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PubMedDate not supplied

[Hereditary angioedema by defict of C1 esterase. Our experience in 8 cases].

Eight cases of hereditary angioedema, all of them with low values of C1-sterase inhibitor are analyzed. In 7 cases the C3 and C4 components of the complement were assessed; the results showed marked descent of C4. The 8 patients came from 4 different families; only 2 of them were males. Six patients presented digestive disorders, reporting colic pain, nausea and vomiting. In 1 of them the abdominal picture was the only evidence of the disease. In 5 patients the angioedema episodes occurred following traumatisms and in 3 because of emotional states. The duration of the attacks varied from several hours to six days. There was a familial history in all cases. Three of the patients had repeated episodes of pharyngolaryngeal angioedema, two of them requiring emergency tracheotomy because of suffocating crisis. Six patients were treated with Epsilon aminocaproic acid (16 to 20 gr daily) or with tranexamic acid (1 to 3 gr. daily). In 4 cases the results were excellent with either of these antifibrinolytic drugs. No side effects were observed in the tranexamic acid therapy whilst they were frequent in the treatment with Epsilon aminocaproic acid.

Adolescent↗
PubMed1985

[Current diagnostic possibilities in hereditary angioedema and acquired angioedema].

Amidolytic assays for the determination of C1 esterase inhibitor have been proposed some years ago; however, the substrates employed lacked sensitivity. The recent development of a C1 esterase-sensitive substrate (N-alpha-methoxycarbonyl-l-lysyl(epsilon-CBO)-glycyl-arginyl-4-nit roanilide) provides a method that can be routinely used. Any interferences with other plasma proteases could not be observed. Normal range was ascertained to be 1.48 +/- 0.23 kU/l; within-run precision revealed C.V.'s of 1.74% (for the normal range) and 7.3% (for the pathological range). This method can be considered most suitable for functional determination of C1 esterase inhibitor and is superior to the determination of antikallikrein activity. To point out to the diagnostic relevance of a functional C1 esterase inhibitor assay some examples are illustrated.

Angioedema↗
PubMed1989

Complement genes C1r and C1s feature an intronless serine protease domain closely related to haptoglobin.

The exon-intron structure of the human complement C1s gene displays a striking similarity with that of the gene encoding haptoglobin, a peculiar transport protein distantly related to the serine proteases. While the protease regions of the serine zymogens are typically encoded by multiple exons, the protease domains of C1s and of its genetically linked and functionally interacting homolog C1r are encoded as intronless domains, not unlike a region of haptoglobin, which in fact is devoid of proteolytic activity. The close similarity of the C1s gene with haptoglobin includes the precise conservation of exon-intron junctions and it extends to upstream exons encoding the short repeats typical of several complement components, but found also in other functionally unrelated proteins. Additional evidence of the common ancestry of C1r, C1s and haptoglobin is the presence, within the protease domain, of a set of sequence markers that distinguish these three proteins from all known serine proteases. The finding of vertebrate serine protease genes with an uninterrupted protease-encoding exon supports the definition of a novel evolutionary branch of this gene family and rules out the hypothesis that regards this unusual exon as an irrelevant byproduct of the extravagant functional divergence of haptoglobin.

Amino Acid Sequence↗
PubMed1976

Evidence that C1s participates in the alternative complement pathway.

Purified C1s, subcomponent of C1, induced electrophoretic conversion of factor B and consumption of hemolytic C3 and C5 in sera genetically deficient in C2 or C4. Blocking of the hemolytic activity of C1s in C2-deficient serum by F(ab')2 anti-C1s resulted in inhibition of the alternative pathway, as indicated by the failure of zymosan or cobra venom factor to induce comsumption of C3 and C6. Zymosan also failed to activate the alternative pathway when C1s was absorbed from C1r-deficient serum using a solid immunoabsorbent. These data, showing that C1s participates in the alternative pathway under certain experimental conditions, suggest the interesing possibility that C1s is important in the activation sequence of both the classical and the alternative pathway more generally.

Animals↗
PubMed1989

Human complement C1r and C1s proteins and genes: studies with molecular probes.

The isolation of complementary DNA clones for both enzymic subcomponents of C1 has made it possible to derive their complete amino acid sequences and to verify and extend previous protein data. We review here recent advances in studies of the C1r and C1s proteins and of the corresponding genes, using molecular probes. The mosaic structure of these proteins has been compared to the exon-intron organization of the C1s gene. Surprisingly, the C1r and the C1s genes feature an intronless serine protease domain, at variance with all vertebrate serine proteases. Moreover, C1r and C1s are related in evolution to haptoglobin, a serine protease analog lacking enzymic activity. The C1r and C1s genes are closely linked in an unusual tail to tail orientation. These findings are discussed with regard to the apparently coordinate expression of these complement components and to the combined nature of most C1r and C1s deficiencies. We also discuss the implications of the successful production of C1r protein using recombinant DNA technology.

Chromosomes, Human, Pair 12↗
PubMed1986

Biosynthesis of the subcomponents C1q, C1r and C1s of the first component of complement (C1) by guinea pig hepatocyte primary cultures.

Thus far, the synthesis of C1q by liver cells has not been demonstrated. To investigate this possibility, viable hepatocytes were isolated from the liver of guinea pigs and primary cultures were established. The cells (10(6) cells/ml) were cultured under serum-free conditions for 8 days and the culture medium was changed every 24 h. The few contaminating Kupffer cells were lysed by preincubating the cell cultures with a monoclonal (22C4-8) antibody directed against a nonpolymorphic Ia determinant and preabsorbed rabbit serum. The hemolytic activity of C1 and its subcomponents C1q and C1r/C1s was tested in the supernatants. Guinea pig hepatocyte primary cultures synthesize and secrete up to 3 X 10(3) effective C1q molecules/cell/24 h and 34 X 10(3) effective C1r/C1s molecules/cell/24 h. The synthesis of C1q and C1r/C1s could be reversibly inhibited by cycloheximide (50 micrograms/ml). Furthermore, to demonstrate de novo synthesis of the C1q subcomponent, endogeneous labeling with 3H-proline (or 14C-proline) was performed. The immunoprecipitated C1q from cellular lysates and culture medium was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and fluorography. Compared to biosynthetically labeled guinea pig C1q from peritoneal macrophages, three corresponding bands (30, 28 and 24 kDa, respectively) were detectable in the fluorograph. The data show that guinea pig hepatocytes are able to synthesize C1 subcomponents, whereby the synthesis of C1q and C1r/C1s occurs independently.

Animals↗
PubMed1988

A rapid and efficient method for the purification of the complement subcomponents C1r and C1s in zymogen form using fast protein chromatography.

The purification of the subcomponents C1r and C1s of the first component of complement involves multiple steps and is time-consuming. This accounts for the frequently observed partial activation of the subcomponents. In this report we propose a simplified procedure of purification using a batch method and fast protein chromatography avoiding a shift of pH. The method provides C1r and C1s in a yield of 35 and 60% respectively. In addition, this study provides a simple and sensitive test to assess functional purity of C1r and C1s with respect to the other C1 subcomponents.

Chromatography, High Pressure Liquid↗
PubMed1986

Characteristics of complement subcomponents C1r and C1s synthesized by Hep G2 cells.

The association and activation states of complement subcomponents C1r and C1s biosynthesized by Hep G2 cells were studied. C1r and C1s are secreted in stoichiometric amounts; in the presence of Ca2+ they are associated in a complex that sediments similarly to plasma C1r2-C1s2. Both compounds are synthesized as monomer proteins of apparent Mr 86 000. C1r is secreted as a dimer. Secreted C1r is not autoactivatable but undergoes proteolysis by exogenous C1r; secreted C1s is also proteolysed by exogenous C1r. In the presence of immune-complex-bound C1q, secreted C1r and C1s are able to reconstitute C1, but normal activation requires extrinsic C1r2-C1s2.

Animals↗
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↗
PubMed1991

Measurement of macromolecular interactions between complement subcomponents C1q, C1r, C1s, and immunoglobulin IgM by sedimentation analysis using the analytical ultracentrifuge.

The interactions between the complement components and with immunoglobulins are greatly enhanced by lowering the ionic strength and become readily measurable by physical techniques. Thus, the binding between C1q and IgM was previously shown to be appreciable (k = 1 x 10(6) M-1) at 0.084 M ionic strength (Poon, P.H., Phillips, M.L., and Schumaker, V.N. (1985) J. Biol. Chem. 260, 9357-9365). We have now found that, at 0.128 M ionic strength, the binding between human C1- (the activated first component of complement) and IgM was strong at physiological concentrations (k = 1 x 10(7) M-1), while under the same conditions binding between C1q and IgM was not observed. To explore the nature of the interactions responsible for this enhanced binding by C1- over C1q, mixtures of the various subcomponents of C1- were studied alone and with IgM. C1r2 did not bind to C1q, even when the ionic strength was reduced to 0.098 M, nor did the presence of C1r2 enhance the binding of C1q to IgM. In contrast, two C1s2 independently bound to C1q (k = 1 x 10(6) M-1), and caused a marked increase in its association with IgM (k = 5 x 10(6) M-1) at 0.098 M ionic strength. No detectable interaction was found between C1s2 and/or C1r2 and IgM in the absence of C1q. Moreover, there was no detectable interaction between the C1(-)-like complex formed between C1r2C1s2 and the collagenous C1q stalks (pepsin-digested C1q) and IgM. These data suggest that the binding of C1s2 to C1q, either alone or together with C1r2, induces a conformational change in C1q which results in additional C1q heads binding to complementary sites on IgM.

Complement C1q↗
PubMedDate not supplied

Familial deficiency of two subunits of the first component of complement. C1r and C1s associated with a lupus erythematosus-like disease.

Complete absence of C1r and almost complete absence of C1s were found in 4 of 8 living siblings. Two of the 4 suffer from a syndrome that combines discoid lupus erythematosus and nondeforming rheumatoid-like arthritis; one of the siblings has mild nephritis. The other 2 C1 deficient family members are clinically well. Evidence from this and other families suggests that deficiency of C1 components or C4 is associated with higher risk of developing a lupus-like disease than is deficiency of C2.

Adolescent↗
PubMed1988

Human genes for complement components C1r and C1s in a close tail-to-tail arrangement.

Complementary DNA clones for human C1s were isolated from cDNA libraries that were prepared with poly(A)+ RNAs of human liver and HepG2 cells. A clone with the largest cDNA insert of 2664 base pairs (bp) was analyzed for its complete nucleotide sequence. It contained 202 bp of a 5' untranslated region, 45 bp of coding for a signal peptide (15 amino acid residues), 2019 bp for complement component C1s zymogen (673 amino acid residues), 378 bp for a 3' untranslated region, a stop codon, and 17 bp of a poly(A) tail. The amino acid sequence of C1s was 40.5% identical to that of C1r, with excellent matches of tentative disulfide bond locations conserving the overall domain structure of C1r. DNA blotting and sequencing analyses of genomic DNA and of an isolated genomic DNA clone clearly showed that the human genes for C1r and C1s are closely located in a "tail-to-tail" arrangement at a distance of about 9.5 kilobases. Furthermore, RNA blot analyses showed that both C1r and C1s genes are primarily expressed in liver, whereas most other tissues expressed both C1r and C1s genes at much lower levels (less than 10% of that in liver). Multiple molecular sizes of specific mRNAs were observed in the RNA blot analyses for both C1r and C1s, indicating that alternative RNA processing(s), likely an alternative polyadenylylation, might take place for both genes.

Amino Acid Sequence↗
PubMed1991

Isolation of human complement subcomponents C1r and C1s in their unactivated, proenzyme forms.

We have modified a standard isolation procedure for C1r and C1s, which employs IgG-Sepharose affinity chromatography followed by DEAE chromatography. As usual, all steps were performed at low temperature and two proteolytic inhibitors, PMSF and NPGB, were added during affinity chromatography on IgG-Sepharose. The novel condition was to keep the pH at pH 6.1 during the entire procedure, where activation was markedly depressed. In addition, purification was improved by washing the IgG-Sepharose column with a buffer free of added divalent cations immediately prior to elution of the C1r and C1s with EDTA. The final yields of highly purified C1r and C1s were about 20%; little or no activated material was detected in these highly purified fractions.

Chromatography, Affinity↗
PubMed1985

Domain structure and associated functions of subcomponents C1r and C1s of the first component of human complement.

The serine protease subcomponents of the activated form of the first component of human complement (C1), C1r and C1s, were observed by electron microscopy after the native proteins and their limited proteolysis products, obtained from autolytic cleavage (C1r) or from incubation with plasmin (C1s) were rotary shadowed. At the monomeric level, both C1r and C1s comprised two globular domains, a smaller interaction domain (corresponding to the NH2-terminal half of the A chain, alpha, and responsible for calcium binding and C1r-C1s interaction) and a larger catalytic domain (corresponding to the COOH-terminal part of the A chain, gamma, disulfide-linked to the B chain and bearing the serine protease active site). The two globular domains are linked by a connecting strand, beta. The (C1r)2 dimer appeared as a "croissant"-like association, where the two monomers interact through their catalytic domains. On the basis of the domain structure of C1r and C1s, a model of the calcium-dependent C1s dimer is proposed, in which the two monomers interact through their NH2-terminal interaction domains; in the same way, a model of the C1s-(C1r)2-C1s catalytic subunit of C1 is presented, in which (C1r)2 forms a core, its distal interaction domains interacting with the corresponding domains of C1s.

Complement Activating Enzymes↗