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PubMed1979

Substrate modulation as a control mechanism in the activation of plasma multienzyme systems.

Since plasma is a homogenous fluid its biochemical systems need special control mechanisms to prevent their unlimited and continuous activity. In general, enzymic activity is not preformed but generated by trigger processes. Activation is then enhanced by cascade reactions. It can be controlled by enzyme inhibitors, by enzymes which destroy co-factors, or by spontaneous decay or enzyme complexes involved in the system. In addition, in some reactions of the complement and Hageman factor-dependent systems the necessity of substrate modulation controls the extent of activation. Thus, factor B of the properdin system is activatable by factor D only when bound to the activated third component of complement, and C3b fragment; similarly C2 is activated and forms the C3 converting complex, C42, only when bound to C4b prior to its cleavage by C1; C5 can be activated by either of the two convertases only when bound to surface-fixed C3b; and the mutural activation of Hageman factor and pre-kallikrein on surfaces proceeds efficiently only when HMW-kininogen is present which complexes with pre-kallikrein and possibly with Hageman factor.

Complement C3↗
PubMedDate not supplied

Necrotic facial papules in an adolescent: C2 deficiency with eventual development of lupus erythematosus.

A 14-year-old girl was admitted to the hospital because of persistent throat pain, fever, fatigue, 25 pound weight loss, and leukopenia. On physical examination she was thin, ill-appearing, and had necrotic papules on the face and palpable cervical lymph nodes. Presumptive differential diagnosis included occult malignancy and infection. Numerous investigative procedures failed to elucidate a source. Vasculitis was eventually appreciated after repeat skin biopsy. Numerous serologic studies were performed and were notable for a very low level of the second component of complement without direct evidence of lupus erythematosus (LE) or other autoimmune conditions. A diagnosis of C2 deficiency-associated vasculitis was made. She was treated with high-dose prednisone and cyclophosphamide with resolution of her symptoms. Two years later she returned with marked malar erythema. Antinuclear and Smith antibodies were then detected and a diagnosis of LE was made. She was treated with hydroxychloroquine and sun-avoidance measures with clearance of the malar rash.

Adolescent↗
PubMed1982

Production of first component of complement by corneal fibroblasts in tissue culture.

Corneal fibroblasts were studied to determine if they have the ability to synthesize and secrete complement components in tissue culture. Culture media were assayed for functional complement activity of C1, C4, C2, C3, C5, C6, and C7 with the use of 50% hemolysis of sensitized sheep RBCs. Only C1 showed a progressive increase in hemolytic activity at days 3, 5, 7, 9, and 11 of tissue culture. This increase in hemolytic C1 could be reversibly inhibited by cycloheximide, an inhibitor of protein synthesis. Corneal fibroblasts may be a potential source of C1 in the cornea.

Aged↗
PubMed1983

Role of complement and polymorphonuclear cells in demethylchlortetracycline-induced phototoxicity in guinea pigs. Inhibition by decomplementation in vivo.

In this study, demethylchlortetracycline was used as a prototype of exogenous phototoxic substances. In vitro, exposure of serum containing demethylchlortetracycline to ultraviolet-A irradiation resulted in the diminution of total complement hemolytic activity and C4, C2, C3, and C5 activities. In addition, chemotactic activity for human polymorphonuclear cells was generated, which was thermostable and antigenically related to human C5 but not human C3. In vivo, phototoxic lesions were induced in guinea pigs upon intradermal injections of demethylchlortetracycline solution, followed by ultraviolet-A irradiation. On a scale of 0-3+, the animals developed a maximal response of 2.5 at 20 h. This clinical response was associated with cellular infiltrate in the dermis, consisting of 29 +/- 2% of neutrophils at 24 h. The participation of the polymorphonuclear cells was evaluated in guinea pigs rendered neutropenic by treatment with cyclophosphamide. In these guinea pigs, demethylchlortetracycline and ultraviolet-A induced a maximal response of 0.75 +/- 0.5, which was associated histologically with 1.2 +/- 0.5% neutrophils in the dermis. The role of complement in this process was studied in guinea pigs congenitally deficient in C4, and in guinea pigs decomplemented by treatment with cobra venom factor. In contrast to normal guinea pigs, C4-deficient animals exhibited a maximal reaction of 0.83 +/- 0.16 at 6 h, which subsided within 24 h. Cobra venom factor-treated guinea pigs developed a maximal response of 0.5 at 0.5 and at 6 h. These clinical changes were associated with the development of an increased vascular permeability, as demonstrated by studies using guinea pigs injected intravenously with Evans blue solution. In animals with a normal complement system, there was intense localized bluing at the sites of phototoxic lesion. In contrast, only minimal bluing was observed in decomplemented guinea pigs. These data indicate that a normal number of polymorphonuclear cells and an intact complement system are required for the full development of demethylchlortetracycline-induced phototoxic lesions.

Animals↗
PubMed1996

Conservation of the RD-BF-C2 organization in the pig MHC class-III region: mapping and cloning of the pig RD gene.

The RD gene, named after the arginine (R) and aspartic acid (D) repeat in the central part of its protein, was initially mapped in the mouse H-2S subregion between C4 and BF. It was later mapped in the same position in the human MHC and here we show it is also conserved in the pig MHC class III region, close to the complement BF gene. A pig RD genomic clone was isolated from a lambda-phage library. Hybridizations on genomic DNA separated with pulsed field gel electrophoresis identified common 220 kb NruI, 130 kb EagI and 200 kb MluI bands for RD, BF and C2. The RD gene has also a 17 kb Kp nI and 11 kb SacI fragment in common with BF but not with C2. The close linkage of the RD and BF genes was further established by hybridization of BF to a genomic lambda-phage clone also containing the RD gene. This genomic RD clone overlaps with a lambda-phage clone previously isolated and containing the complete BF gene and the 3' part of C2. The distance between RD and BF is about 6 kb. The junction between the two complement genes BF and C2 was sequenced and the BF 5' promoter region, overlapping the 3' noncoding region of C2, was compared with that of the human BF promoter. The overall homology was about 80% and all but one identified promoter elements were found in the same position in both genes. The results obtained demonstrate the RD-BF-C2 organization is strongly conserved between human, mouse and pig. No polymorphisms were detected in either the RD gene or in the BF promoter region using polymerase chain reaction and restriction fragment polymorphism analysis.

Amino Acid Sequence↗
PubMed1982

Functional active complement components secreted by guinea pig peritoneal macrophages.

In our studies on complement secretion functional C1, C4, C2, C3, P, D and B were clearly identified in the same cultures. Functional assays did not allow the detection of C5 to C9. Spontaneous C3 activation occurred at a very low level in culture supernatants. The responsible enzyme was identified as a metallo-enzyme. Upon addition of antibody-coated sheep erythrocytes (EA) to culture supernatant it was possible to induce C3 activation as indicated by the apparent formation of EAC1423. Zymosan was also able to activate C3 in culture supernatant after addition of purified functional factor B indicating efficient cooperation of factors of the alternative pathway. Thus in this in vitro system macrophages not only provide C3 but also all factors for spontaneous and induced C3 activation. If these secretory functions reflect in vivo properties of macrophages, our results may indicate that C3 and its activating systems are most relevant for local cooperation between macrophages and the complement system in inflammation and antimicrobial defense. Therefore availability of these essential factors at any time is secured by local production.

Animals↗
PubMed1990

Effect of exercise on complement activity.

Complement measurements of C1, C1q, C2, C3, C4, C5; the anaphylatoxins, C3a, C4a, and C5a; and total hemolytic activity of the classical and alternative pathways were made in 26 experienced adult runners before and after shortterm aerobic exercise. The baseline results were compared with those of nonexercising age-matched controls. In most subjects tested, running resulted in nanogram increases in C3a and C4a with corresponding decreases in the hemolytic activity of C4 (C4H). Baseline values of C3 and C4H were decreased significantly in runners when compared with nonexercising controls. Preliminary studies measuring the effect of exercise on C3a levels were also done in three asthmatic runners. Mean resting and postexercise levels, and exercise-induced increases in C3a anaphylatoxin in the asthmatic subjects were significantly higher than in the nonasthmatic subjects. The findings indicate that short-term exercise results in the activation of C3 and C4 and subsequent generation of C3a and C4a anaphylatoxins, and suggest that both activation of the classical pathway of complement and a selective downregulation of C3 production may occur in persons regularly engaged in aerobic exercise. The exaggerated generation of C3a by asthmatic subjects during exercise raises the possibility that anaphylatoxins play an etiologic role in exercise-induced asthma.

Adult↗
PubMed1998

Deposition of mannan binding protein and mannan binding protein-mediated complement activation in the glomeruli of patients with IgA nephropathy.

Mannan binding protein (MBP) is a C-type lectin and has a high affinity to mannose and N-acetyl glucosamine. It is also known to activate C4 and C2 without C1 component, which is called 'lectin pathway'. We now report the presence of MBP and MBP-mediated complement activation in renal glomeruli of IgA nephropathy patients using an immunohistochemical method. In 7 of 42 cases with IgA nephropathy, MBP was detected in the glomerular mesangial area and colocalized with IgA1. In 19 cases with other types of IC-mediated glomerulonephritis including lupus nephritis and membranous nephropathy or without nephritis, MBP was not detected in the glomerulus. The C2- and/or C4-positive rate was 87.5% in the MBP-positive group and 20% in the MBP-negative group of IgA nephropathy. In addition, MBP-positive cases showed marked mesangial cell proliferation, lower creatinine clearance (53.4 +/- 10.0 vs. 77. 8 +/- 4.7 ml/min) and higher urinary protein excretion (2.5 +/- 0.9 vs. 0.9 +/- 0.2 g/day) compared with MBP-negative cases. These findings suggested that MBP was involved in glomerular complement activation through the lectin pathway and thus induced glomerular injury of IgA nephropathy. Since oligosaccharide chain alterations such as reduced sialic acid and galactose of IgA1 molecule have been reported in IgA nephropathy patients, MBP might bind to the IgA1 molecule via interaction between MBP and sugar chain.

Adult↗
PubMed1987

The complement system in type 1 (insulin-dependent) diabetes.

The complement proteins C1q, r, s, C2, C4, C3, factor B, C5, C6, and the inhibitors, C1 inhibitors, factors I and H were measured in 35 patients with recently diagnosed Type 1 (insulin-dependent) diabetes, 76 patients with longer-duration disease (30 with complications) and 43 first-degree healthy relatives. We found that C1q, C4 and C3 were reduced significantly in all groups of patients (p less than 0.001 for each protein in recent onset and uncomplicated patients; p less than 0.01, p less than 0.01 and p less than 0.05 respectively, for patients with complications) compared to 60 control subjects and that C4 was also reduced in healthy relatives (p less than 0.001). C4 allotypes were examined in 63 subjects (selected from the patient groups) in order to clarify the role of null alleles in the production of the C4 abnormality. These showed serum C4 to be reduced significantly in 50 patients without null alleles (patient mean 0.24 g/l; control subject mean 0.34 g/l) (p less than 0.0001), although levels were lowest in the 13 patients with one or more null alleles (mean 0.19 g/l). Finally, to examine the metabolic basis for the low concentrations of C4 and C3, the turnover of highly-purified, radiolabelled C4 and C3 was measured in seven recently diagnosed patients; four of these had low levels of C4. The data showed that three out of four of these patients had reduced synthesis of C3 and C4 and normal values for fractional catabolic rate. Two patients showed features of C4 hypercatabolism. We conclude that several early complement proteins are reduced in Type 1 diabetes, irrespective of duration or complications.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1970

The reaction mechanism of human C5 in immune hemolysis.

The data presented here indicate that the C5 reaction step may proceed via the specific attachment of C5 to EAC1,4,2,3 and the formation of a hemolytically active C5 intermediate complex. During this process only a minor proportion (less than 4%) of C5 offered to EAC1,4,2,3 becomes bound, although the remaining C5 also participates in the reaction as evidenced by its inactivation in the fluid phase. Once bound, C5 is exceptionally efficient in producing hemolysis, requiring less than seven specifically bound molecules per cell for the production of a hemolytic lesion. The extent of formation of the C5 intermediate complex is primarily dependent on the number of molecules of C4, 2 and C3 present on the cells employed for its generation. In these respects, the mode of action of C5 is completely analogous to that of the other components of complement thus far investigated. The C5 step differs, however, in other aspects. The binding of C5 is influenced by C6 and C7, components which are thought to act subsequent to it in the complement sequence. In addition, the hemolytic activity of the isolated C5 intermediate complex is exceedingly labile, having an average half-life at 30 degrees C of only 9 min. This characteristic distinguishes the C5 step, along with the C2 step, as potentially rate-limiting in the complement reaction. However, unlike C2, C5 remains firmly cell-bound during the decay process and apparently undergoes an alteration in situ which renders it hemolytically unreactive. Finally, C5 is unique in that it readily adsorbs in native form to unsensitized erythrocytes. This nonspecifically bound C5 remains firmly attached, although it may be specifically utilized as a source of C5 by an ongoing complement reaction. The significance of the marked affinity of native C5 for cell-surface receptors remains to be determined.

Adsorption↗
PubMed1994

The organization of the human complement factor I gene (IF): a member of the serine protease gene family.

The human complement factor I gene (IF) was cloned from a flow-sorted cosmid library. The gene spans 63 kb and comprises 13 exons. The first exon, which encodes the leader sequence and 5' untranslated region, is separated from the body of the gene by a large intron of 36 kb. Factor I is a mosaic protein, and there is a correlation between the genomic organization and the modular structure of the protein. The second exon encodes a module found only in complement C6 and C7 (FI/C6/C7); the third and fourth exons encode a single CD5 domain; and the fifth and sixth exons each encode a low-density lipoprotein receptor module. Two very small exons, 21 and 36 bp, then separate the first six exons from the last five that encode the serine protease domain of factor I. Within the serine protease gene family factor I has a unique genomic structure, but it bears a much closer resemblance to trypsin than it does to the other complement system serine proteases, factor B, C2, and C1r/C1s.

Base Sequence↗
PubMed1996

Effect of anticomplement agent K76 COOH on hamster-to-rat and guinea pig-to-rat heart xenotransplantation.

In normal rats, the xenobiotic K76 inhibited the C5 and probably the C2 and C3 steps of complement and effectively depressed classical complement pathway activity, alternative complement pathway activity, and the C3 complement component during and well beyond the drug's 3-hr half-life. It was tested alone and with intramuscular tacrolimus (TAC) and/or intragastric cyclophosphamide (CP) in rat recipients of heterotopic hearts from guinea pig (discordant) and hamster (concordant) donors. Single prevascularization doses of 100 and 200 mg/kg increased the median survival time of guinea pig hearts from 0.17 hr in untreated controls to 1.7 hr and 10.2 hr, respectively; with repeated injections of the 200-mg dose every 9-12 hr, graft survival time was increased to 18.1 hr. Pretreatment of guinea pig heart recipients for 10 days with TAC and CP, with or without perioperative splenectomy or infusion of donor bone marrow, further increased median graft survival time to 24 hr. Among the guinea pig recipients, the majority of treated animals died with a beating heart from respiratory failure that was ascribed to anaphylatoxins. Hamster heart survival also was increased with monotherapy using 200 mg/kg b.i.d. i.v. K76 (limited by protocol to 6 days), but only from 3 to 4 days. Survival was prolonged to 7 days with the addition of K76 of intragastric CP at 5 mg/kg per day begun 1 day before operation (to a limit of 9 days); it was prolonged to 4.5 days with the addition of intramuscular TAC at 2 mg/kg per day beginning on the day of transplantation and continued indefinitely. In contrast to the limited efficacy of the single drugs, or any two drugs in combination, the three drugs together (K76, CP, and TAC) in the same dose schedules increased median graft survival time to 61 days. Antihamster antibodies rapidly increased during the first 5 days after transplantation, and plateaued at an abnormal level in animals with long graft survival times without immediate humoral rejection. However, rejection could not be reliably prevented, and was present even in most of the xenografts recovered from most of the animals dying (usually from infection) with a beating heart. Thus, although effective complement inhibition with K76 was achieved in both guinea pig- and hamster-to-rat heart transplant models, the results suggest that effective interruption of the complement cascade will have a limited role, if any, in the induction of xenograft acceptance.

Animals↗
PubMedDate not supplied

[Results of the microbiological, clinical and immunological examination of children with Reiter's disease].

Infectious agents were detected in 100% of examined children with Reiter's disease (RD). Chlamydia trachomatis were detected in 98% of cases. In children with RD lesions of joints and eyes often took acute forms with cases of sacroiliitis, early muscular atrophy and conjunctivitis. In 95% of the patients the prostatitis manifestations were detected. In children with RD a rised number of CD lymphocytes in combination with the fivefold rised IL-4 content, an essential increase in the activity of C2-C5 components of the complement and a multiple rised level of PSA were registered.

Adolescent↗
PubMed2001

Molecular cloning of the complement (C1r/C1s/MASP2-like serine proteases from the common carp (Cyprinus carpio).

The classical pathway of complement composed of C1, C4, and C2 is an antibody-dependent activation cascade that is present in jawed vertebrates. C1 is a Ca2+-dependent complex of C1q, C1r, and C1s, and analogous to an initiation complex of the lectin pathway of complement, which consists of the mannose-binding lectin (MBL) homologous to C1q and the MBL-associated serine proteases (MASPs) homologous to C1r and C1s. Thus divergence of Clq and MBL and that of C1r, C1s and the MASPs are considered to be crucial events in the establishment and evolution of the classical complement pathway. However, molecular information on the C1 subcomponents is very limited in lower vertebrates. Here we describe two distinct C1r/C1s/MASP2-like cDNA clones (C1r/s-A, C1r/s-B) isolated from the common carp (Cyprinus carpio). They share 83% identity at the amino acid level and have a domain structure similar to that of C1r/C1s/MASPs from other species. The serine protease domain of the carp homologues lacks the histidine loop and is encoded by a single exon containing an AGY codon for the active serine residue, as in mammalian C1r, C1s, and MASP2. Southern blot and PCR analyses indicated that the carp has at least three copies of the C1r/s-A gene and a single C1r/s-B gene. Although phylogenetic tree analysis does not definitively assign carp C1r/s-A and C1r/s-B, they might represent ancestral molecules which later diverged into C1r, C1s, and MASP2 of higher vertebrates.

Alleles↗
PubMed1980

Immunological studies of human placentae: complement components in immature and mature chorionic villi.

The localization and distribution of complement components in term and pre-term normal human placentae have been studied by using haemadsorption and immunofluorescence experiments. The components Clq, C4, C5, C6 and C9 were identified in characteristic locations. Receptors for C3 and C4 were not found. Complement was associated with certain stromal cells, areas of fibrinoid necrosis within the trophoblastic mantle, and in the walls and endothelia of foetal stem vessels. Activation of the complement system on trophoblastic basement membranes (TBM) did not appear to involve the early reacting components of the classical pathway of complement activation, because C1q, C4 and C2 could not be identified on TBM. The C6 component was identified within cytoplasmic granules of foetal stem vessel endothelia, suggesting that it may be synthesized by these cells. These findings put forward the possibility that complement may play an immunobiological role in the materno-foetal relationship during normal human pregnancy.

Basement Membrane↗
PubMed1980

[Anaphylactoid shock during intravenous urography. Possible interaction between complement and fibrinolytic systems (author's transl)].

Shock associated with deep coma was induced by an injection of methylglucamine iodotalamate for descending urography to a 56-years old man without any history of atopy. Under intensive care the acute symptoms were controlled, and consciousness returned to a normal level within 15 days, but the patient remained with right-side monoplegia. Biological investigations showed a fall in total haemolytic complement (CH50) and in C1, C4, C2 and C3 components, as well as in B-factor. Acute fibrinolysis and hypocalcaemia were also present. Two main mechanisms seem to be responsible for the accident : intolerance to the drug, with direct activation of the complement and fibrinolytic systems ; and an immuno-allergic reaction where the contrast medium behaved like an hapten, which became antigenic in the body.

Anaphylaxis↗
PubMed1983

Regulation of immune complex-mediated complement activation by autoantibodies (F-42) isolated from sera of patients with systemic lupus erythematosus.

Sera of some patients with systematic lupus erythematosus (SLE) contain IgG autoantibodies (F-42) which have been shown to stabilize the cell bound classical pathway C3 convertase of complement, C42. C42 is susceptible to inactivation by the plasma protein C4bp while stabilized C42 is relatively resistant to C4bp. The present study demonstrates that F-42 by itself does not induce activation of the classical pathway in vitro but that it is able to modulate the immune complex-induced consumption of C2 and C3 in whole serum. Incubation of incremental concentrations of F-42 with normal human serum (NHS) for 30 min at 30 degrees C did not result in detectable consumption of C1q, C4, C2 and C3. However, when soluble immune aggregates or immune complexes were incubated in NHS together with 100 u/ml of F-42, a significant increase in consumption of C3 was seen as compared to the reaction mixture containing immune complexes or F-42 alone. In addition the presence of F-42 during the immune complex mediated consumption of complement was associated with relative protection of C2 consumption. (Fab)'2 and Fab' fragments of F-42 behaved as intact F-42, except that their activities on a molar basis were less than that of intact F-42. The results presented in this paper suggest that F-42 may play a regulatory role in the immune complex-mediated consumption at C2 and C3 in vivo.

Antigen-Antibody Complex↗