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PubMed1994

Isolation of the Xenopus complement factor B complementary DNA and linkage of the gene to the frog MHC.

C factor B (Bf) is the key component of the C3 convertase of the alternative C pathway, and its gene resides in the class III region of the mammalian MHC. To elucidate the evolution of both the C system and the MHC, we isolated Bf cDNA clones from Xenopus laevis, an ectothermic vertebrate in which the MHC has been well defined at both the biochemical and functional levels. A part of the serine protease domain of the Xenopus Bf mRNA was amplified by reverse transcriptase-PCR, using degenerate primers corresponding to regions encoding the perfectly conserved amino acid sequences found in both the mouse Bf and C2 proteins. A full length Xenopus Bf cDNA clone was isolated from a Xenopus liver cDNA library. The deduced amino acid sequence of 747 residues showed the same domain structure as mammalian Bf and C2: three short consensus repeat domains, a von Willebrand domain and a serine protease domain. Xenopus Bf has 40% and 30% overall amino acid identity to mouse Bf and mouse C2, respectively. Because the amino acid identity between mouse Bf and mouse C2 is 38%, the gene duplication of Bf/C2 probably occurred before the divergence of amphibians and mammals. Southern blotting analysis of the Xenopus Bf gene showed a close linkage to the MHC, indicating that the Bf gene was linked to the class I and class II genes at the time Xenopus shared a common ancestor with mouse and man, 350 x 10(6) yr ago.

Amino Acid Sequence↗
PubMed1981

Complement does not facilitate plasmodial infections.

The influence of the complement (C) system on Plasmodial infections in vivo (Plasmodium berghei in rats) and in vitro (Plasmodium falciparum) has been determined. In rats C3 depletion by treatment of animals with the C3 inactivator isolated from cobra venom factor results in infection that develops more rapidly, reaches a higher peak of parasitemia and is associated with an increased mortality rate (60%), in contrast to a lower degree of parasitemia and lack of mortality in C3-intact rats. The infection of human red cells by P. falciparum is not affected when serum C is inactivated either by heat treatment or by incubation with preformed immune complexes. Furthermore, human sera genetically deficient in C2, C3, C4, or C5 are as effective in facilitating the infection of red cells as is C-intact serum. These data suggest that, in contrast to Babesia sp., the in vitro or the in vivo infection of red cells by Plasmodium sp is not facilitated by the availability of C.

Animals↗
PubMed1983

The first component of human complement (C1): activation and control.

The first component of human complement (C1) is a 750 000 dalton glycoprotein that requires calcium or other specific metal ions to maintain its native structure and function. Under physiologic conditions, C1 comprises two weakly interacting subunits, C1q and C1r2s2, with C1q containing the binding site(s) for activators and C1r2s2 possessing enzymatic potential. C1 circulates in a precursor state and only after "activation" does it acquire functional activity, manifested as enzymatic activity specific for its natural substrates C2 and C4. C1 activation, which is accompanied by limited proteolysis and conformational changes, can be induced by immune complexes or certain nonimmune substances. With C1 binding to an immune complex, the strength of interaction between C1q and C1r2s2 increases. C1 also spontaneously activates at 37 degrees C by an intramolecular autocatalytic mechanism although at a slower rate than that induced by activators. C1 functions are controlled by the serum glycoprotein C1-inhibitor (C1-In) which blocks the enzymatic activities of activated C1 (C1). Under physiologic conditions, C1 has a half-life of only 13 seconds in the presence of C1-In. C1 is efficiently disassembled by C1-In, thereby releasing two inactive C1rC1s(C1-In)2 complexes per C1 molecule, leaving C1q activator-bound with biologically reactive sites uncovered that are not expressed in macromolecular C1. The most recently recognized function of C1-In is that of controlling the C1 activation process itself. While having only limited effect on immune complex-induced C1 activation, C1-In effectively controls certain nonimmune-induced as well as spontaneous C1 activation. Thus C1-In plays an important role in regulating nonspecific complement activation. The latter observation is relevant for the understanding of the human disease hereditary angioedema. An overabundance of spontaneous C1 autoactivation, due to low C1-In levels, might underlie the abnormal activation of complement via the classical pathway detected in the sera of these patients. Finally, recent studies indicate that C1 may have other important biologic functions in addition to initiating the complement cascade.

Angioedema↗
PubMed1987

There are two C4 genetic loci and a null allele in the chimpanzee.

Genetic polymorphism in C4 in the chimpanzee was studied by agarose gel electrophoresis of desialated plasma and development of patterns by immunofixation with antiserum to human C4 and by a C4-sensitive hemolytic overlay. In general, immunofixation patterns showed multiple partially overlapping bands of which only the most cathodal had strong hemolytic activity. In analogy to human C4, the latter were designated C4B, whereas those detected by immunofixation which had little hemolytic activity were designated C4A. Chimp C4A and C4B reacted with human and mouse (monoclonal) anti-C4B and human anti-Ch1 but neither reacted with monoclonal anti-C4A or human anti-Ch2, Ch3, Rg1, or Rg2. On sodium dodecyl sulfate polyacrylamide gel electrophoresis, the alpha chain of C4B showed a slightly lower apparent relative mass than that of C4A at around Mr 93,000. There were three C4A variants and two C4B variants inherited in families as autosomal codominant traits, as C4A-C4B cosegregating pairs with no detectable crossing-over. These pairs were inherited with chimpanzee leukocyte antigen types C2 and BF variants without detectable crossing-over. Half-null C4 haplotypes with C4B QO were observed in family studies. Nine BF, C2, C4A, C4B allelic haplotypic combinations (complotypes) were identified among presumably unrelated chimpanzees.

Alleles↗
PubMed1989

Tissue-specific initiation of murine complement factor B mRNA transcription.

Factor B (Bf) gene expression is regulated independently in hepatic and extrahepatic tissues. In studying murine factor B expression, we found two mature mRNA species for Bf in kidney and intestine (2.7 and 2.4 kb) but in other tissues, including liver, lung, spleen, heart, brain, and skeletal muscle, only a single Bf transcript (2.4 kb) was observed. These two Bf transcripts in kidney or intestine are identical in structure except for a 300 bp 5' extension found in the 2.7-kb mRNA. The long Bf transcript originates from a tissue-specific alternative site of transcriptional initiation upstream of the initiation site for the 2.4-kb mRNA, as determined by primer extension and nuclease protection assays. The upstream initiation site lacks a typical promoter motif and is only 80 bp downstream from the terminus of the murine C2 gene. After stimulation in vivo with endotoxin, only the 2.4-kb mRNA increases in kidney indicating independent regulation of the two Bf transcripts. The differences in 5' untranslated region generated in these two Bf mRNA species may affect local concentrations of factor B protein in kidney and intestine by mechanisms depending on differential translation rates or stability of mRNA.

Acute-Phase Reaction↗
PubMed1976

Mechanism of injury of virus-infected cells by antiviral antibody and complement: participation of IgG, F(ab')2, and the alternative complement pathway.

Antibody-mediated C-dependent lysis of cell lines infected with herpes simplex type 1 virus, influenza A degrees virus, measles virus, and mumps virus occurred by the alternative C pathway with the participation of IgG antibodies. Lysis occurred only with immune human sera, Mg++ EGTA immune sera, and immune sera depleted of C4 or treated with Fab anti-C4. Lysis did not occur with nonimmune sera, Mg++ EDTA immune sera, and immune sera heated 50 degrees C for 25 min, depleted of factor B or treated with Fab antifactor B. Lysis was restored to heated and factor B immunodepleted immune sera by addition of factor B, but not by addition of an excess of C2. Further studies showed that lysis of HeLa cells infected with measles virus was induced by both immune IgG and F(ab')2 but not Fab' in the presence of a nonantibody-containing human C source. Lysis of measles virus-infected cells was also indpendent of movement of viral antigens on the surface of the infected cells, as inhibition of viral antigen capping by cytochalasin B or sodium azide was not associated with abrogation of immune lysis.

Antibodies, Viral↗
PubMedDate not supplied

Enhanced generation of O2- by human neutrophils via a complement iC3b/Mac-1 interaction.

There is evidence for a tumor necrosis factor alpha (TNF alpha)-initiated and CD11b/CD18-dependent burst of superoxide anion (O2-) and hydrogen peroxide production by human polymorphonuclear leukocytes which are adherent to surfaces bearing a variety of proteins. In the current studies neutrophils were stimulated with opsonized (by fresh human serum) zymosan particles in the presence of cytochalasin B, to prevent internalization of particles and to simulate the interaction of neutrophils with protein-bearing surfaces. Under these conditions, the cells demonstrated 2.9-fold greater production of O2- when compared to nonopsonized zymosan particles. Heat inactivation or cobra venom factor treatment of human serum prior to opsonization resulted in 98% and 66% reductions, respectively, in O2- responses. C3 and factor B were required for this response, since sera deficient in either component caused 56 and 68% reductions, respectively, in O2- production. Sera deficient in Clq, C2, C4, C5, C6, C7 or C9 showed no defect in their ability to enhance O2- responses to zymosan particles. Monoclonal antibody to iC3b, but not monoclonal antibodies to C3c or C3d, caused a 29% reduction (p < 0.01) in O2- generation. Antibodies to CD18 (R15.7) or CD11b (CL44 and 60.1) reduced the incremental production of O2- by 76, 71 and 77%, respectively. Two antibodies directed against CD11a as well as the isotype-matched control (MOPC 21) were without effects. These data suggest that, in this model of neutrophil activation, the pathway for O2- generation is a Mac-1 (but not LFA-1)-dependent pathway and also requires iC3b. These findings may be relevant to complement-mediated, neutrophil-dependent vascular injury in vivo.

Complement C3b↗
PubMed1977

Requirements for the solubilization of immune aggregates by complement: assembly of a factor B-dependent C3-convertase on the immune complexes.

During the solubilization of immune precipitates BSA-rabbit antibodies to BSA by human complement, at least three stages can be distinguished. (A) Generation of alternative pathway C3-convertase sites associated with the immune complexes. During the first minutes of interaction between the immune aggregates and serum, before any solubilization has taken place, properdin (P), factor B, and C3 moieties are incorporated into the lattice. The washed precipitates have C3-convertase activity, which can be completely inhibited by antibodies to factor B, but not to C2. The assembly of the convertase is temperature-dependent, and does not take place in the absence of Mg++. The immune complex-associated C3-convertase activity decays rapidly at 37 degrees C, but it can be restored by addition of purified factor B and properdin. (B) Amplification. When the aggregates bearing C3-convertase are incubated with purified C3, solubilization takes place. It appears that solubilization is caused by the accumulation of a large number of C3 fragments on the Ag-Ab lattice. In solubilized complexes, the molar ratios of Ab/C3 are close to one. (C) Spontaneous release. The final step in the solubilization process is a secondary reaction, during which some rearrangement of the lattice takes place. It occurs in medium devoid of serum and does not require divalent cations.

Antigen-Antibody Complex↗
PubMed2006

Structure of complement component C2A: implications for convertase formation and substrate binding.

C2a provides the catalytic center to the convertase complexes of the classical and lectin-binding pathways of complement activation. We determined two crystal structures of full-length C2a, with and without a pseudo ligand bound. Both structures reveal a near-active conformation of the catalytic center of the serine protease domains, while the von Willebrand factor A-type domains display an intermediate activation state of helix alpha7 with an open, activated metal-ion-dependent adhesion site. The open adhesion site likely serves to enhance the affinity for the ligand C4b, similar to "inside-out" signaling in integrins. Surprisingly, the N-terminal residues of C2a are buried in a crevice near helix alpha7, indicative of a structural switch between C2 and C2a. Extended loops on the protease domain possibly envelop the protruding anaphylatoxin domain of the substrate C3. Together with a putative substrate-induced completion of the oxyanion hole, this may contribute to the high substrate specificity of the convertases.

Amino Acids↗
PubMed1984

Studies of complement autoactivatability in hereditary angioedema: direct relationship to functional C-1-INA and the effect of classical pathway activators.

It has been observed earlier that the hemolytic complement in diluted sera obtained from patients with hereditary angioedema (HAE) undergoes spontaneous decay when incubated at 37 degrees C. Employing individual serum from patients at different stages of this disease it was demonstrated that this spontaneous loss of hemolytic complement also occurs without dilution and is directly linked to the absence of functional C-1-INA. Incubation of HAE serum resulted in a loss of activity which appears to be dependent upon the concentration of functional C-1-INA. While C-1-INA levels less than 50 micrograms/ml lead to rapid depletion with time, reconstitution of deficient sera with highly purified C-1-INA or of undiluted NHS inhibited spontaneous activation. Furthermore, NHS was rendered susceptible to autoactivation when its C-1-INA was depleted by passage over an anti-C-1-INA Sepharose 4B affinity column in the presence of 10 mM EDTA, indicating that in the absence of functional C-1-INA, C1 undergoes an uninhibited spontaneous autoactivation which leads to the consumption of C4 and C2 but not C3. Consumption of C3 was observed, however, in HAE sera that contained a significant amount of immune complexes. Incubation of HAE sera with highly purified Hageman factor fragment (5 micrograms/ml), or aggregated IgG (2 mg/ml) was found to accelerate the rate of decay when compared to untreated samples while sera from patients under treatment with Danazol or Stanozolol failed to autoactive. These results suggest that, the absence of C-1-INA, may, by itself trigger the dissociation and autoactivation of C1 in the sera of such patients; however, the presence of other complement activators accelerates the reaction. This inherent property of HAE sera, i.e., spontaneous autoactivation at 37 degrees C, may be a useful screening test but direct determination of C-1-INA activity is required to establish the precise diagnosis.

Angioedema↗
PubMed1990

Hormonal regulation of complement biosynthesis in human cell lines--I. Androgens and gamma-interferon stimulate the biosynthesis and gene expression of C1 inhibitor in human cell lines U937 and HepG2.

C1 inhibitor (C1inh), a member of the serine protease inhibitor gene superfamily, is a glycosylated plasma protein inhibiting the proteolytic activities of C1r and C1s and involved in the regulation of coagulation, fibrinolysis and kinin-releasing systems. In this study, the in vitro effect of androgen hormones, dehydroepiandrosterone (DHEA), testosterone (TEST) and recombinant human gamma-interferon (gamma-IFN), has been determined on the production of C1inh in human cell lines. In both human monocytoid/histiocytoid cell line U937 and in hepatoma derived cell line HepG2, DHEA and TEST upregulated the gene expression and secretion of C1inh. The most pronounced effect was detected in the concn range 10(-7)-10(-9) M of the hormones. Under the same conditions DHEA and TEST had no detectable effect on the biosynthesis of C3, C2 and factor B by these cells, but DHEA at higher concn (10(-4) M) slightly increased that of C4 in HepG2 cells. Both in U937 and in HepG2 cells recombinant gamma-IFN markedly increased the gene expression and secretion of C1inh. This effect of gamma-IFN was abolished by histamine.

Carcinoma, Hepatocellular↗
PubMed1983

Nature of the metal ion requirement for assembly and function of the first component of human complement.

The first component of human complement (C1) was reconstituted from equimolar concentrations of its purified subunits C1q, C1r, and C1s, in the presence of each of nine different metal ions for the purpose of studying the qualitative and quantitative nature of the metal ion requirement for C1 assembly and function. For C1 reconstituted with each metal ion, three assays characteristic of C1 were performed as follows: (1) spontaneous C1 activation in the absence of the regulatory protein C1-inhibitor was assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis by simultaneously quantifying the specific proteolysis of the C1r and C1s subunits; (2) C1 activation induced by aggregated IgG in the presence of C1 inhibitor was similarly analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis; and (3) formation of 16 S macromolecular C1 was determined in the analytical ultracentrifuge. For all experiments, trace metal contaminants were removed from buffers and proteins. All divalent cations tested from the first transition period of the periodic table (i.e. Ca2+, Mn2+, Co2+, Ni2+, and Zn2+) effectively mediated the formation of functional macromolecular C1. Dose curves showed maximal C1 assembly and activation at ion concentrations of 30 to 50 microM for each of the above metal ions. However, when ion concentrations were increased above 50 microM, C1 assembly and activation became inhibited. The further to the right in the periodic table, the better inhibitor was the metal ion. Competition experiments indicated that the ion binding sites mediating inhibition are distinct from those promoting activation. Other metal ions that also effectively mediated C1 assembly and function were Cd2+ and Tb3+; however, Mg2+ and Ba2+ were ineffective. All metal ions that mediated C1 assembly and activation also promoted C2 consumption by C1 in normal human serum treated with aggregated IgG. In conclusion, the assembly and function of C1 can be mediated by numerous metal ions. In direct opposition to accepted theory, there is no specific requirement for calcium.

Calcium↗
PubMed1983

Familial systemic lupus erythematosus: immunogenetic studies in eight families.

Familial SLE provides a unique opportunity to study the relationships of previously associated genetic factors (HLA and complement component deficiencies) to the occurrence of SLE, other immune disorders, and autoantibodies in families. Thus, eight families containing two or more affected members with SLE (n = 22) and their relatives (n = 40) were examined for HLA genotypes, complement components and autoantibodies. Among the 40 non-SLE relatives, 7 (18%) had other immune diseases, including thyroid disease in 2, rheumatoid arthritis in 2, ITP in 2, and Henoch-Schönlein purpura in one. This compared to 4 of the 22 SLE patients (also 18%) of whom 3 had thyroid disease and one PSS. Eleven non-SLE relatives (28%) had ANA, which was in high-titer in 5 (13%). Eleven (28%) had antibodies to ssDNA, and one had a BFP. Only the SLE patients had antidsDNA, Ro(SSA), Sm or nRNP. A heterozygous C2 deficiency (C2D) was found in only one of the seven kindreds studied, and followed an A25, B18 DR7 haplotype. Heterozygous C2D, however, was inherited by only one of three family members with SLE. HLA-DR2 occurred in 36% and DR3 in 36% of SLE patients, which was not significantly different from either non-SLE family members or unrelated local controls. Sib pair analysis of seven sets presented here and seven from two published reports, demonstrated only random distribution with SLE. Similarly, other immune disorders and autoantibodies followed no consistent HLA haplotypes or DR specificities. Interestingly, DR2 and/or DR3 were found in five of the six patients (83%) having anti-ro(SSA) antibodies (p = NS). These data strongly suggest that genetic factors (other than HLA and complement component deficiencies) and/or environmental factors are necessary for the expression of SLE and other immune abnormalities in lupus families.

Adult↗
PubMed1985

Familial exercise-induced anaphylaxis.

An 18-year-old hispanic male, his two brothers, father, two paternal uncles, and paternal grandfather experienced cutaneous and cardiorespiratory symptoms during vigorous exercise beginning at about 10 years of age. The propositus was challenged by running to exhaustion and by immersion in hot water. In neither case were allergic signs or symptoms noted; however, plasma histamine rose from undetectable levels to 1.0 and 3.7 ng/ml, respectively. Furthermore, C2 and C5 were significantly reduced and fell during exercise.

Adolescent↗
PubMed1996

A single mouse glutathione synthetase gene encodes six mRNAs with different 5' ends.

To understand more about the role of glutathione (GSH) in metabolism, we have cloned both cDNA and genomic sequences for mouse glutathione synthetase (GSH syn), the enzyme that catalyzes the last step in the synthesis of glutathione. The mouse cDNA contains an open reading frame (ORF) of 474 aa and shares 64 and 95% deduced amino acid sequence identity with Xenopus cDNA and rat cDNA, respectively. The cDNA complements Schizosaccaromyces pombe strains deficient in GSH syn. The gene is a single-copy gene spanning approximately 30 kb and is composed of at least 15 exons. Steady-state RNA levels and enzyme activity levels are highest in kidney, about 3-fold lower in liver, and 8- to 10-fold lower in lung and brain. We have identified six different GSH syn RNAs: three, termed types A1, A2, and A3, have different 5' ends that localize to different sites in the gene, but appear to encode the same protein (474 aa). Types B, C1, and C2 all have unique 5' ends and type-specific ORFs, which are shorter than that for types A1, A2, and A3. In liver only type A1 GSH syn RNA is detectable, while in kidney 90% of GSH syn RNA is type A1 and types B and C account for about 10%.

Alternative Splicing↗
PubMed1982

Comparative influence of blood-borne nonbacterial particles and Staphylococcus aureus on fibronectin, complement and immunoglobulin.

Opsonic fibronectin deficiency has been documented in septic injured patients and suspected to reflect acute depletion due to blood-borne nonbacterial particulates. In the present study, the comparative effect of intravenous infusion of heat-killed Staphylococcus aureus or gelatin-coated nonbacterial test particles on immunoreactive fibronectin, IgG and C3 was investigated. These two test particles were selected because of their known dependence upon adequate opsonization for efficient RES phagocytic removal. The intravenous injection of gelatin-coated RE test lipid emulsion (50 mg/100 gm body weight) resulted in an acute depletion of serum fibronectin with no major alteration in circulating IgG or C3. This selective depletion of fibronectin was followed by a rapid restoration and elevation of fibronectin level within 24 hours. In contrast, intravenous infusion of heat-killed S. aureus (1 X 10 11/rat) resulted in an acute depletion of fibronectin and C2 within 60 minutes. The deficiency of these opsonic proteins after bacterial challenge was followed by elevation of fibronectin and normalization of C2. IgG was not significantly changed at any time. The decline in fibronectin and C3 was greater with an increase in bacterial dose. These studies emphasize the specificity of the opsonic deficiency induced by gelatin-coated particles. Additionally, the suggest that opsonic deficiency with S. aureus bacteremia may be, in part, functionally related to disturbances of fibronectin. The role of fibronectin deficiency in documented states of opsonic deficiency with sepsis warrants consideration.

Animals↗
PubMed1996

Autoantibodies to the collagen-like region of C1q are strongly associated with classical pathway-mediated hypocomplementemia in systemic lupus erythematosus.

We have investigated the presence of autoantibodies to the collagen-like region (CLR) of C1q and its relationship with classical pathway-dependent hypocomplementemia in patients with SLE. Antibodies to CLR/C1q were quantitated in the plasma of 113 unselected patients with SLE by ELISA, using purified CLR as antigen. Plasma concentration of C3, CH50 activity and C2 hemolytic activity were determined according to standard procedures. The prevalence of IgG antibodies to CLR/C1q in the study population was 33.6%. Plasma titers of anti-CLR/C1q autoantibodies showed a strong negative correlation with CH50 activity (p < 0.0001) and with plasma levels of C3 (p < 0.0001). Eighty-five percent of patients with severe complement consumption exhibited high titers of anti-CLR/C1q antibodies in plasma, independently of clinical disease activity. Anti-CLR/C1q antibodies were present in the plasma of 38% of patients with moderate classical pathway consumption and 14% of patients with no evidence of complement consumption. Analysis of sequential samples from six patients over a period of 18 to 24 months demonstrated that changes in CH50 activity mirrored those of the plasma titers of anti-CLR/C1q antibodies. Acquired hypocomplementemia through the classical pathway is strongly associated with the presence of anti-CLR/C1q autoantibodies in SLE. The results suggest that anti-CLR/C1q antibodies may perpetuate classical pathway activation, independently of clinical disease activity.

Autoantibodies↗
PubMed1986

The value of rocket immunoelectrophoresis for C4 activation in the evaluation of patients with angioedema or C1-inhibitor deficiency.

The correct diagnosis and characterization of C1-inhibitor deficiency depends on both clinical observations and laboratory evaluation of complement in plasma. Rocket immunoelectrophoresis for C4d is a sensitive assay for C4 activation in plasma. We have evaluated the value of this assay in identifying patients with C1-inhibitor deficiency. C4 activation was assessed in the plasmas of 15 patients with hereditary angioedema, five patients with variant form of hereditary angioedema, and four patients with acquired C1-inhibitor deficiency. Control groups consisted of 27 patients with chronic idiopathic urticaria and/or angioedema and seven normal volunteers. C4 activation was detected in all 52 plasma samples collected from the 24 patients with C1-inhibitor deficiency. The degree of C4 activation increased during attacks of angioedema and decreased (but remained elevated) during treatment with attenuated androgens. The concentrations of C4, C2, and C1 inhibitor were also measured; however, none of these measurements identified all of the patients with C1-inhibitor deficiency. Thus, we conclude that the measurement of C4 activation is one of the best tests available to evaluate a patient for C1-inhibitor deficiency, and a normal result will exclude the diagnosis of C1-inhibitor deficiency.

Androgens↗