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PubMed1983

Heat-induced fragmentation of human plasma fibronectin.

Human plasma fibronectin was found to undergo fragmentation during heat-denaturation, leading to artifacts in SDS-polyacrylamide gel electrophoretic analyses. Electrophoretic patterns of heated samples showed a progressive decrease in intact fibronectin chains (225 kDa) which coincided with the appearance of increasing amounts of numerous smaller components having molecular weights ranging from 10 000 to 200 000. The fragmentation was temperature-dependent, being undetectable after 2 h at 60 degrees C, but detectable after 30 min at 70 degrees C or as little as 2 min at 100 degrees C. After 2 h at 100 degrees C, the intact monomer was no longer visible. Neither mercaptoethanol nor SDS was required for fragmentation. Sterile filtration or pretreatment with inhibitors of proteolytic enzymes had no effect. Treatment with amines did not diminish the degradation, indicating that the process differs from heat-fragmentation of alpha 2-macroglobulin and complement proteins, which occurs at a reactive internal thiolester bond. Fibronectin fragmentation was highly pH-dependent, being markedly accelerated under acidic conditions, suggesting that autolytic cleavage of the peptide chain at acid-labile aspartyl bonds was responsible for this phenomenon.

Complement C3↗
PubMed2002

Complement C2 receptor inhibitor trispanning and the beta-chain of C4 share a binding site for complement C2.

Complement C2 receptor inhibitor trispanning (CRIT) of the Schistosoma parasite binds human C2 via the C2a segment. The receptor in vivo functions as C2 decoy receptor by directly competing with C4b for binding to C2. As a result, CRIT is able to limit the extent of classical pathway (CP) C3 convertase formation. We report that the CRIT-extracellular domain 1 (ed1) peptide inhibits CP-mediated complement activation with an ICH(50) of approximately 0.1 microM, the C-terminal 11 aa of CRIT-ed1, named H17, even more effectively. The beta-chain region F222-Y232 of C4 shares 55% identity and 73% similarity with H17. Peptides based on this region also inhibit CP in a dose-dependent manner. As further evidence of C2 binding we showed CRIT-ed1 peptides and homologous C4 beta-chain peptides to inhibit complement in C2 hemolytic assays. We have predicted C4 beta-c F222-Y232 as a C2 binding site which we have termed the CRIT-ed1 domain, and the sequence [F/H]EVKX(4/5)P as a consensus C2-binding sequence. Anti-CRIT-ed1 cross-reacts with the C4 beta-chain and F222EVKITPGKPY232 appears to be the key epitope recognized by this Ab. Furthermore, anti-CRIT-ed1 was found to inhibit CP activation in a total hemolytic assay. We believe that Schistosoma CRIT-ed1, as well as C4 beta-chain peptides based on the CRIT-ed1 domain, function as interface peptides. These peptides, based on C2-binding sequences in CRIT, or C4, competitively inhibit the binding of C2 to C4b and thus limit the activation of C. The C4 peptides, unlike CRIT-ed1, did not inhibit the cleavage of C2 by C1s.

Amino Acid Sequence↗
PubMed1995

The third component of Xenopus complement: cDNA cloning, structural and functional analysis, and evidence for an alternate C3 transcript.

Although the third component of complement has been purified from two amphibian species, Xenopus laevis and the axolotl, only limited information is available about its primary structure in these species. We now present (a) 95% of the cDNA sequence encoding C3 from a Xenopus laevis/Xenopus gilli (Xenopus LG) hybrid (b) an analysis of the C3 convertase and factor I cleavage sites in Xenopus C3, and (c) evidence for an alternative form of C3. The Xenopus LG sequence has a 57% nucleotide and 52% amino acid sequence identity to human C3 and contains one potential N-glycosylation site in the beta-chain. The deduced amino acid sequence showed that the C3 convertase and factor I cleavage sites (Arg-Ser) are conserved in Xenopus C3 and protein sequencing of Xenopus C3 fragments fixed on zymosan during complement activation demonstrated that Xenopus C3 is indeed cleaved by C3 convertase and factor I at these sites. Our screening of a liver cDNA library identified an unusual C3 clone with a deletion of 2502 bp, suggesting the presence of a novel C3 transcript in Xenopus LG liver. The presence of this C3 transcript was confirmed by reverse transcription polymerase chain reaction using Xenopus LG liver mRNA and specific oligonucleotide probes. This transcript encoded a putative 102-kDa protein comprising the beta-chain of C3, together with the first 59 residues and the last 103 residues of the alpha-chain; it would therefore lack many of the ligand binding sites found in the intact alpha-chain. However, the molecule may be an analog of a truncated C3 molecule that is found in the serum of allergic dermatitis patients and acts as an inhibitor of eosinophil cytotoxicity and neutrophil adherence.

Amino Acid Sequence↗
PubMed1995

Comparative study of four proteases from spent culture media of Porphyromonas gingivalis (FAY-19M-1).

Four gelatin cleaving proteases were partially purified from culture media of Porphyromonas gingivalis (FAY-19M-1) by sequential chromatography on columns of DEAE-Sepharose, Sephadex G-100 and chromatofocusing on PBE-94. The molecular mass of each of these proteases, estimated by relative mobility on gelatin-containing SDS-PAGE, was 50 kDa (Pool D1b), 120 kDa (Pool E1a), approximately 160 kDa (Pool E1b) and > 300 kDa (Pool A1a), respectively. These proteases also differed with respect to charge characteristics, inhibition profile and cleavage specificity. Protease pools A1a and E1a were inhibited by thiol modifying reagents. Protease pool A1a was also inhibited by N-tosyl-L-lysine chloromethyl ketone, and E1a was inhibited by antipain. Protease pool D1b was inhibited by E-64, leupeptin and antipain, and protease E1b was not inhibited by either of these inhibitors. The detailed substrate specificity of these proteases was checked by using chromogenic substrates, synthetic peptides and native proteins. Protease E1b was very active in degrading collagen, fibrinogen, fibronectin, IgG, IgA, third component of complement (C3), serum albumin, transferrin and varies; is directly proportional to 1-acid glycoprotein as substrates. Fibrinogen, fibronectin and complement C3 component were also cleaved by A1a, D1b and E1a. Synthetic peptides insulin B chain, cecropin P-1 and magainin were cleaved by E1b. Based on FAB analysis E1b showed preferential cleavage at hydrophobic or neutral residues. Protease A1a was active towards chromogenic substrates with either lys or arg in P1 position. Protease D1b cleaved chromogenic substrates with arg in P1 position and cleaved synthetic peptides magainin and (KIAGKIA)3-NH2 at lys residues also. Protease E1a showed glycyl-prolyl peptidase activity.

Amino Acid Sequence↗
PubMed2005

Further characterization of reproductive abnormalities in mCd59b knockout mice: a potential new function of mCd59 in male reproduction.

CD59 is a GPI-linked membrane protein that inhibits formation of the membrane attack complex of complement. We reported recently that mice have two CD59 genes (termed mCd59a and mCd59b), and that the targeted deletion of mCd59b (mCd59b-/-) results in spontaneous hemolytic anemia and progressive loss of male fertility. Further studies of the reproductive abnormalities in mCd59b-/- mice reported in this study revealed the presence of abnormal multinucleated cells and increased apoptotic cells within the walls of the seminiferous tubules, and a decrease in the number, motility, and viability of sperm associated with a significant increase in abnormal sperm morphologies. Both the capacitation-associated tyrosine phosphorylation and the ionophore-induced acrosome reaction as well as luteinizing hormone, follicle-stimulating hormone, and testosterone serum levels were similar in mCd59b-/- and mCd59b+/+. Surprisingly, the functional deficiency of the complement protein C3 did not rescue the abnormal reproductive phenotype of mCd59b-/-, although it was efficient in rescuing their hemolytic anemia. These results indicate that the male reproductive abnormalities in mCd59b-/- are complement-independent, and that mCd59 may have a novel function in spermatogenesis that is most likely unrelated to its function as an inhibitor of membrane attack complex formation.

Anemia, Hemolytic↗
PubMed1977

Immunoglobulins, proteinase inhibitors, albumin, and lysozyme in human cervical mucus. I. Communication: hormonal profiles and cervical mucus changes--methods and results.

The serum levels of luteinizing hormone (LH), estradiol-17beta, and progesterone were determined simultaneously with the concentrations of immunoglobulin (Ig) G, IgA, C'3, alpha1-antitrypsin, inter-alpha-trypsin inhibitor, alpha1x-antichymotrypsin, albumin, and lysozyme in cervical mucus during nine ovulatory cycles. Spinnbarkeit and ferning were also assessed, and the basal body temperature was measured and recorded during these cycles. The profiles were synchronized according to the LH peak. The midcycle period, characterized by the rapid increase and decline of estrogen and the beginning rise of progesterone, shows a prounced minimum of immunoglobulins, C'3, proteinase inhibitors, albumin, and lysozyme in cervical mucus, which is known to be most receptive to sperm penetration at this time. Although the variation of cervical mucus values is considerable during the early proliferative and the luteal phases, the midcycle values appear to be constantly low, showing slight differences among the profiles of the different parameters. The statistical evaluation and the assessment of the significance of parameters for ovulation detection and the assessment of the fertile period as well as the correlation of these parameters with basal body temperature will be the subject of the second communication of this series.

Adult↗
PubMed1987

Degradation in vivo of articular cartilage in rheumatoid arthritis and juvenile chronic arthritis by cathepsin G and elastase from polymorphonuclear leukocytes.

Peroxidase-anti-peroxidase (PAP) staining and specific antibodies against cathepsin G and elastase from polymorphonuclear leukocytes (PMN) were applied to pannus-free and microscopically intact superficial articular cartilage. Restricted local deposits containing cathepsin G and elastase were found in three of ten patients with seropositive rheumatoid arthritis (RA), in one of three patients with seronegative RA and in one patient with juvenile chronic arthritis (JCA). Similarly, localized deposits of IgG and C3 were found in the patients with seropositive RA and JCA, but not in the patient with seronegative RA. Adjacent sections exhibited esterase activity in and around the PMN. In proteinase-positive areas from patients with seropositive RA the inhibitors alpha 1-proteinase inhibitor (alpha 1-PI) and alpha 2-macroglobulin (alpha 2-MG) were present in two of three and one of three patients, respectively. In JCA only alpha 1-proteinase inhibitor was present, and in seronegative RA no inhibitors were found. No staining of articular cartilage was observed in a patient with psoriatic arthritis. One of three cases with osteoarthritis exhibited patchy superficial staining for IgG only. In articular cartilage covered by pannus, in three patients with seropositive RA, in one with seronegative RA and in the patient with JCA a few regions with variably dense PMN infiltrates were observed. Cathepsin G, elastase and esterase activity were found in and around the PMN. In one of the three patients with seropositive RA the adjacent cartilage-pannus junction exhibited distinct staining for cathepsin G and elastase, but not for IgG/C3 and proteinase inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)

Arthritis, Juvenile↗
PubMedDate not supplied

Processing of serum proteins underlies the mass spectral fingerprinting of myocardial infarction.

The MALDI-TOF spectra of peptides from the sera of normal and myocardial infarction patients produced patterns that provided an accurate diagnostic of MI. In myocardial infarction, the spectral pattern originated from the cleavage of complement C3 alpha chain to release the C3f peptide and cleavage of fibrinogen to release peptide A. The fibrinogen peptide A and complement C3f peptide were in turn progressively truncated by aminopeptidases to produce two families of fragments that formed the characteristic spectral pattern of MI. Time course and inhibitor studies demonstrated that the peptide patterns in the serum reflect the balance of disease-specific-protease and aminopeptidase activity ex vivo.

Amino Acid Sequence↗
PubMedDate not supplied

The role of complement and activated microglia in the pathogenesis of Alzheimer's disease.

A variety of inflammatory mediators including complement activation products, protease inhibitors, and cytokines are colocalized with beta-amyloid (A beta) deposits in the Alzeimer's disease (AD) brain. Activation products of the early complement components C1, C4, and C3 are always found in neuritic plaques and to a lesser extent in varying numbers of diffuse plaques. In contrast to these findings, no immunohistochemical evidence was obtained for the presence of the late complement components C7 and C9 and the complement membrane attack complex in the neuropathological lesions in AD brains. The mRNA encoding the late complement components C7 and C9 appears to be hardly or not detectable. These findings indicate that in AD the complement system does not act as an inflammatory mediator through membrane attack complex formation, but through the actions of the early complement products. In this review we focus on the role of complement in the pathological amyloid cascade in AD. In our opinion, the early complement activation products play a crucial role as mediators between the A beta deposits and the inflammatory responses leading to neurotoxicity.

Alzheimer Disease↗
PubMed1992

Inactivation of human serum bactericidal activity by a trypsinlike protease isolated from Porphyromonas gingivalis.

A protease was isolated from an outer membrane vesicle preparation of Porphyromonas gingivalis ATCC 33277 and assessed for its ability to inactivate the bactericidal activity of normal human serum. The enzyme, which was activated by reducing agents, was found to be a trypsinlike protease with a molecular mass of approximately 80 kDa. Prior to being tested in the bactericidal assay, pooled human serum was preincubated with the partially purified enzyme. Under conditions in which the trypsinlike protease was activated, a strong reduction of the serum bactericidal activity against Capnocytophaga ochracea was noted. On the other hand, no reduction of the bactericidal action of serum was observed when the serum-protease mixture was preincubated in the presence of an inhibitor of the enzyme. As determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the protease was shown to degrade immunoglobulins G and M as well as complement factor C3. This study confirms the previous hypothesis that the proteases of P. gingivalis can interfere with the protective action of human serum.

Blood Bactericidal Activity↗
PubMed1986

Genetic markers in rheumatoid arthritis.

Genetic as well as environmental factors are believed to be of importance in the etiology of rheumatoid arthritis (RA). There are a number of previous studies of genetic markers in RA, but so far no genetic linkage and only a few associations have been found. Of the associations only one (with the HLA antigen DR4) appears to be well documented. In most previous association studies the patients have not been divided according to sex and family history of RA. In this investigation the HLA antigens A, B and DR and five serum protein systems (Bf, C3, Pi, Hp and Tf) were studied in patients with erosive RA, from northern Sweden. Special attention was paid to variations in the strength of associations according to sex and family history of polyarthritis. The following results were found: The frequency of the HLA antigen B27 was significantly increased in the North-Swedish population (16.6%) and among patients with a family history of polyarthritis (42.6%). In agreement with previous investigations a significantly increased frequency of the DR4 antigen was found in the RA patients. In the properdin factor B (Bf) system the S phenotype was found to be significantly increased in male patients and in patients with a family history of polyarthritis, a more severe form of RA and high titres of rheumatoid factor. No significant differences with respect to phenotype or gene frequencies were found in the C3 complement system. Thus, the association between RA and C3 found in previous investigations was not confirmed. A significant increase of rare alpha-1-antitrypsin (Pi) types (MS, MZ, MF and SZ) was found among RA patients. However, the increase concerned mainly Z heterozygotes and was more strongly pronounced among male patients. In the haptoglobin system a significant increase of the Hp2 gene and the Hp2-2 type was found among patients with a family history of polyarthritis, more pronounced among males. A significant increase of the transferrin gene C2 and of the C2 type was found among male RA patients, more pronounced among patients with a family history of polyarthritis. In 6 out of 8 gene loci studied significant associations were found, which is in agreement with a multifactorial etiology of RA.(ABSTRACT TRUNCATED AT 400 WORDS)

Arthritis, Rheumatoid↗
PubMed1987

Biochemically damaged erythroblasts bind natural serum antibodies and activate complement.

Friend leukaemia erythroblasts which had been damaged biochemically by treatment with inhibitors of cellular metabolism (sodium fluoride, sodium azide) or of protein synthesis (cycloheximide, puromycin) were incubated with heat-inactivated or fresh mouse serum and tested for surface-bound IgG and C3c, respectively, by reaction with FITC-immunoconjugates followed by flow-cytofluorometry. Erythroblasts exposed to sodium azide, cycloheximide or puromycin showed specific binding of IgG; the extent of binding was related to the concentration of the drugs and duration of treatment. Moreover, prolonged exposure of the cells to the inhibitors of protein synthesis lead to a dose-dependent activation of complement. The results suggest that the opsonization of biochemically-damaged Friend leukaemia erythroblasts with IgG and C3 may facilitate their interaction with macrophages.

Antibodies, Anti-Idiotypic↗
PubMed1978

The complement profile in relation to the "reactor" state: a study in the immediate post-partum period.

C56 (activated "reactor") could be generated by adding zymosan to only nineteen out of the fifty serum samples obtained from southern Chinese women 3 to 5 days after a normal spontaneous delivery. As a group, post-partum sera showed a 25% increase in total haemolytic complement, an almost two-fold increase in haemolytic C5, C4 and C8 plus C9 activity, a 50% increase in antigenic C3 and haemolytic C2, C1 and factor B activity, a less than 20% increase in haemolytic C6 and C7 activity, and a 20% decrease in factor D and C1 inhibitor activity. Consequently, their C5:C7 ratios were significantly elevated. This finding supports, in part, the theory that the "reactor" state or ability to generate C56 depends on a relative excess of C56 over C7. However, comparison of the complement profile between sera with and those without "reactor" activity did not reveal any difference, except a greater elevation of C5 in the latter. It appears possible that a grossly excessive level of C5 may, in fact, be unfavourable to the generation of C56.

Complement C5↗
PubMed1985

Atypical hypocomplementemic vasculitis syndrome in a child.

We report a patient who developed recurrent urticaria and angioedema at age 2 years, severe hypocomplementemic glomerulonephritis at 11 years, and end-stage renal disease at 14 years. His disease resembled the hypocomplementemic vasculitis syndrome but was atypical in its early age of presentation, severe hypocomplementemia, and progression to end-stage renal disease. Serum C1q levels were extremely low, and C4, C2, C3, and C5 levels were significantly reduced. Serum C1 inhibitor (C1INH) levels were slightly low, presumably from consumption. Circulating C1INH-C1r-C1s complexes were evidenced by reduced ratios of functional to antigenic C1INH and antigenic C1r to C1s. Family members had normal functional and antigenic levels of all complement components studied. The patient's serum, erythrocytes, platelets, and mononuclear cells did not activate complement when mixed with normal target serum. Absence of a circulating complement activator and the low serum C3 and C5 levels suggested the presence of a solid-phase complement activator, possibly related to renal or systemic vascular endothelium. As in patients with homozygous deficiencies of classical pathway components, a severe, prolonged, acquired C1q deficiency may have predisposed this patient to the development of glomerulonephritis.

Angioedema↗
PubMed1989

[Complement activation during cardiopulmonary bypass: mechanism and prevention].

The mechanism of complement activation during cardiopulmonary bypass was studied for the prevention. In ten patients undergoing open-heart procedures, the serum levels of complement fractions (C3, C4, and C3 activator) were measured by a single radial immune diffusion method. In four of ten patients, the plasma levels of C3a, C4a, and C5a fractions were studied by the radioimmunoassay 2 antibodies method. The serum levels of C3, C4, and C3 activator decreased after cardiopulmonary bypass. The plasma levels of C3a, C4a, and C5a increased after bypass. The lower level of C3 activator shows that C3 activator was not excessively produced during cardiopulmonary bypass. Therefore it can be thought that much C4b2a from classical pathway as well as C3a over-production localizing extra-corporeal circuits and little inhibitors on alternative pathway resulted in increased complement activation. The prevention should be done from these etiologies.

Adult↗
PubMed1983

Functional properties of membrane-associated complement receptor CR1.

It was previously shown that membrane receptors for C3b (CR1) purified from human erythrocytes were powerful inhibitors of the complement cascade and that they encompass the regulatory functions of the serum proteins beta 1H (H) and C4-binding protein (C4bp). In the present report we study the functional properties of membrane-associated CR1. When tonsil lymphocytes, which contain between 30 and 60% of CR1-bearing B cells, are incubated with the red cell complement intermediate EAC14oxy2lim or EAC14oxy23lim, they inhibit both C42 and C423 in a dose-dependent manner. These effects are mediated by membrane-associated molecules. Indeed, mild trypsinization of the lymphocytes abolishes their activity, and formaldehyde-fixed cells are as effective as viable cells. The inhibitory effects are in part mediated by CR1. The lymphocyte activities are reversed about 60% if monoclonal antibodies to CR1 or fluid phase C3b are present in the incubation medium. Moreover, upon addition of C3b-inactivator (l), lymphocytes release C3c fragments from EAC14oxy23b. The release of C3c was also abolished by antibodies to CR1. These results support the idea that CR1, as well as other molecules from the lymphocyte membrane, can function as inhibitor(s) of complement activation in their vicinity.

Animals↗
PubMed2002

Further characterization of galloyl pedunculagin as an effective autophosphorylation inhibitor of C-kinase in vitro.

The inhibitory effect of galloyl pedunculagin (GP) isolated from Platycarya strobilacea on the activity and autophosphorylation of Ca(2+)- and phospholipid-dependent protein kinase (C-kinase) was examined in vitro. It was found that (i). GP inhibited the activity (phosphorylation of complement C3 from guinea pig) of C-kinase alpha (rat brain) in a dose-dependent manner with an ID(50) of approx. 0.12 micro M (ii). GP at lower doses (ID(50)=approx. 6 nM) inhibited autophosphorylation of C-kinase alpha; and (iii). the GP-induced inhibition of autophosphorylation of C-kinase alpha and its enzyme activity was a manner non-competitive to ATP. Similar inhibitory effect of GP on autophosphorylation of recombinant human C-kinase eta (rhC-kinase eta) and its phosphorylating activity was observed. These results suggest that GP is an effective autophosphorylation inhibitor of these two C-kinase isoforms (alpha and eta) in vitro. In addition, the CD analysis suggests that the proline-containing six amino acid residues (PVLTPP) including a threonine residue (autophosphorylation site) at the C-terminal region (positions 635-640) of C-kinase alpha may be one of the GP-binding sites.

Animals↗