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PubMed1982

[Hereditary complement deficiencies].

Complement deficiencies of all nine C-components have been observed. Hereditary defects of early components of the classical pathway - C1, C4, C2 - are often associated with diseases of the immuncomplex-type especially with systemic lupus erythematosus, dermatomysitis, vasculitis and nephritis. Deficiencies of C3 and C3b inactivator are linked to severe and recurrent bacterial infections. Patients with hereditary defects of the so-called late components, C5-C9, show increased susceptibility to recurrent disseminated infections by neisseria gonorrhoeae and meningitidis. The most frequent of the defects of the complement system is the hereditary deficiency of C1-inactivator which is associated with hereditary angioneurotic edema. In this paper the C-defects and their genetics are described and possible pathomechanisms are discussed.

Complement Activating Enzymes↗
PubMed1984

The role of immune complexes in the activation of the first component of human complement.

Immune complex-induced C1 activation and fluid phase C1 autoactivation have been compared in order to elucidate the immune complex role in the C1 activation process. Kinetic analyses revealed that immune complex-bound C1 activates seven times faster than fluid phase C1 spontaneously activates. The rate of spontaneous C1 activation increased after decreasing the solution ionic strength. In fact at one-half physiologic ionic strength (i.e., 0.08 M), the kinetics of spontaneous C1 activation were indistinguishable from the kinetics of activation of immune complex-bound C1 at physiologic ionic strength. The enhanced fluid phase C1 activation at low ionic strength resulted neither from C1 nor C1q aggregation, nor from selective effects on the C1r2S2 subunit; however, at the reduced ionic strength, the C1 association constant (defined for C1q + C1r2S2 in equilibrium C1qr2S2) did increase to 2.3 X 10(8) M-1, which is equal to that for C1 bound to an immune complex at physiologic ionic strength. Therefore, C1 can spontaneously activate in the fluid phase as rapidly as C1 on an immune complex when the strength of interaction between C1q and C1r2S2 is the same in both systems. In conclusion, under physiologic conditions, C1q and C1r2S2 are two weakly interacting proteins. Immune complexes provide a site for the assembly of a stable C1 complex, in which C1q and C1r2S2 remain associated long enough for C1q to activate C1r2S2. Thus, immune complexes enhance the intrinsic C1 autoactivation process by strengthening the association of C1q with C1r2S2.

Antigen-Antibody Complex↗
PubMed1984

Functional studies on the secreted form of human C4 (C4s), two incompletely processed two-subunit C4 molecules (beta - alpha + gamma and beta + alpha - gamma), and pro-C4.

The functional properties of the secreted form of C4 (C4s), which has a Mr approximately 5000 greater than the predominant C4 molecule found in plasma (C4p), two incompletely processed two-chain C4 molecules (beta - alpha + gamma and beta + alpha - gamma), and the extracellular C4 precursor (designated pro-C4(E)] were evaluated. All four molecules are secreted in parallel by a human hepatoma-derived cell line (Hep G2). Secretion of hemolytically active C4 is linear up to approximately 12 hr, peaks at 24 hr, and then progressively decreases over the next 48 hr. This loss of C4s functional activity parallels the proteolytic conversion of C4s to C4bs. To compare the hemolytic efficiencies of C4s and C4p, a solid-phase competitive radioimmunoassay was developed to permit measurement of the small quantities of C4 antigen in these cultures. The hemolytic efficiencies of C4s and C4p were similar. These results indicate that extracellular processing of C4s to C4p does not modulate the hemolytic activity of the molecule. Consistent with their ability to bind methylamine, both the alpha s-chain and the alpha - gamma subunit undergo denaturation-induced autolysis. The extracellular and intracellular pro-C4 molecules are also sensitive to autolytic cleavage. Interestingly, the beta - alpha subunit is resistant to autolysis. In experiments in which C4s and C4p were cleaved by C1-s to C4bs, C4(beta - alpha + gamma), C4(beta + alpha - gamma), and pro-C4(E) were resistant to C1-s cleavage and thus hemolytically inactive relative to C4s. These data indicate that processing of C4 to a three-chain structure is required to provide the proper conformation for efficient activation by C1.

Animals↗
PubMed1984

Generation of the classical pathway C3 convertase (EAC4b2a) by proteolytic enzymes.

The formation of EAC 4b2a is a two step reaction: first, the temperature- and time-independent binding of C2 to EAC4b2a resulting in EAC4b2 , secondly, the enzymatically triggered conversion of EAC4b2 to EAC4b2a . In the classical cascade of complement activation, the generation of C3 convertase activity is triggered by the C1 esterase, C1-s, which is part of C-1. Evidence is presented that the enzymes trypsin, chymotrypsin, plasmin, and pronase are also able to activate EAC4b2 to EAC4b2a . Kinetic studies showed that the formation of C3 convertase by these enzymes was dependent on concentration, temperature, and time. The optimal conditions were found as follows: trypsin, 2 micrograms/ml (final conc.) for 8 min at 23 degrees C; chymotrypsin 165 micrograms/ml for 18 min at 23 degrees C; plasmin 0.8 units/ml for 15 min at 23 degrees C; pronase 1.25 microgram/ml for 15 min at 23 degrees C. Even under optimal (tmax) conditions the number of generated EAC4b2a differed from enzyme to enzyme: trypsin (= 100%), pronase (58.3%), chymotrypsin (47.9%), and plasmin (12.9%). The enzymes were also able to generate C3 convertase activity from C2 which was adsorbed to EAC1i4b , a C1 inactivator treated and therefore hemolytically inactive intermediate ( EAC1i4b2 ). These findings underline the biological importance of C1 esterase replacing enzymes.

Animals↗
PubMed1981

[The complement system in familial Mediterranean fever: studies in 41 families (author's transl)].

A total increase of blood complement components, particularly C4, is found in subjects with familial Mediterranean fever both before and after colchicine therapy. This effect differs from the serum haptoglobin and orosomucoïd concentration decreases detected after identical therapy, confering diagnostic value to this inflammatory syndrome. This could be of both hepatic and extrahepatic origin. For the latter, it is possible that up take of circulating monocytes, macrophage precursors, by the connective tissue of the serum sub-mesothelial layer is responsible for the lesion.

Complement C1 Inactivator Proteins↗
PubMed1982

Kinetic studies of phagocytosis. III. The complement-dependent opsonic and anti-opsonic effects of normal and sle sera.

The influence of serum on phagocytosis related to the complement system was examined by means of a kinetic phagocytosis method using IgG-coated particles, isolated polymorphonuclear neutrophil leucocytes (PMNs), fresh serum, in vitro activated sera and in vivo activated sera. The previously described opsonic properties of C3b and C4b were confirmed by the enhancement of phagocytic rate by the opsonization of IgG particles with C3 and C4. An anti-opsonic effect of serum was revealed by the initial inhibition of PMN phagocytosis of IgG-coated particles in the presence of fresh serum. In vitro activated norma fresh serum and in vivo activated SLE sera mediated a prolonged or even irreversible inhibition of phagocytosis dependent on the degree of complement activation. Investigation of this anti-opsonic effect of serum, which was heat-labile, suggested that it was caused by an inhibition of the interaction between the Fc receptor and IgG mediated by the C1q component of the C1 complex.

Complement Activating Enzymes↗
PubMed1996

Exon structure of the gene encoding the human mannose-binding protein-associated serine protease light chain: comparison with complement C1r and C1s genes.

Mannan or mannose-binding protein (MBP) requires a novel serine protease termed MBP-associated serine protease (MASP) for activation of the complement cascade. In this study, we analyzed MASP genomic clones and found that the light chain (catalytic domain) is encoded by six exons, whereas those of the complement C1 subunits, C1r and C1s, and the haptoglobin segment have been reported to be encoded by a single exon. We confirmed the intron-lacking sequence of C1r by analysis of its genome. These results, in conjunction with those obtained by constructing a phylogenetic tree for these proteins, suggest that the MASP gene is prototype and that the intron-lacking sequences of the other serine proteases have a more recent history.

Binding Sites↗
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↗
PubMed1993

A new member of the C1s family of complement proteins found in a bactericidal factor, Ra-reactive factor, in human serum.

The Ra-reactive factor (RaRF) found in vertebrate sera activates the C4 and C2 components of complement. The C4/C2-activating component of mouse RaRF has been found to contain a 100-kDa serine protease called P100. In the present study, we cloned a cDNA with cDNA of mouse RaRF P100 as a probe from a human liver cDNA library. An open reading frame of 2097 nucleotides encoding a protein of 699 residues was found in the cloned cDNA of 4489 nucleotides. This protein exhibits 87.4% amino acid homology with mouse P100, and 36.4% and 37.1% homologies with that of the C1r and C1s subcomponents of human complement, respectively. The characteristic nodules and domain of C1r and C1s were highly conserved in this protein. This indicates that the P100, together with the C1r and C1s, forms a unique protein family having the same module/domain constitution.

Amino Acid Sequence↗
PubMed1983

Structural and circular-dichroism studies on the interaction between human C1-esterase inhibitor and C1s.

The reaction between complement factor C1s and C1-esterase inhibitor has been investigated by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis, N-terminal amino acid analysis and c.d. studies. It is confirmed that a very stable stoichiometric 1:1 complex with a molecular weight of about 180000 is formed, involving the light chain of C1s. On the sodium dodecyl sulphate/polyacrylamide gels a small peptide with a molecular weight of about 5000 can be seen, which may be released from the C-terminal portion of the inhibitor moiety in a manner analogous to that occurring in other similar proteinase-inhibitor reactions. By N-terminal amino acid analysis, a newly formed threonine residue is found in the complex, suggesting that the inhibitor peptide chain is cleaved in the complex between C1s and C1-esterase inhibitor. The stabilizing bond may therefore be an ester bond. C.d. studies of the native C1-esterase inhibitor indicated the presence of about 38% alpha-helix, about 24% beta-structure and about 38% unordered structure. By gradual cleavage of the disulphide bridges under non-denaturating conditions, gradual changes in the c.d. spectra occurred, suggesting loss of ordered secondary structures. The c.d. spectra of the complex between C1s and C1-esterase inhibitor indicate that tryptophan residues are affected by the complex-formation.

Amino Acids↗
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↗
PubMed1983

Biosynthesis in vitro of complement subcomponents C1q, C1s and C1 inhibitor by resting and stimulated human monocytes.

The capacity of cultured human monocytes to synthesize and to secrete the subcomponents of C1 and C1 inhibitor was examined. Non-stimulated monocytes secreted C1q and C1s from day 5 of culture. C1s reached a plateau immediately at its maximum level, whereas C1q secretion increased progressively until the end of the second week. Between day 12 and day 25, C1q secretion remained nearly constant (1-15 fmol/day per microgram of DNA, depending on the donor), whereas C1s secretion decreased and even in some cases stopped. C1r and C1 inhibitor were not secreted in detectable amounts by these resting cells. Stimulation of monocytes by yeasts, immunoglobulin G-opsonized sheep red blood cells or latex beads did not modify consistently C1q and C1s secretion. Activation by conditioned media from mitogen-, antigen- or allogeneic-stimulated lymphocyte cultures increased C1q production from 2 to 7 times and re-activated C1s secretion. Under the same conditions of activation, C1 inhibitor was secreted (up to 300 fmol/day per microgram of DNA) and C1r became detectable in culture supernatants. Isolated human monocytes are thus able to synthesize the whole C1 subcomponents; C1, if assembled, could be protected from non-immunological activation by locally produced C1 inhibitor. Activated monocytes appear to be a good tool for studying the assembly of C1 subcomponents and the role of C1 inhibitor in this process.

Cells, Cultured↗
PubMed2003

Complement C1r and C1s genes are duplicated in the mouse: differential expression generates alternative isomorphs in the liver and in the male reproductive system.

C1r and C1s are the serine proteases that form the catalytic unit of the C1 complex, the first component of complement. In the present study, we found that the genes encoding murine C1r and C1s are duplicated. One set of these genes, referred to as c1rA and c1sA, are primarily expressed in the liver and are therefore the homologues of the human C1r and C1s genes. The other two genes, termed c1rB and c1sB, are expressed exclusively in male reproductive tissues, specifically the coagulating gland and the prostate. The predicted C1rB and C1sB proteins share 96 and 93% amino acid identity with C1rA and C1sA respectively. Most of the substitutions are clustered in the serine protease domains, suggesting differences in catalytic efficiencies and/or substrate specificities or alternatively adaptation to different physiological environments. The high homology of C1rB and C1sB with C1rA and C1sA in the non-catalytic regions indicates that they are probably capable of assembling the C1 complex. The expression of alternative genes encoding isomorphs of activating components of complement in male reproductive tissues raises the possibility of new mechanisms of complement activation in the male genital tract or of novel functions for complement proteases in reproduction.

Amino Acid Sequence↗
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↗