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PubMed1978

C-1 inactivator and cold-promoted activation of factor VII.

When exposed to temperatures between -5 degree and +5 degree C, plasma from pregnant women and from certain blood donors show shortening of the Thrombotest clotting time, kallikrein formation, and activation of blood-clotting factor VII. This phenomenon has been called cold-promoted activation of factor VII (CPA). In this study, it was found that CPA-positive plasma or serum samples which had been exposed to low temepratures showed spontaneous disappearance of C-1-inactivator activity in parallel to the shortening of the Thrombotest clotting time. C-1-inactivator antigen was not affected by storage at 4 degree C. In these CPA-possitive samples the loss of C-1-inactivator activity is caused partially by the formation of kallikrein at this temperature because when kallikrelin was added to C-1 inactivator, the latter was inactive when tested in the esterolytic assay. The formation of Hageman factor fragments may add to further loss. Purified C-1 inactivator effectively inhibited the CPA phenomenon, whereas alpha2-macroglobulin did so only weakly. This finding indicates that during exposure of CPA-positive plasma samples to low temperatures, Hageman factor fragments, which are inhibited only by C-1 inactivator, induce the activation of the kallikrein system and blood clotting factor VII. The reported lowered activity of C-1 inactivator in pregnancy is probably an artifact caused by generation of CPA during storage, since in fresh samples the levels were compeletely normal. Similarly, various subjects classified as belonging to the variant type of HANE (low C-1-inactivator activity with a normal antigen content) were found to have normal C-1-inactivator activity when determinations were made on fresh instead of frozen samples. It is recommended that plasma or serum samples should not be exposed to temperatures between -5degree and +5degree C prior to the determination of C-1-inactivator activity. Moreover, during purification procedures of kallikrein-binding antiproteases such as C-1 inactivator and also alpha2-macroglobulin, the occurrence of CPA should be avoided by the use of CPA-negative plasma as starting material.

Cold Temperature↗
PubMed1989

Distribution of complement in the sclera.

In the present study, we compared hemolytic activities of C1, C4, C2, C3, C5, C6 and C7 in the anterior and posterior sclera. Additionally, we used radial immunodiffusion to measure levels of Factor B, IgG, IgA and albumin in the anterior and posterior sclera. Except for C1, complement levels were significantly higher in the posterior than anterior sclera. Additionally, levels of immunoglobulins as well as albumin were significantly higher in the posterior than anterior sclera. These results suggest that the posterior sclera has a better adjacent vascular supply than the anterior sclera. On the other hand, the results of this study show that the anterior sclera has more C1, the recognition unit of the classical pathway, than the posterior sclera. Because there is nearly twice as much C1 in the anterior sclera, it may be easier for antigen-antibody complexes, whether formed in the sclera itself or derived from the neighboring vessels, to set off the complement cascade in the anterior sclera. This finding may help explain why scleritis associated with immune complex disease is more common in the anterior than posterior sclera.

Adult↗
PubMed1975

C1-bypass complement-activation pathway in patients with chronic urticaria and angio-oedema.

During the routine screening of 152 patients with urticaria or angio-oedema for hypocomplementaemia, 4 patients were found to have low serum levels of the third component of complement (C). These patients were noteworthy and differed from previous reports of patients with urticaria-like skin lesions and hypocomplementaemia because of the absence of immune-complex disease. In addition to the low C3, 2 of these patients were unique on the basis of low serum levels of haemolytic C1, C1q, C1s, and properdin factor B, but normal concentrations of C4 and C2. These C abnormalities may reflect a new clinical entity, and these cases form the first description in man of the C1-bypass complement-activation pathway.

Adult↗
PubMed1979

Isolation of the globular region of the subcomponent q of the C1 component of complement.

Digestion after heat treatment of the subcomponent q of the C1 component of complement by collagenase leads to the isolation of the globular region of the protein. This product ('heads') is composed of three chains giving an overall molecular weight of about 57000. About half of the collagen-like region present in C1 q is lost after digestion. The 'heads' are shown to be soluble and hemolytically active products.

Amino Acids↗
PubMed1985

Complement profile in a C1 inhibitor deficient family.

Complement components and anaphylatoxins in a C1 inhibitor (C1INH) deficient family were studied. C4a was increased when C1INH was decreased, and C3a was increased in subjects with systemic lupus erythematosus (SLE)-like symptoms and with angioedema attacks. Danazol was effective in controlling the clinical as well as complement abnormalities including low CH50, C1INH and C4, which increased within 10 days after danazol treatment was started. Two-dimensional immunoelectrophoresis of C1INH showed that there was no functionally or electrophoretically abnormal C1INH present before or after danazol treatment. C3a and C4a were considered to play important roles in the pathogenesis of angioedema and associated SLE-like symptoms.

Anaphylatoxins↗
PubMedDate not supplied

[Parameters of cellular and humoral immunity in patients with diabetes mellitus in the early stages of disease development; experience in treatment with the immunosuppressant azathioprine].

A total of 40 patients with type I diabetes mellitus, in whom the disease was diagnosed 1 to 12 months previously, were examined. An imbalance between the T and B cellular components of the immunity was found in the patients with the early stages of the disease, as was an elevated titer of the complement C1 component as against the reference group. The degree of the immunologic shifts was in direct correlation with the HLA A9 antigen expression, this relationship being the most marked in cases with the HLA DR3 and DR4. The incidence of these antigens expression was significantly higher in the patients with marked immunity shifts, than in those with negligible immunity changes. Therapy with an immunosuppressant azathioprine was associated with a noticeable reduction of the initially elevated cellular immunity parameters (total T and B lymphocyte counts, T helpers-inductors, DR carriers) and a trend towards a reduction of all the components and total activity of the classical route of the complement activation predominantly at the expense of the C1 and C5 components. The efficacy of this drug in therapy of new cases of insulin-dependent diabetes mellitus was confirmed, and the indisputable relationship between the efficacy of immunity suppression, that helped achieve a clinical remission, and the disease duration, was demonstrated. Monitoring of the cellular and humoral immunity parameters, of the activity of the classical route of the complement activation permitted an indirect judgement on the usefulness of immunity suppression for the correction of immunity disorders as factors contributing to the development of microvascular disturbances in insulin-dependent diabetes mellitus.

Adolescent↗
PubMed1986

Kinetics of interaction of C1 inhibitor with complement C1s.

The kinetics of inhibition of the complement serine protease, C1s, by its only known inhibitor, C1 inhibitor, have been measured by a variety of methods. One method continuously monitors the loss of esterolytic activity with a synthetic substrate coupled to a chromogen while another monitors the formation of a stable (covalent) complex by high-pressure size-exclusion chromatography under dissociating conditions. Additional methods employ fluorescence probes to follow the formation of bimolecular complexes but are not expected to distinguish between covalent product and noncovalent (reversible) intermediates. There was good agreement between rate constants obtained by the various methods over a broad range of inhibitor concentrations, suggesting that noncovalent intermediates do not accumulate to a significant extent. The reaction appears to be pure second order with a bimolecular rate constant of 6.0 X 10(4) M-1 s-1 at 30 degrees C, independent of Ca2+, and an activation energy of 11.0 kcal/mol. The rate increases up to 35-fold in the presence of heparin which was shown to bind to all three components (enzyme, inhibitor, and complex) with similar affinity (Kd = 2.0-3.3 microM). The fluorescent probe 1,1'-bis(anilino)-4-,4'-bi(naphthalene)-8,8'-disulfonate [bis(ANS)] bound to the complex with Kd = 0.26 microM under conditions where the individual components had little affinity for the dye, consistent with the generation of one or more hydrophobic binding sites on the protein surface during complex formation.

Complement Activating Enzymes↗
PubMed2002

Structural biology of the C1 complex of complement unveils the mechanisms of its activation and proteolytic activity.

C1 is the multimolecular protease that triggers activation of the classical pathway of complement, a major element of antimicrobial host defense also involved in immune tolerance and various pathologies. This 790,000 Da complex is formed from the association of a recognition protein, C1q, and a catalytic subunit, the Ca2+-dependent tetramer C1s-C1r-C1r-C1s comprising two copies of each of the modular proteases C1r and C1s. Early studies mainly based on biochemical analysis and electron microscopy of C1 and its isolated components have allowed for characterization of their domain structure and led to a low-resolution model of the C1 complex in which the elongated C1s-C1r-C1r-C1s tetramer folds into a more compact, "8-shaped" conformation upon interaction with C1q. A major strategy used over the past years has been to dissect the C1 proteins into modular segments to characterize their function and solve their structure by either X-ray crystallography or nuclear magnetic resonance spectroscopy (NMR). The purpose of this review is to focus on this information, with particular emphasis on the architecture of the C1 complex and the mechanisms underlying its activation and proteolytic activity.

Animals↗
PubMed1990

Ca2+ binding properties and Ca2(+)-dependent interactions of the isolated NH2-terminal alpha fragments of human complement proteases C1-r and C1-s.

The NH2-terminal alpha fragments of human complement proteases C1-r and C1-s were obtained by limited proteolysis of the native proteins with trypsin, and isolated. C1-r alpha extended from residues 1 to 208 of C1-r A chain, with at least two cleavage sites within disulfide loops, after lysine 134 and arginine 202. C1-s alpha comprised residues 1-192 of the C1-s A chain, with one cleavage site within a disulfide loop, after arginine 186. C1-r alpha was monomeric either in the presence or absence of Ca2+ but formed Ca2(+)-dependent dimers with native C1-s. C1-s alpha dimerized in the presence of Ca2+ and formed Ca2(+)-dependent tetramers (C1-s alpha-C1-r-C1-r-C1-s alpha) with native C1-r. C1-r alpha and C1-s alpha associated in the presence of Ca2+ to form C1-r alpha-C1-s alpha heterodimers. Equilibrium dialysis studies indicated that each alpha region binds Ca2+ with a dissociation constant ranging from 19 microM (native proteins) to 38 microM (fragments). C1-r alpha, C1-r alpha-C1-s alpha, and the native C1-s-C1-r-C1-r-C1-s tetramer bound 0.9, 1.9, and 4.0 Ca2+ atoms/mol, respectively, whereas dimers C1-s alpha-C1-s alpha and C1-s-C1-s incorporated 2.9 and 3.0 Ca2+ atoms/mol. It is concluded that each alpha region contains one high affinity Ca2+ binding site. This 1:1 stoichiometry is maintained upon heterologous (C1-r-C1-s) interaction, whereas the homologous (C1-s-C1-s) interaction provides one additional binding site.

Amino Acid Sequence↗
PubMed1990

Proteolysis of the heavy chain of major histocompatibility complex class I antigens by complement component C1s.

The major histocompatibility complex (MHC) class I antigens contain a light chain, beta 2-microglobulin, non-covalently associated to the transmembrane heavy alpha-chain carrying the allotypic determinants. Since the C1q complement component is known to associate with beta 2-microglobulin, and we recently found that activated C1s complement was capable of cleaving beta 2-microglobulin, we decided to investigate the proteolytic activity of C1 complement towards the heavy chain of class I antigens. Our results demonstrate that human C1s complement cleaves the heavy chain of human class I antigens into at least two fragments, with apparent molecular weights of 22,000 and 24,000 g/mol on sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), under both reducing and non-reducing conditions. The cleavage of the heavy chain is inhibited by the presence of C1 esterase inhibitor. The molecular weights of the fragments are in agreement with the cleavage located in the area between the disulphide loops of the alpha 2-and alpha 3-domains of the heavy chain. In addition human C1s complement is able to cleave H-2 antigens from mouse in a similar fashion but not rat MHC class I antigen or mouse MHC class II antigen (I-Ad). Mouse MHC class I antigen-specific determinants could also be detected in supernatant from mouse spleen cells incubated with C1r and C1s. These results indicate the presence in the body fluids of a non-membrane-bound soluble form of the alpha 1-and alpha 2-domains which represent the binding site for antigenic peptides.

Animals↗
PubMed1976

Mode of interaction of different polyanions with the first (C1,C1) the second (C2) and the fourth (C4) component of complement. IV. Activation of C1 in serum by polyanions.

Treatment of serum with dextransulphate polyvinylsulphate or polyanetholsulphonate resulted in a dose-dependent activation of C1 and C3; this was found for normal serum as well as for C4-deficient guinea-pig serum. Activation of C1 and C3 occurred at the same concentration of polyanions. The consumption of C3 in C4 deficient serum and the requirement of factor D of the alternative pathway indicate that C3 is activated via the alternative pathway.

Animals↗
PubMed1990

Two-domain structure of the native and reactive centre cleaved forms of C1 inhibitor of human complement by neutron scattering.

The C1 inhibitor component of human complement is a member of the serpin superfamily, and controls C1 activation. Carbohydrate analyses showed that there are seven O-linked oligosaccharides in C1 inhibitor. Together with six N-linked complex-type oligosaccharides, the carbohydrate content is therefore 26% by weight and the molecular weight (Mr) is calculated as 71,100. Neutron scattering gives an Mr of 76,000 (+/- 4000) and a matchpoint of 41.8 to 42.3% 2H2O, in agreement with this carbohydrate and amino acid composition. Guinier plots to determine the radius of gyration RG were biphasic. Neutron contrast variation of C1 inhibitor in H2O-2H2O mixtures gave an overall radius of gyration RG at infinite contrast of 4.85 nm, from analyses at low Q, and a cross-sectional RG of 1.43 nm. The reactive centre cleaved form of C1 inhibitor has the same Mr and structure as the native molecule. The length of C1 inhibitor, 16 to 19 nm, is far greater than that of the putative serpin domain. This is attributed to an elongated structure for the carbohydrate-rich 113-residue N-terminal domain. The radial inhomogeneity of scattering density, alpha, is large at 59 x 10(-5) from the RG data and 28 x 10(-5) from the cross-sectional analysis, and this is accounted for by the high oligosaccharide content of C1 inhibitor. The scattering data were modelled using small spheres. A two-domain structure of length 18 nm based on two distinct scattering densities accounted for all the contrast variation data. One domain is based on the crystal structure of alpha 1 antitrypsin (7 nm x 3 nm x 3 nm). The other corresponds to an extended heavily glycosylated N-terminal domain of length 15 nm, whose long axis is close to the longest axis of the serpin domain. Calculation of the sedimentation coefficient s0(20),w for C1 inhibitor using the hydrodynamic sphere approach showed that a two-domain head-and-tail structure with an Mr of 71,000 and longest axis of 16 to 19 nm successfully reproduced the s0(20),w of 3.7 S. Possible roles of the N-terminal domain in the function of C1 inhibitor are discussed.

Borohydrides↗
PubMedDate not supplied

Circulating immune complexes and the complements system in lupus nephropathy.

From a group of 75 patients with systemic lupus erythematosus (SLE), 30 patients with lupus nephropathy presenting concomitant changes of the CIC level, of the complement system (C3 and C1q factors) and proteinuria were chosen for the study. In these 30 patients, no statistically significant correlation was observed between CIC level and the value of serum complement. Low serum complement was observed in 89% of the cases while low complement values associated with increases of the CIC level were observed only in 57.8% of the cases. From the values of the C3 and C1 complement factors it results that in 76.6% of the cases of lupus nephropathy the activation of complement was achieved in the classical way. The value of proteinuria presented no significant correlation with any of the parameters investigated. The serum immunogram presented varied aspects and the components of the CIC structure revealed a great diversity of this structure.

Antigen-Antibody Complex↗
PubMed1988

Increased plasma concentrations of complement modulating proteins (C1 inhibitor, C4-binding protein, factor H and factor I) in psoriasis.

By using single radial immunodiffusion we measured the plasma levels of four complement modulating proteins, i.e., C1 inhibitor, C4-binding protein, factor H and factor I in 19 psoriatic patients in comparison with those of healthy controls. Except for C1 inhibitor which was only marginally elevated, they were found to be significantly increased in psoriatic patients. When psoriatic patients were classified into subgroups based on the clinical severity, the levels of factor H and those of factor I showed a close positive correlation with the activity and extent of the skin lesions, whereas such clear relationship could not be found with C1 inactivator or with C4-binding protein. These results offer additional support for the hypothesis that the complement system is involved in psoriasis.

Adult↗