiency, as in the present case, is exceptional.

Adolescent↗
PubMed1983

Kinin formation in hereditary angioedema plasma: evidence against kinin derivation from C2 and in support of "spontaneous" formation of bradykinin.

Hereditary angioedema (HAE) is due to a functional deficiency of the inhibitor of the activated first component of complement (C1 INH). This abnormality is thought to be responsible for the generation of a kininlike peptide in HAE plasma that is derived from the second component of complement (C2). Specifically, a combination of C2 cleavage by C1s and C2 fragment cleavage by plasmin has been reported to generate a kinin that is distinguishable from bradykinin. We have attempted to generate this peptide by activating the classical complement pathway by incubation of plasma with immune complexes and then adding plasmin or by incubating purified C1s with C4 and C2 and then adding either plasmin or trypsin. We performed a total of 13 experiments, and in no case was a kininlike molecule generated as assessed by contraction of the estrus rat uterus. However, incubation of EDTA-treated HAE plasma at 37 degrees C for time intervals up to 1 hr progressively generated a smooth muscle-contracting activity. This activity was resistant to tryptic digestion but was destroyed after incubation with carboxypeptidase B, an inhibition profile consistent with that of bradykinin. We therefore propose that bradykinin alone, or in combination with other factors heretofore unrecognized, might be responsible for the swelling that is characteristic of hereditary angioedema.

Angioedema↗
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↗
PubMed1981

Renal transplantation in a patient with hereditary deficiency of the second component of complement.

The HLA haplotype A 10,B18 has been associated with hereditary deficiency of the second component of complement(C2). In an effort to detect individuals homozygous for C2 deficiency, a thorough audit of HLA serotyping results in 3,100 individuals was performed, and a single patient homozygous for the A10, B18 haplotype was identified. Detailed complement studies in this patient's serum and plasma revealed previously undetected selective absence of C2 antigen and haemolytic activity, and a hereditary basis for this deficiency was indicated by half-normal levels of C2 haemolytic activity in both of his children. The patient was of special interest in that he had previously developed renal failure which was treated by cadaver kidney transplantation. C2 antigen was undetectable in serum and plasma samples taken prior to and up to 9 months following transplantation. This experience suggests that HLA serotyping can be a valuable screening technique for the detection of individuals with C2 deficiency, and that renal transplantation does not reconstitute normal levels of C2.

Adult↗
PubMed1982

Prostaglandins and prostaglandin synthetase inhibitors regulate the synthesis of complement components by human monocytes.

The addition of prostaglandins E2 (PGE2), PGD2, PGI2, 6-keto PGF1 alpha and thromboxane B2 (TXB2) to human monocyte cultures, inhibited the production of the second component of complement (C2). PGF2 alpha did not significantly affect C2 production. As the former compounds, but not the latter increase intracellular cAMP, it was thought that the effect was mediated by this action. The addition of cyclo-oxygenase and lipoxygenase inhibitors to monocyte cultures enhanced the synthesis of complement components and other proteins in a dose-dependent fashion: cyclo-oxygenase inhibitors being more potent in this regard than lipoxygenase inhibitors. The enhancing effect of cyclo-oxygenase inhibitors paralleled their ability to inhibit cyclo-oxygenase activity. The enhancement of C2 synthesis by the addition of cyclo-oxygenase and lipoxygenase inhibitors was reversed by the addition of PGs to the cultures. It is concluded that the production of PG by monocytes could provide an endogenous mechanism to control the synthesis of complement components and other proteins.

Arachidonic Acids↗
PubMed1996

Incomplete functional deficiencies of the fourth (C4) and second (C2) components of complement in a patient with linear frontoparietal scleroderma and his family. Deficiencies determined by a gene not linked to human leukocyte antigen system.

BACKGROUND: In a previous study, a patient suffering from linear frontoparietal scleroderma and some of his family members were found to have an incomplete functional deficiency of the second component (C2) of complement (C). In this study, the proband and the rest of his family members were investigated for functional deficiencies of C2 and the fourth component of C (C4). A search for null alleles of C2 (C2*Q0) and C4 (C4*Q0) was made to find out whether their occurrence is responsible for incomplete functional deficiencies. HLA analysis was performed to find out whether deficiencies are linked to HLA alleles known to be associated with C4*Q0 and C2*Q0. Possible large deletions at C4 and 21-hydroxylase (21-OH) gene loci were also investigated in some family members. OBSERVATIONS: The proband had a combined functional deficiency of C4 and C2. Some of his family members had a partial functional deficiency of C4, some of C2 and some of C4 and C2; none had null alleles of C2 (C2*Q0), factor B (B*Q0) or C4B (C4B*Q0). C4*Q0 or functional C4 deficiency in this family was not associated with HLA-A1;B8;DR3 alleles. C2 deficiency was also not associated with HLA antigens known to be associated with type I and II C2 deficiencies. No gene deletion or unusual polymorphism at C4A and 21-OHA loci could be seen by restriction fragment length polymorphism (RFLP) studies. CONCLUSIONS: Combined and isolated partial functional deficiencies of C4 and C2 observed in the proband and many of his family members were not caused by C activation or null alleles. They were not linked to HLA system and were reminiscent of those observed previously in a family in which C4 deficiency was determined by a gene not linked to the HLA system.

Alleles↗
PubMed1981

[Comparison of consumption kinetics of the C4 and C2 components of complement by immune complexes "in vitro" (author's transl)].

We study the consumption kinetic of the fourth and second component of complement by the C1 esterase in different systems with EA or EAC1 and fresh NHS, or functionally purified C4 and C2 preparations. The results show that the two kinetics are similar with a comparable decrease in both C4 and C2 activities till 90 seconds (the mean residual values are from 21 to 34% at this time). The results show moreover that the consumption of the C2 component requires necessarily the presence of the C4 component. The C4 reaction kinetic compared with the C2 "in vitro" one refutes the hypothesis of a greater sensitivity of the C4 component compared with the C2, for the enzymatic action of the C1 esterase. So, a discrepancy in the reaction speed cannot be evoked in order to explain the obvious C4 depression in the consumption hypocomplementemia, and different hypothesis have to be investigated, such as, for instance, a lower synthesis rate of the C4 component compared with the C2 one.

Animals↗
PubMed1997

Combined heterozygous deficiency of the classical complement pathway proteins C2 and C4.

Genetic deficiencies of components of the classical pathway of complement activation are associated with an increased risk for the development of autoimmune and immune complex-mediated diseases. In the present study we report on the molecular and clinical features associated with combined heterozygous C4 and C2 deficiency in 15 individuals investigated within six families. Approximately 30% of the individuals manifested SLE or another autoimmune condition. Heterozygous C2 deficiency was related to a 28-bp deletion in the C2 gene (C2 deficiency type I), in most cases within the HLA-A25 B18 C2Q0 BfS C4A4B2 DR2 haplotype. Among 13 partial C4-deficient haplotypes transmitted, 8 carried C4A*Q0 alleles and 5 C4B*Q0 alleles. In seven cases the C4A*Q0 alleles were associated with a deletion of the C4A/CYP21P genes within the HLA-B8 C2C BfS C4AQ0B1 DR3 haplotype. In three cases, the C4B*Q0 allele was associated with a deletion of the C4B/CYP21P genes within the HLA-B18 C2C BfF1 C4A3BQ0 DR3 haplotype. In the other cases, C4A*Q0 or C4B*Q0 was dependent on as yet uncharacterized defects in the C4 gene or in C4 gene expression. In view of the relatively high frequency of heterozygous C4 deficiency in the normal Caucasian population, the expected frequency of the combined deficiency should approximate 0.001.

Adult↗
PubMed1978

Inherited deficiency of second component of complement and HLA haplotype A10,B18 associated with inflammatory bowel disease.

A patient with inflammatory bowel disease and sacroiliitis had haplotypes A10,B18 and Aw32,b18 at the major histocompatibility locus. Serum total complement and C2 hemolytic complement activities were undetectable; levels of the remaining C1-C9 components were normal. The parents, both siblings, and a child each had half-normal levels of C2 and either the A10,B18 or the Aw32,b18 hla haplotype. In a second unrelated family, an only child and both parents developed inflammatory bowel disease. The father and child had HLA haplotype A10,B18, but, along with the mother, each had normal serum levels of hemolytic C and C2. Homozygous C2 deficiency, often in association with the A10,B18 haplotype, has previously been linked with various autoimmune diseases and with propensity to infection. Our findings suggest that C2 deficiency or this haplotype also may predispose to inflammatory diseases of the intestine.

Adult↗
PubMed1987

Human complement proteins D, C2, and B. Active site mapping with peptide thioester substrates.

The specificity and reactivity of complement serine proteases D, B, Bb, C2, and C2a were determined using a series of peptide thioester substrates. The rates of thioester hydrolysis were measured using assay mixtures containing the thiol reagent 4,4'-dithiodipyridine at pH 7.5. Each substrate contained a P1 arginine residue, and the effect of various groups and amino acids in the P2, P3, P4, and P5 positions was determined using kcat/Km values to compare reactivities. Among peptide thioesters corresponding to the activation site sequence in B, dipeptide thioesters containing a P2 lysine residue were the best substrates for D. Extending the chain to include a P3 or P4 amino acid resulted in loss of activity, and neither the tripeptide nor the tetrapeptide containing the cleavage sequence of B was hydrolyzed. Overall, D cleaved fewer substrates and was 2-3 orders of magnitude less reactive than C1s against some thioester substrates. C2 and fragment C2a had comparable reactivities and hydrolyzed peptides containing Leu-Ala-Arg and Leu-Gly-Arg, which have the same sequence as the cleavage sites of C3 and C5, respectively. The best substrates for C2 and C2a were Z-Gly-Leu-Ala-Arg-SBzl and Z-Leu-Gly-Leu-Ala-Arg-SBzl, respectively, where Bzl is benzyl. B was the least reactive among these complement enzymes. The best substrate for B was Z-Lys-Arg-SBzl with a kcat/Km value of 1370 M-1 s-1. The catalytic fragment of B, Bb, had higher activity toward these peptide thioester substrates. The best substrate for Bb was Z-Gly-Leu-Ala-Arg-SBzl with a kcat/Km similar to C2a and 10 times higher than the value for B. Both C2a and Bb were considerably more reactive against C3-like than C5-like substrates. Bovine trypsin hydrolyzed thioester substrates with kcat/Km approximately 10(3) higher than the complement enzymes. These thioester substrates for D, B, and C2 should be quite useful in kinetic and active site studies of the purified enzymes.

Animals↗
PubMed1975

Complement inhibitor(s) released by leukocytes. I. Pretreatment of sheep erythrocytes with supernatants of mouse spleen and thymus cells inhibit whole complement activity and C2 utilization.

Sheep erythrocytes pretreated with supernatants of mouse spleen or thymus cells become resistant to lysis by guinea pig complement. The inhibitory activity (IA) reduces the utilization of C2 by EAC14. Because IA binds to the surface of sheep erythrocytes and does not inhibit C1 irreversibly, it is probably a hitherto undescribed inhibitor of complement.

Animals↗
PubMed1998

Requirement for the alternative pathway as well as C4 and C2 in complement-dependent hemolysis via the lectin pathway.

Mannan-binding lectin (MBL) is a C1q-like molecule opsonic for several micro-organisms. MBL can activate C4, C2, and later acting complement components in the presence of serine proteases similar to but distinct from C1r and C1s via the lectin pathway of complement activation. We report here that mannan-coated MBL-sensitized erythrocytes are lysed via the lectin pathway in human serum-Mg-EGTA. The surprising occurrence of MBL-initiated lysis in the absence of calcium contrasts with the calcium requirement for C1q-initiated activation of C4 and C2. C2 is required, and lysis is significantly enhanced when indicator cells presensitized with C4 and then coated with mannan (EAC4-M) are used. The alternative pathway also is required, since lysis is lost when either factor D or factor B is removed and is restored upon reconstitution with the purified protein. Even though MBL is a C-type lectin, it is retained on mannan-coated erythrocytes in the absence of calcium. This contrasts with the absence of calcium-independent retention on mannan immobilized on polystyrene plates or beads, and helps explain the MBL-initiated hemolysis in Mg-EGTA. These investigations show that the alternative pathway as well as C4 and C2 of the classical pathway are required for complement-dependent hemolysis via the lectin pathway and provide a method for assay of lectin pathway-mediated complement activity in human serum that should be useful in unraveling the molecular interactions of this pathway.

Calcium↗
PubMed1975

Inherited C2 deficiency and systemic lupus erythematosus: studies on a family.

A patient is described in which an inherited defect in the synthesis of C2 complement component coexisted with the disease systemic lupus erythematosus. The family studies show evidence of the autosomal recessive nature of the inheritance of the C2 synthesis defect. Of particular interest was the finding of a great-aunt who also had homozygous C2 deficiency. This great-aunt suffered from discoid lupus erythematosus as well. The occurrence of various autoantibodies in the serum from the family members, the typing for blood groups, HL-A antigens, and some serum protein markers are reported and discussed. The C2 deficiency may be a critical defect in the host defenses to infection that predisposed to the development of autoimmune disease.

Adolescent↗
PubMed1993

Activation of the C4 and C2 components of complement by a proteinase in serum bactericidal factor, Ra reactive factor.

Ra-reactive factor (RaRF) is a C-dependent bactericidal factor that binds specifically to LPS of Ra chemotype strains of Salmonella and kills the bacteria by triggering the C cascade. In the present study, we investigated the components of mouse RaRF that activate C4 and C2. The RaRF bound to LPS-coated E, and activated the C4 on the surface of E, causing the C4 to bind to the cells. Diisopropyl fluorophosphate (DFP) bound to RaRF and inhibited its ability to activate C4 and C2. Cleavage of the alpha-chain of C4 by RaRF generated a polypeptide with a size similar to that of the alpha'-chain of C4b, which is known to be a product of the cleavage of C4 by C1s subcomponent of C1. A fraction with the ability to activate C4 and C2 was separated from RaRF by gel-permeation chromatography in the presence of EDTA and acetonitrile. This fraction contained a DFP-binding polypeptide with an apparent m.w. of 100,000. This polypeptide is not the C1s in mouse C1 because the sizes of this polypeptide and of the fragments produced by its reduction were different from those of DFP-binding proteinases in mouse C1. These results indicate that mouse RaRF contains a C1s-like serine proteinase that is capable of activating C4 and, probably, C2.

Animals↗