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PubMed1982

Ultrastructure of cobra venom factor-dependent C3/C5 convertase and its zymogen, factor B of human complement.

The molecular architecture of the cobra venom factor (CVF)-dependent C3/C5 convertase (EC 3.4.21.47) of human complement was deduced from electron microscopy of the purified bimolecular complex (CVF,Bb) and its isolated subunits, CVF and Bb. Negatively stained CVF imaged as an irregularly shaped cylindrical structure, with approximate dimensions of 137 A x 82 A (length x diameter). The zymogen Factor B appeared globular with a diameter of about 80 A and its image suggested a bipartite structure of two compact, closely associated regions, one about twice as large as the other. Bb, the larger, catalytic site-bearing cleavage fragment of Factor B, revealed two globular domains, each 40 A in diameter, connected by a short linker region about 10 A long and thick. CVF and Bb could be distinguished in micrographs of the CVF,Bb complex: Bb attached to one end of the CVF molecule through only one of its two domains, and in an orientation making the long axes of both molecules approximately orthogonal. It is suggested the naturally occurring C3 convertases (C3b,Bb and C4b,2a) have a similar morphology.

Complement Activating Enzymes↗
PubMed1999

Rat complement factor I: molecular cloning, sequencing and expression in tissues and isolated cells.

Factor I (FI) is a regulatory serine protease of the complement system which cleaves three peptide bonds in the alpha-chain of C3b and two bonds in the alpha-chain of C4b thereby inactivating these proteins. The human protein and the recently characterized mouse factor I are heterodimers of about 88,000 MW which consist of a non-catalytic heavy chain of 50,000 MW which is linked to a catalytic light chain of 38,000 MW by a disulphide bond. For the screening of a rat liver cDNA library we used a hybridization probe produced by polymerase chain reaction (PCR) using degenerated primers which corresponded to conserved parts of the human and the murine factor I nucleotide sequences. One of the identified sequences, which had a length of 2243 base pairs (bp), contained the complete coding region and the whole 3' untranslated region. The length of the coding region in rat consisted of 1812 bp followed by a 3' untranslated region of 207 bp including the polyadenylation signal and the beginning of the poly A tail. Comparison of the rat cDNA-derived coding sequence revealed identities of 87% to the mouse and of 78% to the human FI nucleotide sequence. The translation product of rat FI mRNA was 604 amino acid residues (aa) in length with an identity of 85% to the mouse (603 aa) and 69% to the human protein (583 aa). The comparison of the molecular mass predicted by the primary structure and derived from rat FI isolated from rat serum as detected in immunoblot analyses suggested a glycosylation of more than 20% of the total mass of the FI protein. Expression studies using reverse transcription (RT)-PCR assays indicated that FI-specific mRNA could neither be identified in B cells, nor in T cells, monocytes or granulocytes from rat and human peripheral blood nor in rat peritoneal macrophages. These data were in agreement with the results of RT-PCR obtained with several human lymphoma cell lines (Jurkat, MOLT-4, HUT102, Wil 2-NS, Ramos, Raji, U937) all of which were devoid of FI-specific mRNA. In accord with our data from two rat hepatoma cell lines (FAO and H4IIE) and one from man (HepG2) only isolated rat hepatocytes (HC) but neither Kupffer cells (KC), hepatic stellate cells (HSC; Ito cells) nor sinusoidal endothelial cells (SEC) expressed FI-specific mRNA. FI mRNA was also detected in human umbilical vein endothelial cells (HUVEC) and in the uterus and small intestine of the rat. Spleen and lymph nodes did not contain any detectable FI-specific mRNA.

Amino Acid Sequence↗
PubMed1985

Polymorphism of the fourth component of complement in Graves' disease and type I diabetes mellitus.

The distribution of major histocompatibility complex (MHC) phenotypes in unrelated patients with Graves' disease or Type I diabetes mellitus and healthy controls was examined. HLA-B8 was increased in both the Graves' disease patients (p = .0018) and diabetes mellitus patients (p = .0246) relative to controls. Although C4A*QO is known to show strong linkage disequilibrium with HLA-B8, we could not demonstrate a difference in the frequency of this allele between either group of patients and the controls because the null C4A*QO cannot be accurately estimated from phenotype data. An unusual variant C4B*3 occurred three times in 117 controls, 10 times in 61 Graves' disease patients (p = .0012) and 13 times in 48 diabetic patients (p = 0.74 X 10(-5]. Although C4B*3 is known to show strong linkage disequilibrium with HLA-B15, the frequencies of B15 in the two patient groups did not differ from that of the controls considered here. When 28 MHC haplotypes (supratypes) from 14 unrelated patients with Type I diabetes were compared with 27 non-diabetes supratypes occurring in the same families but not in the patients, 8/28 Type I diabetes supratypes were C4AQOB1+, HLA-B8+, and 4/28 were C4B*3+, whereas 1/27 non-diabetes supratypes was C4AQOB1+, B8+, and 0/27 was C4B*3+. Of the four C4B*3+ diabetes positive supratypes, two were HLA-B15, one was B5 and one was B40. Finally, the second haplotype of 11 diabetes mellitus patients known to carry one high risk C4 haplotype was investigated. The second haplotype was the common type C4A3B1 in only 3/11, whereas at least 5/11 had second haplotypes containing C4B*QO, C4B*3, C4B*2 or C4A*4.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1988

Interaction of nucleophilic compounds with complement component C4.

Drugs which induce systemic lupus erythematosus as a toxic side effect have been shown to inhibit the covalent binding of C4, which is an important event in immune complex clearance in normal individuals. Human C4 is encoded at two polymorphic loci, C4A and C4B within the Major Histocompatibility Complex and patients with idiopathic SLE are more likely to have a non-functional (null) C4A gene. The C4A and C4B gene products differ in reactivity with C4A being more reactive with nitrogen nucleophiles, including hydralazine and isoniazid (drugs which induce SLE), than with oxygen nucleophiles. We have established an assay system which allows the effect of nucleophiles on C4 in animal sera to be investigated. It has been found that in comparing reactivity of guinea-pig C4 with human C4A and human C4B that guinea-pig C4 is like human C4A and shows greater reactivity towards nitrogen nucleophiles than towards oxygen nucleophiles. This suggests that the guinea-pig should be a good animal model for drug-induced SLE.

Animals↗
PubMed1999

Function of human factor H and I on xenosurface.

The cell membrane-bound forms of mini-factor H with 1-4 short consensus repeats (fH-PI) and factor I (fI-PI) were constructed. Swine endothelial cell (SEC) lines and Chinese hamster ovary (CHO) cell expressing fH-PI or fI-PI were established and confirmed by flow cytometry. The cell lysate of the SEC line expressing fH-PI showed strong cofactor activity for the cleavage of C3b, and fI-PI demonstrated the protease activity for C4b and C3b not only in the fluid phase but also on the cell membrane. In addition, fH-PI blocked human complement-mediated cell lysis by approximately 30-40%. An SEC line with a low expression of fI-PI showed a weak inhibition of cell lysis in human serum, whereas a CHO cell transfectant with a high expression of fI-PI showed over a 60% inhibition of cell lysis. The results suggest that fH-PI and fI-PI have potential for use in clinical xenotransplantation.

Animals↗
PubMed1992

Pig apolipoprotein R: a new member of the short consensus repeat family of proteins.

Apolipoprotein R (apoR) is a 23-kDa protein found on very low-density lipoprotein (VLDL), on chylomicrons, and in the d > 1.21 g/mL fraction of pig plasma. The plasma concentration of apoR is 5.1 micrograms/mL, with 11.5% of apoR found on VLDL. In vitro, apoR can transfer from the d > 1.21 g/mL infranatant onto artificial lipid emulsions or human chylomicrons but not onto human VLDL. An apoR cDNA was isolated from a pig liver lambda gt11 expression library. DNA sequence analysis of the apoR cDNA revealed 67% identity with the 3'-terminal region of human C4b-binding protein alpha-chain cDNA (C4BP alpha). C4BP alpha is a 70-kDa glycoprotein that regulates both the coagulation and the complement cascades. In plasma, C4BP alpha exists as disulfide-linked multimers consisting of seven C4BP alpha chains and a single C4BP beta chain. Like C4BP, apoR forms high molecular weight disulfide-linked complexes in plasma. However, unlike C4BP alpha, apoR complexes do not appear to contain C4BP beta. ApoR mRNA was detected in pig liver, spleen, lung, bone marrow, and lymph node, but was absent in intestine and white blood cells. This distribution is consistent with the production of apoR in terminally differentiated macrophages but not in blood monocytes. ApoR mRNA was not detected in RNA isolated from human liver or lung. ApoR may be a lipoprotein-borne regulator of either the coagulation or the complement cascades.

Amino Acid Sequence↗
PubMed1981

Genetic analysis of C4 deficiency.

The inherited structural polymorphism in the fourth component of complement was studied in the family of a child with homozygous deficiency of this protein. It was shown that a number of family members, including the child's parents, carried a C4 haplotype, C4A*QO C4B*QO, that produced no detectable protein at either the Chido (C4B) or Rodgers (C4A) locus. The family contained individuals with one, two, three, or four expressed C4 genes, and the mean serum C4 levels in such individuals roughly reflected the number of structural genes.

Chromosome Mapping↗
PubMedDate not supplied

The effect of low-density lipoprotein apheresis on plasma thrombomodulating factors.

The authors have investigated the effects of double-membrane filtration with hollow fiber membranes made of different artificial materials and low-density lipoprotein (LDL)-adsorbent dextran sulfate cellulose (DS) columns on coagulation-related proteins and complement components to evaluate their hemocompatibility. All membrane filters showed similar sieving effects, which depended upon the molecular weights of the proteins. In the double-membrane filtration system, free protein S, protein C, antithrombin III, and alpha 1-antitrypsin were returned to the intracorporeal circulation, whereas alpha 2-macroglobulin and fibrinogen were almost completely removed from the circulation; C4b-binding protein (C4BP)-protein S complexes were also trapped by the second membrane, and in some instances were even blocked by the first membrane, if it was made of material that activated the classic pathway of the complement system. The DS column adsorbed C4BP-protein S complex, but free protein S was almost completely recovered in the eluate.

Antithrombin III↗
PubMed2002

Structure and function of complement C5 convertase enzymes.

The multisubunit enzymes of the complement system that cleave C5 have many unusual properties, the most striking of which is that they acquire their specificity for C5 following cleavage of another substrate C3. C5 convertases are assemblies of two proteins C4b and C2a (classical or lectin pathways) or C3b and Bb (alternative pathway) and additional C3b molecules. The catalytic complexes (C4b, C2a or C3b, Bb) are intrinsically unstable ( t (1/2)=1-3 min) and the enzymes are controlled by numerous regulatory proteins that accelerate this natural decay rate. Immediately after assembly, the bi-molecular enzymes preferentially cleave the protein C3 and exhibit poor activity toward C5 (a K (m) of approx. 25 microM and a C5 cleavage rate of 0.3-1 C5/min at V (max)). Efficient C3 activation results in the covalent attachment of C3b to the cell surface and to the enzyme itself, resulting in formation of C3b-C3b and C4b-C3b complexes. Our studies have shown that deposition of C3b alters the specificity of the enzymes of both pathways by changing the K (m) for C5 more than 1000-fold from far above the physiological C5 concentration to far below it. Thus, after processing sufficient C3 at the surface of a microorganism, the enzymes switch to processing C5, which initiates the formation of the cytolytic membrane attack complex of complement.

Animals↗
PubMed1983

Extended HLA/complement allele haplotypes: evidence for T/t-like complex in man.

The chromosomal distribution of alleles for HLA-A,-B,-C, and -DR and the serum complement protein alleles of factor B and C2 and C4 was studied in normal Caucasian families. Eight combinations of HLA-B, DR, BF, C2, C4A, and C4B markers were found to occur in haplotypes at frequencies significantly higher than expected. In these combinations, which were defined as extended major histocompatibility complex haplotypes, HLA-A showed limited variation. A possible mechanism for the maintenance of extended haplotypes are human analogs of murine t mutants which are characterized by crossover suppression and male transmission bias. One human 6p haplotype, HLA-B8, DR3, SCO1, GLO 2, was found to be transmitted from males to 83% of their offspring. The same haplotype with GLO 1 had no transmission bias. It is suggested that this GLO 2-marked chromosome is a human analog of a murine t mutant.

Alleles↗
PubMed1993

Extended major histocompatibility complex haplotypes in celiac patients in the west of Ireland.

The highest reported prevalence of celiac disease (gluten-sensitive enteropathy) is found in the West of Ireland. Recent genetic data have suggested that major histocompatibility complex-linked loci may have a dominant genetic effect for disease susceptibility in this population compared with a recessive effect in other groups. To further understand the role of the MHC in celiac disease in the West of Ireland, we analyzed markers for 22 MHC haplotypes from celiac patients and compared them with 18 nontransmitted haplotypes found in the parents of celiac children, and with reported haplotypes from other populations. An extended MHC haplotype including [HLA-B8, DR3, DQw2, Bf*S, C4A*Q0, and C4B*1] accounted for 50% of celiac haplotypes but only 27% of nontransmitted parental haplotypes. Compared with other reported haplotypes in celiacs, patients from the West of Ireland show a higher prevalence of HLA-A1 as a component of this extended haplotype, suggesting that although the core haplotype is similar between Irish patients and others, the celiac population in the West of Ireland differs at other HLA loci. We did not observe any other common haplotypes among our patients unlike the situation in other populations. These differences may underlie the possible dominant effect of HLA-linked loci and the unusually high prevalence of celiac disease in the Irish population. We also found that the serum levels of complement components C3c, C4, and factor B were significantly lower among celiac patients than nonceliacs. The lower serum level of C4 appears to be related to the presence of deletions and null alleles at the C4A and C4B loci in celiacs.

Adult↗
PubMed1983

Identification and structural characterization of two incompletely processed forms of the fourth component of human complement.

Immunoprecipitates of human C4 from EDTA-plasma were incubated with [14C]methylamine and analyzed by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis and fluorography. In addition to finding label in the alpha-chains of the secreted (C4s) and predominant plasma (C4p) forms of C4, two additional molecules with apparent molecular weights of approximately 168,000 (p168) and approximately 125,000 (p125) covalently incorporated methylamine, indicating the presence of an internal thioester bond. These two molecules were present at a concentration of approximately 5% of total plasma C4 and were not immunoprecipitated by antisera to C3 or alpha 2-macroglobulin. A human hepatoma-derived cell line (HepG2), in addition to synthesizing C4s and small quantities of the polypeptide precursor of C4 (pro-C4), was found to secrete p168 and p125 at concentrations of 14 +/- 4.8 and 21 +/- 9.2% (mean +/- SD), respectively, of total secreted C4. These molecules were not found intracellularly. Both molecules were present on reduced, but not nonreduced, SDS-polyacrylamide gels. Chido (C4B) and Rodgers' (C4A) alloantisera precipitated the C4A and C4B variants of pro-C4, p168, p125, and C4s. Both tryptic and Staphylococcus aureus V8 protease peptide analyses showed homology between p168 and the beta- and alpha-chains and between p125 and the alpha- and gamma-chains. Partial NH2-terminal sequencing revealed that the beta-chain was NH2-terminal in p168 and that the alpha-chain was NH2-terminal in p125. Taken together, these data indicate that p168 and p125 represent uncleaved beta-alpha- and alpha-gamma-fragments of pro-C4, respectively. Thus, in most individuals, plasma C4 consists of five structurally distinct molecules, the single polypeptide precursor (pro-C4), the three-subunit secreted (C4s) and predominant plasma (C4p) forms of C4, and two incompletely processed two-subunit molecules with uncleaved beta-alpha- (p168) or uncleaved alpha-gamma (p125)-subunits. In addition, all five molecules are observed for both C4A (Rodgers) and C4B (Chido) structural genes.

Amino Acid Sequence↗
PubMed1986

A product of the C4B locus lacking hemolytic activity.

An unusual C4B allotype, C4B 4I, was identified in a study of C4 polymorphism in Japanese. This variant was defined as C4B using a murine monoclonal antibody specific for the C4d region of C4B. Hemolytic assay, however, revealed that the C4 variant, C4 BI was hemolytically inactive in contrast to other well-defined C4B locus products.

Alleles↗
PubMed2003

Membranoproliferative glomerulonephritis associated with hereditary deficiency of the 4th component of complement.

A 10-year-old female patient was found positive for urine protein and occult blood on Japanese school urinary screening. Examination of the blood was normal except low values of the complement system with CH50 13.5 U/ml, C3 45 mg/dl and C4 3 mg/dl. Renal biopsy demonstrated a focal membranoproliferative glomerulonephritis (MPGN). As for the activity of each component of the complement in the early stage of the disease, the C4 activity was markedly declined and the activity of classical pathway component was also decreased, but the activity of alternative pathway component was normal. On the HLA examination, the patient demonstrated a C4 double null haplotype (C4A2, Q0, BQ0 phenotype). A null C4 gene at both the C4A and C4B loci was found in her mother, aunt and grandfather on the mother's side and C4B null allele in her father and her grandmother on the mother's side. The development of the disease is found in 1 case and not in the other, although both have the genetic defect and the mechanism by which the complement is activated remains unknown. Thus, there appear to be many subjects to be studied as to the relationship between the defect of C4 gene and immune competence.

Child↗
PubMed1983

The complement-mediated binding of soluble antibody/dsDNA immune complexes to human neutrophils.

The complement-mediated binding of soluble antibody/3H-dsDNA immune complexes (prepared in vitro) to human polymorphonuclear leukocytes (PMN) has been investigated quantitatively. Studies with isolated complement components in conjunction with experiments on the binding of these complexes to human red blood cells suggest that the binding to both cell types is mediated predominantly by CR1 (C4b-C3b) receptors but that CR3 (iC3b or C3d-g) receptors may play a role in binding to PMN but probably not to RBC. Our results also indicate that under the standard conditions of these assays (37 degrees C, 20 to 40 min incubations) there is no significant internalization of the soluble antibody/dsDNA immune complexes after they are bound by the PMN.

Antigen-Antibody Complex↗
PubMed1987

Persistently circulating C3 nephritic factor (C3 NeF)-stabilized alternative pathway C3 convertase (C3 CoF) in serum of an 11-year-old girl with meningococcal septicemia--simultaneous occurrence with free C3 NeF.

Hemolytic complement was found to be absent in the serum of an 11-yr-old girl (R.N.) with meningococcal septicemia. C1, C4, and C2 were slightly decreased, C3 was absent, C5-C9 within the normal range. B levels immunochemically and electrophoretic mobility of B were normal. C3d was greater than 1000% of a pooled EDTA-plasma standard indicating hypercatabolism of C3. On incubation of the patient's serum with normal human serum activation of C3 occurred even in the presence of 0.04 M EDTA. The amount of C3b generated was, however, greater without any chelating agent or in Mg-EGTA. On gel filtration of the serum two protein containing peaks were found to be responsible for activation of C3: the IgG containing peak was able to activate C3 in normal human serum without chelating agents and in Mg-EGTA but not in the presence of EDTA. The IgM-containing peak activated the third component of complement even in the presence of EDTA. The factor responsible for this phenomenon was termed C3 converting factor (C3 CoF). The IgG fraction of the patients serum caused activation of C3 in Mg-EGTA. However, in the presence of EDTA no activation of C3 could be induced even if physiological concentrations of the patients IgG were added to normal human EDTA-plasma. Thus the activity of the patient's IgG did not differ from typical C3 nephritic factor. The decay of C2 in EAC42 intermediates in the presence of the patient's IgG was uninfluenced indicating that it did not carry autoantibody activity against the classical pathway convertase C4b,2a, an activity recently termed NFc.(ABSTRACT TRUNCATED AT 250 WORDS)

Child↗
PubMed1994

Deficiency of the fourth component of complement (C4): a family case.

In this report, an apparently healthy 38-year-old woman with a remarkably low serum C4 value is described together with other family members who had moderately low serum C4. Plasma C4 typing disclosed that the proband inherited two C4B "null" haplotypes. In addition, Southern blot analysis of the C4 gene indicated that the C4A gene was partially deleted on one of these two haplotypes in the proband. We thus concluded that a de novo deletion on the inherited half-null haplotype was the likeliest cause of the low C4 level.

Adult↗
PubMed1985

Haplotype study on C4 polymorphism in Japanese. Associations with MHC alleles, complotypes, and HLA-complement haplotypes.

Genetic polymorphism of the fourth component of human complement (C4) was investigated in 83 Japanese families which have been typed for HLA-A,-B,-C,-DR, C2, and BF. Four common C4A alleles and four common C4B alleles were observed. The allele frequencies estimated from unrelated parents were as follows: C4A3, 0.686; A4, 0.132; A2, 0.106; AQ0, 0.067; ARares, 0.009; C4B1, 0.587; B2, 0.167; B5, 0.088; and BQ0, 0.158. Eight different C4 haplotypes were observed with frequencies of more than 0.01. The estimated haplotype frequencies were as follows: C4A3-B1, 0.513; A4-B2, 0.114; A2-BQ0, 0.106; A3-B5, 0.088; AQ0-B1, 0.059; A3-BQ0, 0.047; A3-B2, 0.038; A4-B1, 0.015; and Rares, 0.021. Strong positive gametic associations were found in the following C4-HLA haplotypes: C4A2BQ0-A24, C4A2BQ0-Bw52, C4A3B5-Bw54, C4A3B5-Bw59, C4A4B2-Bw46, C4A3B5-Cw1, C4A2BQ0-DR2, and C4A3B5-DR4. Eleven complotypes were observed with frequencies of more than 0.01. C4A2BQ0 and C4A3B5 were exclusively associated with BFS-C2C. BFF was associated with C4A3B1. C2AT, C2B, and C2BH were associated with C4A3B1, A4B2, and C4A3B1, respectively. Eight different HLA-complement haplotypes were found to be characteristic of Japanese. These combinations are considerably different from those reported in Caucasoid populations.

Alleles↗