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PubMed1988

Role of EAC1q4 in C1a transfer reaction (C1aTR) and further information on the nature of the EAC1q4 site.

The complement intermediates EAC1, EAC4, and EAC1q4 were prepared with guinea pig, porcine, as well as human complement. EAC4 and EAC1q4 were made from EC4 and EAC14 respectively. The C1a transfer reaction (C1aTR), the second step of Borsos' C1a fixation and transfer test, was carried out with various combinations of these intermediates. It was found that the EAC1q4, instead of the EAC4, was the C1a acceptor, and the C1rs subcomponents rather than the whole C1 molecule should have to transfer in the C1aTR. The EAC41 derived from EC4 generated no EAC1q4 in EDTA medium as the EAC14 did. This presented evidence for the joining of C4 to A in the EAC1q4 site.

Animals↗
PubMed1989

Autoantibody facilitated cleavage of C1-inhibitor in autoimmune angioedema.

C1-inhibitor (C1-Inh) is an important inhibitor of the inflammatory response and deficiency of this inhibitor, which may be hereditary or acquired, is associated with recurrent episodes of edema. Recently, an autoimmune form of angioedema has been described that is associated with functional deficiency of C1-Inh and an autoantibody that impedes C1-Inh function. In this report we describe the isolation of C1-Inh from the monocytes and plasma of a patient with autoimmune angioedema and demonstrate that the patient's monocytes secrete structurally and functionally normal C1-Inh, but show that this protein circulates in the patient's plasma in an inactive, structurally altered form. Furthermore, using analytic gel electrophoresis techniques it is demonstrated that the patient's autoantibody facilitates cleavage of normal C1-Inh, by its target proteases, to the same species of C1-Inh that is found circulating in the patient's plasma. This autoantibody facilitated cleavage of normal C1-Inh is apparently a consequence of destabilization of protease/inhibitor complexes. These findings contribute to our understanding of protease/C1-Inh interactions and document important observations on pathogenic mechanisms in autoimmune disease.

Angioedema↗
PubMed2000

Usefulness of detection of complement activation products in evaluating SLE activity.

Complement activation products, such as C1rs-C1inh, specific for the activation of the classical pathway, C3b(Bb)P, specific for the activation of the alternative pathway and SC5b-9, specific for common terminal pathway of the complement cascade, were measured in healthy donors and in patients with clinically active and inactive systemic lupus erythematosus (SLE). Plasma levels of C3b(Bb)P and SC5b-9 were moderately, those of C1rs-C1inhibitor (C1rs-C1inh) were markedly elevated in patients with clinically inactive SLE, compared with healthy controls. The difference between active and inactive stages of the disease was best reflected by C3b(Bb)P plasma concentration (P<0.001), which also showed the highest correlation with the SLEDAI (Rs=0.41 P<0.001) and which was the most useful in distinguishing active and inactive sample pairs as well. The difference between SC5b-9 levels in the active and inactive stages was also significant (P=0.007), while that of C1rs-C1inh did not differ significantly (P=0.136). The correlation of the SLEDAI with SC5b-9 was 0.3 (P=0.015), while with C1rs-C1inh it was 0.21 (P=0. 089). These findings suggest that the measurement of complement activation products, especially that of the alternative pathway, are sensitive markers of the activity of SLE and can be used for clinical purposes.

Adult↗
PubMed1984

Isolation, molecular properties and allotype of mouse C1q.

Mouse C1q, a subcomponent of the first component of complement, was purified from mouse EDTA plasma by a combination of precipitation with polyethyleneglycol, affinity chromatography on IgG-Sepharose, ion exchange chromatography and molecular sieving. Mouse C1q was compatible with human C1q in the sense that it shows C1 hemolytic activity by the combination with human C1-r and C1-s. The molecular weight of mouse C1q as estimated by SDS-PAGE was approximately 410,000 and almost the same as that of human C1q. After treatment of mouse C1q with 4 M urea, three distinct subunits were obtained on SDS-PAGE in non-reducing condition. Moreover it was shown that there are small, yet definite differences in the molecular weights of the subunits between the two mouse strains. Three subunits of the C1q from C3H and ICR showed apparent molecular weights of 62,000, 58,000 and 53,000 but those of DDI showed 62,000, 55,000 and 51,000. These results suggested the existence of allotype of mouse C1q, and indeed, alloantisera made by injecting the C1q of ICR to DDI reacted in Ouchterlony double diffusion test with plasma of ICR, C3H, AKR and BALB/c, but not with DDD, DKI, C57BL/10 and C57BL/6.

Animals↗
PubMed1990

Receptor expression and functional status of cultured human eosinophils derived from umbilical cord blood mononuclear cells.

Selective use of recombinant human cytokines has enabled the culture of large numbers of eosinophils from human cord blood mononuclear cells, raising the possibility of their use as a model of eosinophil function. Cultured eosinophils (CE) were compared with normal-density peripheral blood eosinophils (PBE) in terms of their membrane receptor expression and function. Fc gamma R and CR1 expression of CE and PBE was similar. In contrast, the specific mean fluorescence for LFA-1 alpha, p150,95 alpha, ICAM-1, and HLA-DR was significantly elevated for CE compared with PBE. CE responded in PAF-induced chemotaxis in a similar fashion to PBE. CE gave higher numbers of both resting and platelet activating factor (PAF)-stimulated immunoglobulin G (IgG)- and C3b-dependent rosettes than PBE. CE and PBE had comparable capacity to kill IgG- and C-opsonized schistosomula in terms of both baseline values and PAF-induced enhancement of cytotoxicity. Baseline adherence by CE and PBE to plasma-coated glass was essentially the same, but stimulated adhesion (PAF) of CE was lower. Compared with PBE, CE generated less than half the amounts of extracellular and cell-associated PAF induced by calcium ionophore A23187 stimulation. Unlike PBE, CE did not generate PAF after exposure to IgG-coated Sepharose particles. CE stimulated with IgG-coated beads generated small quantities of LTC4, while A23187 stimulation resulted in approximately half the LTC4 levels observed with PBE. The total cell content of eosinophil peroxidase (EPO) was similar for CE and PBE. These data suggest that although CE and PBE have many phenotypic and functional properties in common there are quantitative differences that may be a consequence of their immaturity and/or the influence of the cytokines used in their culture.

Animals↗
PubMed1990

Binding of the pentamer/hexamer forms of mannan-binding protein to zymosan activates the proenzyme C1r2C1s2 complex, of the classical pathway of complement, without involvement of C1q.

The serum lectin, mannan binding protein (MBP), was isolated in a yield of 40 micrograms/liter from pooled normal human serum by affinity chromatography on mannan-Sepharose, followed by gel-filtration and ion-exchange chromatography and finally by passage down an anti-IgM Sepharose column. A rabbit antiserum was prepared against the purified MBP and an enzyme-linked immunoassay developed that used both the specificity of the polyclonal antibody and the Ca+(+)-dependent carbohydrate binding property of MBP. Assay of the sera from 103 blood-donors showed a wide range of MBP levels, ranging from 0 to 870 micrograms/liter. MBP, after interaction with zymosan, caused efficient activation of a C1r2 125I-C1s2 complex that was prepared by incubation of 125I-C1s2 with serum, from a patient with a complete genetic deficiency of C1q, followed by gel-filtration on Sepharose 6B. The purified MBP is composed of a mixture of trimers, tetramers, pentamers, and hexamers of an approximate 90-kDa structural unit as judged by chromatography, SDS-PAGE and electron microscopy studies. Only the molecules in the pentamer/hexamer fraction, which have a similar overall structure to that of C1q, appeared to cause efficient, zymosan-dependent, activation of C1s within the C1r2C1s2 complex. The pentamer/hexamer form of MBP may therefore play an important role in antibody-independent activation of the C system during the early stages of certain infections.

Calcium↗
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↗
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↗
PubMed1993

Preferential gene expression in quiescent human lung fibroblasts.

The exit from the proliferative cell cycle into a reversible quiescence (G0) is an active process that is not yet well understood at the molecular level. Investigation of G0-specific gene expression is an important step in studying the mechanism regulating the entrance to quiescence. Using the human embryo lung fibroblast (WI38) as a model system, we have isolated complementary DNA clones that are expressed at a higher level in quiescent cells than in logarithmically growing cells. We have identified complementary DNAs from eight genes including collagen alpha 1(VI), collagen alpha 1(III), decorin, complement C1r, collagen alpha 1(I), collagen alpha 2(I), and two novel genes, Q6 and Q10. We have named this class of quiescence-inducible genes quiescins. Expression of these genes was induced just as proliferation slowed, as indicated by the level of histone H2B mRNA, [3H]-thymidine incorporation, and cell number. The level of expression of the novel genes, Q6 and Q10, increased at the same time as the other genes. Q6 has two mRNAs of 3 and 4 kb, whereas Q10 mRNA is about 1.0 kb. The expression of the quiescins was not induced by blocking the cell cycle in S phase with aphidicolin or in G1 with lovastatin. However, the genes were highly induced by trypsinization or scraping of the cells during logarithmic growth. This induction was not blocked by inhibitors of RNA synthesis. The expression of decorin and Q6 was very low in SV40-transformed cells (VA13) either in logarithmic growth or at high density, whereas the gene Q10 was expressed more highly in VA13 than in WI38 cells. The finding that expression of some components of the extracellular matrix is induced as cells enter G0 suggests that they may have a role in both the induction and the maintenance of the quiescent state. The quiescins will serve as molecular markers for the investigation of mechanisms that regulate the onset of quiescence.

Aphidicolin↗
PubMed1997

The human complement C1 complex has a picomolar dissociation constant at room temperature.

Periodic sampling of serum or reconstituted C1 initially diluted 1/2000 and 1/4000 (that is, to 0.1 and 0.05 nM) into a recombinant C1s-containing solution showed a gradual decline of hemolytic activity until equilibrium was approached, consistent with a simple dissociation, reassociation equilibrium, presumably C1 <--> C1q + C1r2C1s2. The presence of excess (5 nM) recombinant C1s minimized further dissociation of the C1r2C1s2, allowing the first step to be studied independently of the dissociation of C1r2C1s2 <--> C1r2 + 2 C1s. Reassociation experiments were also performed, starting with the dissociated C1 diluted to the same concentrations and following the regain of hemolytic activity to approximately the same values, showing that the same equilibrium had been achieved from both directions. Analysis of the kinetic data yielded forward and reverse rate constants and the equilibrium constant, for which values of approximately 72 and 3 pM were estimated at 0 and 23 degrees C, respectively. The effects of temperature, ionic strength, Ca2+ ion concentration, and activation of the zymogen on the equilibrium constants were explored; extreme sensitivity to temperature, ionic strength, and activation were found. At 23 and 30 degrees C, slow activation of C1 was also evident. Highly purified, reconstituted C1 yielded approximately the same values for the kinetic and equilibrium parameters as serum C1, suggesting that the structure of the reconstituted complex was similar to or identical with that of the serum C1 complex.

Calcium↗