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PubMed1992

Characterization of recombinant C1 inhibitor P1 variants.

Twelve human C1 inhibitor P1 variants were constructed by site-directed mutagenesis of the codon for arginine 444 and were expressed in COS-1 cells to analyze the functional properties. The ability to bind to target proteases, as well as potential substrate-like behavior, was investigated with radioimmunoassays. The P1-Lys variant retained binding capacity toward C1s, plasmin, and kallikrein. In addition, complex formation with C1s was detected for P1-Asn and P1-His. All other P1 substitutions resulted in C1 inhibitor variants that neither complexed with nor were inactivated by C1s, kallikrein, beta-factor XIIa, or plasmin. Electrophoretic studies confirmed that P1-Lys and P1-His can form sodium dodecyl sulfate-resistant complexes with C1s. In contrast, the C1s-P1-Asn complex dissociated upon addition of sodium dodecyl sulfate. Kinetic experiments by the method of progress curves generated association rate constants (kon) with C1s of 4.2 x 10(4) M-1 s-1 for recombinant wild-type C1 inhibitor and 1.7 x 10(4) M-1 s-1 for P1-Lys. For P1-Asn and P1-His, kon was decreased approximately 100-fold. The results from inhibition experiments were compatible with a model of reversible inhibition, although the observed dissociation rate for wild-type C1 inhibitor is too low (1-2 x 10(-6) s-1) to be physiologically relevant. The overall inhibition constant (Ki) was estimated to be 0.03 nM. With P1-Asn, reversible inhibition could be demonstrated directly upon dilution of preformed complexes; the observed dissociation rate constant was 3.2 x 10(-4) s-1; and Ki increased to approximately 380 nM. These findings are discussed in relation to inhibitor specificity and inhibition mechanism.

Amino Acid Sequence↗
PubMed1977

Characterization of C-reactive protein and the complement subcomponent C1t as homologous proteins displaying cyclic pentameric symmetry (pentraxins).

Partial amino acid sequences of rabbit C-reactive protein, a peptide derived from human C-reactive protein by cyanogen bromide cleavage, and the C1t subcomponent of the human complement component C1 have been determined. Extensive sequence homology between these proteins establish their evolutionary relationships. In addition, examination of C-reactive proteins by negative-stain electron microscopy revealed that the protein is composed of five subunits arranged in cyclic symmetry. This structure is similar to that reported for both C1t and the amyloid P-component. The extensive structural relationship suggests similar or overlapping functions and the term pentraxin is proposed to describe these homologous proteins.

Amino Acid Sequence↗
PubMed1985

Complement-mediated hemolytic activity of succinylated concanavalin A: preparation and activity of cell intermediates.

Succinylated concanavalin A (SCon A) lyses sheep erythrocytes (E) in the presence of complement, whereas the native tetravalent lectin, Con A, is inactive. We have studied the ability of E-SCon A (ES) to interact with early acting guinea pig (gp) or human (hu) complement components (C1, C2, C4) and found that cell intermediates ESC1, ESC4, ESC14, and ESC142 can be generated that are analogous to intermediates conventionally prepared with E and rabbit IgM (pentameric) anti-Forssman antibody. Titration of gp or hu C1, C4, and C2, and quantification of the number of activated C1 molecules bound to ESC4 by the C1 fixation and transfer test showed in each case that an average of one effective site per cell was sufficient to cause cell lysis. Determination of tmax for optimal formation of ESC142 sites depended on the species combination of components used to make the intermediates, and the decay of ESC142 and EAC142 sites or sites generated with ESC4, EAC4, and trypsin-activated C2 were similar. The sugar alpha-D-methylglucopyranoside (alpha-MGP) inhibited binding of SCon A to E and eluted the lectin from ES, whereas galactose was nearly inactive, consistent with lectin sugar-binding selectivity. In contrast, both sugars were ineffective in eluting SCon A or C4hu from ESC4hu, indicating that C4hu blocked the interaction between lectin and alpha-MGP, perhaps by steric hindrance. SCon A is a divalent functional analogue of IgM anti-Forssman antibody that may be a uniquely suited reagent specific for cell membrane glycoconjugates for studying the mechanism of binding and activation of complement components.

Animals↗
PubMed1977

Complement system in human colostrum: presence of nine complement components and factors of alternative pathway in human colostrum.

Evidence has been obtained for the presence in human colostrum of all nine components of complement (C), C1 through C9, and factors of the alternative pathway. Samples of colostrums collected from five women at 1-4 days after normal parturition were assayed for the haemolytic activities of individual components. As compared with normal human sera, the activities of each component ranged from 0.03 to 7% of those in sera. The activities of C4, C7 and C9 were relatively high, while that of C1 was extremely low. In most of the cases, the activities of individual components gradually increased following delivery, when expressed as the activity per unit weight (g) of protein in the colostrum. When the colostrums were treated with cobra venom factor, most of the colostrums showed 10-20% reduction in the C3 activity. This finding indicates the presence of factors such as B and D which are involved in the activation of C through the alternative pathway. The role as a defense factor of the C system in human colostrum and milk is discussed in connection with the ability of secretory IgA to react with C.

Colostrum↗
PubMed1980

Studies on the composition and elimination of circulating immune complexes in leukaemia.

Longitudinal studies for the detection of circulating immune complexes (CIC-s) were performed in leukaemic patients using three methods in parallel. Results of these studies indicated that immune complexes in leukaemia are heterogeneous and their composition changes in the course of the disease. These results were supported by the changes in the concentration of a complement component (C1) and in the IgG subclasses in the immune complex-enriched fraction prepared by polyethylene glycol precipitation from different serum samples of individual patients with leukaemia. CIC-s from leukaemic patients are normally engulfed by granulocytes of healthy donors. The phagocytic capacity of leukaemic blast cells is hampered. The phagocytic activity through Fc and C3 receptors of peripheral mononuclear cells of leukaemic patients did not run parallel. On the basis of these studies it may be surmised that the total phagocytic capacity of the leukaemic patients cannot keep pace with the increased rate of immune complex formation.

Antigen-Antibody Complex↗
PubMed1977

Effect of concanavalin A on the classical complement pathway.

Lysis of sheep erythrocytes (E) sensitized with anti-Forssman antiserum (EA) is inhibited by the action of concanavalin A (Con A) on whole guinea pig complement (GPC). The degree of inhibition observed for a given quantity of GPC was dependent on the Con A concentration. Specifically, Con A inhibits the activity of the early acting complement components C1 and C2 in the fluid phase, but has no significant effect on lysis once these components are bound to EA. Results of tmax experiments performed in the presence or absence of Con A showed that inhibition of C2 activity results from a direct interaction between Con A and C2 and not from a decreased number of effective EAC14 sites. Furthermore, since Con A pretreated or untreated EAC14 cells had the same tmax value, Con A and C2 apparently do not compete for the same binding site on the indicator cells. The lectin has no observable effect on either fluid phase or cell-bound C4 activity. Under similar conditions, wheat germ or soy bean agglutinin, leucoagglutinin or pokeweed mitogen did not inhibit hemolysis.

Antibodies↗
PubMed1991

Interaction of the envelope glycoprotein of human immunodeficiency virus with C1q and fibronectin under conditions present in human saliva.

Human saliva has been shown to reduce the infectivity of human immunodeficiency virus (HIV) particles in vitro. The factors in human saliva involved in this inhibition of HIV infectivity are unknown, although the salivary sediment of normal individuals has the major HIV neutralizing activity. Interestingly, the first complement component (C1) has been detected on the surface of the salivary sediment in the whole saliva of normal individuals. At the relatively low ionic strength of saliva, we determined that purified human C1q bound with high affinity to the envelope glycoprotein of HIV. Normally, the interaction of the C1q globular heads with immune complexes causes C1 activation. However, direct interactions between C1 and rgp120 (or rgp160) did not lead to C1 fixation, as determined by hemolytic studies with rate-limiting levels of C1, nor did rgp120 cause C1 activation as determined by activated C1s-mediated C4 conversion in normal human serum. Using ELISA, it was observed that intact C1, with the C1r2C1s2 tetramer associated with the collagen-like stem of C1q, did not bind to immobilized rgp120, whereas free C1q did bind. In addition, digestion of the C1q stem portion with collagenase completely eliminated its binding to rgp120. These findings suggest that the collagen-like stem region of C1q, rather than the globular heads, may participate in the binding to the envelope glycoprotein of HIV. Fibronectin, which is present in submandibular saliva, appeared to bind to rgp120 and to enhance the interaction of C1q with rgp120. It is conceivable that C1q and fibronectin, in binding and sequestering HIV particles (i.e. to the salivary sediment), may play an important role in the reduction of HIV transmission via saliva. Further studies will be needed to test the latter speculation.

Blotting, Western↗
PubMed1998

Complement component 1 inhibitor (C1-INH) like protein on murine spermatozoa: anti-C1-INH inhibits in vitro fertilization.

We investigated if complement component 1 inhibitor-like (C1-INH-L) protein found on human spermatozoa exists on mouse spermatozoa and is relevant to reproduction. We used Western blot analysis and immunofluorescence assays to detect C1-INH on murine sperm and tested the effects of the antibodies to C1-INH and albumin (negative control) on in vitro mouse sperm motility and fertilization. C1-INH-L, with molecular weight similar to human C1-INH (100 kDa), was present on the surface of spermatozoan head and midpiece. Treating mouse sperm with anti-C1-INH reduced the mouse sperm motility (P < 0.01), in vitro fertilization (P < 0.01) and embryo development rates (P < 0.01). Anti-albumin failed to do so. We conclude that C1-inhibitor-like protein is present on mouse sperm surface and appears to be relevant to reproduction.

Albumins↗
PubMed1988

Genetic polymorphism of human C1R subcomponent of the first complement component in the Japanese population.

Genetic polymorphism of the C1R subcomponent of human complement component C1 has been investigated in neuraminidase treated EDTA plasma samples of 440 healthy Japanese individuals living in Tokyo by means of thin-layer polyacrylamide gel isoelectric focusing (PAGIEF) at pH 3.5-9.5 in the presence of 8.0 M urea followed by an electroblotting with enzyme immunoassay. Three common and three rare alleles were detected in the Japanese population. Of these, two common alleles were identical to C1R*1 and C1R*2 and other new alleles were tentatively designated C1R*3, C1R*4, C1R*5 and C1R*6, respectively. The results of the family studies suggested that the genetic model for C1R polymorphism assumed autosomal codominant Mendelian inheritance. The allele frequencies were estimated as C1R*1 = 0.4216, C1R*2 = 0.3602, C1R*3 = 0.2068, C1R*4 = 0.0091 and C1R*R(C1R*5 and C1R*6) = 0.0023, respectively. The distribution of allotypes fitted the Hardy-Weinberg equilibrium. The C1R system provides a useful genetic marker for human genetics, anthropologic studies and forensic science.

Alleles↗
PubMed1989

Genetic studies of low-abundance human plasma proteins. XI. Linkage analysis and population genetics of the C1S subcomponent of the first complement component.

Although subcomponents C1r and C1s of the first complement component, C1, have been established to be in the same linkage group as the proline-rich protein gene cluster on chromosome 12p13.2, no direct analysis of linkage between the C1R and C1S structural gene loci has been available. We have detected through a population screening study 5 families which are heterozygous at the structural loci for both C1R and C1S. Three of the 5 families, 21 individuals, were informative for linkage. A maximum lod score of 1.505 at theta = 0.00 was found in a two-point analysis between C1R and C1S. Ten populations were screened for structural variation at the C1S locus. Only US Whites and a Kodiak Island Eskimo group expressed heterogeneity. The frequencies of the designated alleles, C1S*1 and C1S*2, were 0.992 and 0.007, respectively, in the US White population and 0.998 and 0.002, respectively, in the Kodiak Island Eskimo population. In addition, the product of a putative new allele, designated C1S*4, was observed in a single US White individual but segregation of this variant was not observed in the limited family data available.

Blood Proteins↗
PubMed1975

On the mechanism of cytolysis by complement: evidence on insertion of C5b and C7 subunits of the C5b,6,7 complex into phospholipid bilayers of erythrocyte membranes.

The doughnut hypothesis of cytolysis by complement [Mayer, M. M. (1972) Proc. Nat. Acad. Sci. USA 69, 2954-2958] describes an annular structure made up of C5b-9 (complement factors C5b, C6, C7, C8, and C9) which becomes inserted in the lipid bilayer of the cell membrane, thus creating a hole. We now present initial explorations of this hypothesis. EAC1-6 and EAC1-7 (sheep erythrocytes carrying rabbit antibody and complement factors C1 through C6 or C1 through C7, respectively), prepared with either 125I-C3 or 125I-C5 were incubated with trypsin and the release of bound 125I was measured. In the case of 125I-C3, all of the radioactivity was released by trypsin from both intermediates. With 125I-C5, trypsin released all of the 125I from EAC1-6, but only 40-55% from EAC1-7. Possible reasons for resistance of the C5b subunit in EAC1-7 to tryptic digestion are discussed; in terms of the doughnut hypothesis it would be due to shielding by lipid molecules as a consequence of insertion into the lipid bilayer. In accord with this interpretation we have also found that C5b in EAC1-7, but not in EAC1-6, resists elution by 0.3 M NaC1. Similarly, we have found that 125I-C7 in EAC1-7 resists stripping by trypsin. Hence, we now propose the hypothesis that hydrophobic polypeptide chains from the C5b and the C7 subunits of C5b,6,7 complex become inserted in the phospholipid bilayer and that subsequent reactions with C8 and C9 open a channel across the membrane.

Animals↗
PubMed1986

Interaction of purified lipoteichoic acid with the classical complement pathway.

Glycerophosphate-containing lipoteichoic acids (LTAs) interact with the first component of the classical complement pathway (C1). This resulted in the activation of the classical complement pathway in serum, shown by the consumption of C1, C2, and C4. The dose-dependent interaction of LTAs with purified C1 and C1q was dependent on the negative charges of the phosphate groups of LTA. It was reduced by charge compensation through D-alanine ester substituents and by sterical hindrance through di- and trihexosyl residues linked to position 2 of the glycerol moieties. The charge density of LTA may also play a role: poly(digalactosylglycerophosphate) LTAs, in which the phosphate groups are in a greater distance from each other, were less effective, and the loss of micellar organization by deacylation of LTA drastically reduced the complement activation capacity.

Complement Activating Enzymes↗
PubMed1987

Recurrent febrile panniculitis and hepatitis in two patients with acquired complement deficiency and paraproteinemia.

Repeated episodes of febrile panniculitis and hepatitis were the main clinical features in two patients with an IgG1 kappa paraproteinemia and severe depletion of the early components of the classical pathway of complement (acquired C1 inhibitor deficiency). They did not have episodes of cutaneous angioedema or evidence of immune complex disease. In the more severely affected patient, the episodes responded to steroids. These features have not been described with acquired C1 inhibitor deficiency and may be related to complement activation.

Complement Activation↗
PubMed2005

Classical pathway complement activity in schizophrenia.

There is considerable evidence to suggest a role for complement in the pathogenesis of schizophrenia, but the data related to the classical pathway complement activity in patients with schizophrenia are conflicting. In the present study, the total hemolytic activity of the complement and the activities of individual complement components, C1, C2, C3 and C4, were determined in the blood serum of schizophrenic patients with positive family history of the disease and healthy subjects. In comparison to the healthy subjects, the mean values of the hemolytic activities of the C1, C3 and C4 complement components in the serum of the schizophrenic patients were significantly higher, and the mean value of the hemolytic activity of the C2 complement component was significantly lower. However, no significant difference was found between the mean values of the total hemolytic activity of complement in schizophrenic patients and healthy subjects. The C3 hemolytic activity was 2.17 times higher in medicated patients than in drug-free patients. Within each group examined no significant difference was found between smokers and non-smokers or between males and females. The results of this study suggest that the pathogenesis of schizophrenia is associated with alterations in activities of complement classical pathway components.

Adult↗
PubMed2001

The inhibition of TNK-t-PA by C1-inhibitor.

TNK-t-PA is a recombinant mutant of tissue plasminogen activator that has a longer half-life and higher selectivity for fibrin than normal tissue plasminogen activator (t-PA). In addition, it is reported to be serpin resistant because of reduced inhibition by plasminogen activator inhibitor-1. In this study, we have investigated the inhibition of TNK-t-PA by the serpin C1-inhibitor. TNK-t-PA is inhibited with a second-order rate constant of 7.5 per mol/l per s compared with 4.5 per mol/l per s for t-PA. In both cases, the stoichiometry was close to 20, indicating that C1-inhibitor was predominantly a substrate for both forms of t-PA. The formation of cleaved C1-inhibitor was seen on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and the t-PA-C1-inhibitor (or TNK-t-PA-C1-inhibitor) complex seen on SDS-PAGE and by zymography. Although the rates of inhibition are very slow in vitro, the fact that in vivo formation of the t-PA-C1-inhibitor complex after infusion of t-PA has been well documented suggests that TNK-t-PA will also be inhibited by C1-inhibitor in vivo and, perhaps more importantly, could cause a significant reduction in C1-inhibitor concentration.

Complement C1 Inactivator Proteins↗