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PubMed2003

Innate immunity and brain inflammation: the key role of complement.

The complement inflammatory cascade is an essential component of the phylogenetically ancient innate immune response and is crucial to our natural ability to ward off infection. Complement is involved in host defence by triggering the generation of a membranolytic complex (the C5b-9 complex) at the surface of the pathogen. Complement fragments (opsonins; C1q, C3b and iC3b) interact with complement cell-surface receptors (C1qRp, CR1, CR3 and CR4) to promote phagocytosis and a local pro-inflammatory response that, ultimately, contributes to the protection and healing of the host. Complement is of special importance in the brain, where entrance of elements of the adaptive immune system is restricted by a blood-brain barrier. There is now compelling evidence that complement is produced locally in response to an infectious challenge. Moreover, complement biosynthesis and activation also occurs in neurodegenerative disorders such as Alzheimer's, Huntington's and Pick's diseases, and the cytolytic/cytotoxic activities of complement are thought to contribute to neuronal loss and brain tissue damage. However, recent data suggest that at least some of the complement components have the ability to contribute to neuroprotective pathways. The emerging paradigm is that complement is involved in the clearance of toxic cell debris (e.g. amyloid fibrils) and apoptotic cells, as well as in promoting tissue repair through the anti-inflammatory activities of C3a. Knowledge of the unique molecular and cellular innate immunological interactions that occur in the development and resolution of pathology in the brain should facilitate the design of effective therapeutic strategies.

Animals↗
PubMed1985

Immunoglobulins and complement components in human aortic atherosclerotic intima.

Concentration and preferential retention of immunoglobulins and complement components were studied in comparison with other plasma proteins in 42 human aortae with atherosclerosis. Saline and acid extracted IgG, IgA, IgM, C1q, C3c, C4, C9, C3A, C-reactive protein, alpha 1-antitrypsin, alpha 2-macroglobulin, albumin, transferrin and fibrinogen were quantitatively determined using the radial immunodiffusion. The fibrous plaques and their adjacent areas contained higher levels of each protein than intima with only fatty streaks. No significant differences were found between the fibrous plaques and their adjacent areas presenting intimal thickenings. Saline eluted IgG and IgA were significantly higher in the fibrous plaque intima than in intimal samples with fatty streaks and were the only proteins detected in the acid eluates. The complement components were present in all saline eluates, while C-reactive protein was found in 23 samples. Crossed immunoelectrophoretic studies showed the activation of saline C3 and C4. In 8 cases serum levels of the studied proteins were compared with their concentration in saline eluates obtained from intima and media. The immunoglobulins and complement components presented higher intima/serum and lower media/intima retention ratios than the other studied proteins suggesting their preferential retention in the intima. The presence of immune related proteins in the atherosclerotic intima and their preferential retention might be explained not only by an altered permeability but also in relation to their function.

Adult↗
PubMed1994

Blood cytokine and complement levels in patients with sepsis.

We measured serum levels of endotoxin, cytokines, and eicosanoids and investigated their relationship to serum complement levels in patients with sepsis. Serum endotoxin (Et) levels (5.3 +/- 2.4 pg/ml) were within the normal range, but levels of tumor necrosis factor-alpha (TNF-alpha, 114 +/- 104.94 pg/ml), interleukin 6 (IL-6, 86.7 +/- 50.9 pg/ml), interleukin 8 (IL-8, 86.8 +/- 49.7 pg/ml), type-II phospholipase A2 (type II PLA2, 211.3 +/- 193.9 ng/ml), leukotriene B4 (LTB4, 88.7 +/- 27.2 pg/ml), thromboxane B2 (TXB2, 58.7 +/- 50.9 pg/ml) and 6-keto-prostaglandin F1 alpha (PGF1 alpha, 21.0 +/- 11.0 pg/ml) levels were above normal. Levels of C3a (1088.4 +/- 83.8.7 ng/ml) and C4a (1951.5 +/- 1697.8 ng/ml) were also above normal; C3 (66.0 +/- 25.6 mg/dl) and C4 (23.6 +/- 5.3 mg/dl) were within the normal range, and C5a was lower than the detectable limit in all but one of the subjects. Serum TNF-alpha was significantly correlated with C3a (p < 0.001). Serum IL-6 had a significant negative correlation with C3 (p = 0.002) and C4 (p = 0.010). Type II PLA2 was significantly correlated with C3a (p < 0.001). There were no significant correlations between serum Et or IL-8 and serum C3, C4, C3a or C4a. Our findings suggest that increased levels of TNF-alpha, IL-6, and Type II PLA/ in patients with sepsis contribute to activation of the complement system.

Adult↗
PubMed1983

IgG rheumatoid factors behaviour in young normal subjects following vaccination.

In order to contribute to explain the finding of Rheumatoid Factors of the IgG class in all normal subjects, even at low levels, a study on their behaviour in a group of young subjects serving in the army, at the time of anti-typhoid and antitetanic vaccination, and in the following two months, was conducted. Parallely some aspecific serological parameters of autoimmunity were determined. The results demonstrate, first of all, a good antibody response to the vaccine in all subjects observed. Immunoglobulins of the IgG, IgA, and IgM class were normal in all samples. Complement factors C3 and C4 were slightly decreased after the second dose of vaccine, suggesting a modest consumption probably due to immune complexes formation. Factor C3A showed a slight increase, may be to be considered as its property of an acute phase reactant. Autoantibodies determined by immunofluorescence were constantly negative. IgM rheumatoid factors became transitory positive in a significant proportion. IgG rheumatoid factors demonstrated a two-phase increase, more evident after the second dose of vaccine. We can conclude, mainly for the latest parameter, that these results reveal an autoimmune serological response, even quantitatively modest, concomitant to the specific sensitization resulting from vaccination.

Adult↗
PubMed1975

Evidence for complement activation by the alternate pathway in the arthritis of hypogammaglobulinemic patients.

The chronic, rheumatoid synovitis in four patients (two children and two adults) with immunodeficiency was studied by means of immunopathological examination of synovial tissues and fluids. Their immunodeficiencies were extensively studied, with various tests for humoral and cell-mediated immunity. The two children were boys with Bruton's disease. One adult, female, had common variable immunodeficiency. One adult male had severe hypogammaglobulinemia. All patients had isolated deposits of complement component C3 in their synovial membranes, usually without traces of immunoglobulins. Depressed levels of complement component C3 were found in the joint fluid, in contrast to high levels in the corresponding serum in one patient. Components of the alternate pathway, properdin and C3A, were found in the tissues, but not components of the classic pathway, C1q and C4. The findings suggest that chronic, rheumatoid arthritis in hypogammaglobulinemic patients may be related to activation of C3 by the alternate pathway.

Agammaglobulinemia↗
PubMed1998

Adsorption of complement, cytokines, and proteins by different dialysis membrane materials: evaluation by confocal laser scanning fluorescence microscopy.

The membranes tested in the present study were cellulose triacetate (CTA), polymethylmethacrylate (PMMA), and polyacrylonitrile (PAN). The adsorption by each membrane of albumin, IgG, C3a, interleukin-1beta (IL-1beta), interleukin-6 (IL-6), human neutrophil elastase (HNE), and tumor necrosis factor alpha (TNFalpha) was examined and semiquantitatively graded by confocal laser scanning fluorescence microscopy (CLSFM). After clinical use the dialyzers were treated with antibodies for these proteins and cytokines. Then the samples were incubated with fluorescein isothiocyanate-labeled anti-IgG antibody and observed by CLSFM. The changes in the blood levels of C3a and cytokines were also studied. In the CTA membrane, the adsorption of these substances, except for albumin and HNE, was less than in the synthetic membranes. The PAN membrane revealed the most abundant adsorption, especially for IL-1beta, IL-6, and TNFalpha. Although a marked elevation of C3a in the blood was observed in the CTA membrane, considerable adsorption was evident in the PMMA and the PAN membranes. Because the changes in the blood levels could be affected by membrane adsorption, both the blood levels and the adsorption of the biocompatibility parameters should be evaluated when membrane biocompatibility is discussed.

Acrylic Resins↗
PubMed1985

Model structure for the inflammatory protein C5a.

The complement cleavage product C5a is a potent stimulant of inflammatory processes; thus, inhibition of C5a activity is of therapeutic interest. The three-dimensional structure of the major portion of C5a was modeled from the homologous C3a crystal structure by comparative modeling techniques. The model shows that core residues of C5a are completely conserved, while external residues differ from C3a. Even though the amino-terminal 12 residues of C3a are disordered in the crystal, this sequence in C5a may form an amphipathic helix. The distribution of species sequence differences in the complete C5a structure suggests a possible receptor binding site.

Amino Acid Sequence↗
PubMed1987

[Evaluation of the biocompatibility of a new cellulose membrane by studying the complement system and histamine liberation].

This biocompatibility of the new cellulosic membrane hemophane (HE) is compared to that of cuprophane (CU) in ten maintenance hemodialysis (HD) patients dialyzed on the two types of membranes in randomized order, under otherwise similar technical conditions. Total white blood cell (WBC) and differential counts, blood concentrations of C3a, and C3d and histamine are determined at start of dialysis (TO) and 10, 20 and 180 minutes thereafter. HE is distinct from CU in exerting a minor effect on the generation of C3a, a minor drop of leucocytes during the course of dialysis (P less than 0.01) and also by a lesser increase in blood histamine concentration (P less than 0.05). Histamine liberation is observed on CU together with the generation of anaphylotoxin C3 and with a diminution of circulating basopolymorpho-nuclear cells. According to the variations observed for these three parameters (C3a, leucocytosis and blood histamine concentration), HE appears as being more biocompatible than CU.

Aged↗
PubMedDate not supplied

Complement activation and use of a cell saver in cardiopulmonary bypass.

Complement activation was evaluated in ten patients undergoing cardiopulmonary bypass (CPB) and intraoperative blood salvage with a cell saver (CS) to assess the inflammatory response related to the CS. The washed red blood cell concentrate was reinfused after protamine injection. Plasma C3a was measured by radioimmunoassay preoperatively, 5 min before CPB, at 5, 60, and 90 min during CPB, 5 min after protamine infusion, at the end of surgery, and after 24 hr. In addition, a clinical score based on renal, pulmonary, neurologic, and myocardial postoperative evolution was given (0-8) to every patient. Results were compared with the C3a changes and clinical scores obtained from 26 routine (no CS) cardiac surgical patients. Results showed maximal C3a generation after protamine and no further activation in cases of CS concentrate reinfusion, which ranged from 400 ml to 2,000 ml. No difference in clinical score was observed between the CS (1 +/- 1) and control (0.85 +/- 0.6) groups. The authors conclude that the CS does not enhance complement activation resulting from extracorporeal circulation and can be safely used as a blood saving strategy in cardiac surgery.

Adult↗
PubMed1985

Correlation of inflammatory RA disease activity with laboratory parameters.

Fifty-one patients with rheumatoid arthritis were examined at 6-month intervals during a 2-3-year investigation period. Correlations of an inflammatory activity index calculated from nine criteria with several laboratory parameters were computed. ESR correlated most closely, followed by the IgM concentration of circulating immune complexes, hemoglobin, C3A, and fibrinogen.

Adult↗
PubMedDate not supplied

Complement in hematological neoplasias.

Total hemolytic complement (CH50) and eight antigenic fractions of the complement system were determined in 30 patients with hematological neoplasias, distributed into the following groups: six cases of non-Hodgkin's lymphomas (NHL), seven cases of chronic lymphocytic leukemia (CLL), five cases of Hodgkin's disease (HD), seven cases of acute leukemia (AL), three cases of chronic myeloid leukemia (CML) and two cases of multiple myeloma (MM). CH50 was titred accordingly to a modification of the Kabat and Mayer method, C1q, C1s, C3, C4, C5, INHC1, C3A and properdin were determined with specific antisera by Manani and Laurell's techniques. The results obtained showed significant increase in CH50 above normal values in patients with HD, AL, and CML, especially the former, even in early stages. C1s was found to be increased in CML and AL, as well as C3 in CML. C4 is increased in CML and HD. C5 follows a course similar to C4, being also increased CLL and MM. C9 is increased in all groups, except NHL. A significant increase in C3A was found in NHL, HD and AL. There were no significant variations in C1s, INHC1 and properdin in any of the former groups. No correlation was found between clinical course and complement increase. The role of complement in neoplastic disease is discussed.

Chronic Disease↗
PubMed1994

Site-specific mutagenesis of residues in the human C5a anaphylatoxin which are involved in possible interaction with the C5a receptor.

To check and clarify existing data on receptor-interacting residues in the human C5a anaphylatoxin, we tested mutant C5a proteins obtained by site-directed mutagenesis of a recombinant human C5a (rhC5a) cDNA clone for structural and functional integrity. Amino acid positions in three different regions of the molecule were investigated: Arg74 at the C-terminus, Arg40 and Pro45 located in the core region, and Lys14 and Lys19, Lys20 in the N-terminus. Des-Arg74-rhC5a displayed only a residual 3-4% functional activity in the myeloperoxidase-release assay from human granulocytes while retaining the three-dimensional solution structure of wild-type (wt)-rhC5a as shown by circular dichroism (CD) spectroscopy. Des-Arg74-rhC5a was able to activate the human C5a receptor transiently expressed in Xenopus oocytes, but was inactive in the heterologous guinea pig (gp) ileum-contraction assay. These results reveal profound differences between the guinea pig and human C5a-receptor ligand-binding characteristics. Exchange of the core residue Arg40 by a glycine did not significantly affect functional C5a activity, in contrast to a previous observation [Mollison, K. W., Mandecki, W., Zuiderweg, E. P., Fayer, L., Fey, T. A., Krause, R. A., Conway, R. G., Miller, L., Edalji, R. P., Shallcross, M. A., Lane, B., Fox, J. L., Greer, J. & Carter, G. W. (1989) Identification of receptor-interacting residues in the inflammatory complement protein C5a by site-directed mutagenesis, Proc. Natl Acad. Sci. USA 86, 292-296], nor did exchange of the conserved Pro45 residue by the C3a analogue glutamic acid, a mutation expected to alter the whole geometry of the loop connecting helix III-helix IV (including Arg40) of the C5a molecule. Thus, participation of this loop in receptor interaction appears unlikely. While exchange of the N-terminal Lys14 residue by alanine did not significantly affect functional activity, a double replacement of Lys19 and Lys20 by alanine residues reduced activity more than 30-fold. These results confirm Lys19 and/or Lys20 as a putative receptor-interacting site, although we could not obtain a CD spectrum of this important mutant due to poor expression.

Amino Acid Sequence↗
PubMed1969

Anaphylatoxin release from the third component of human complement by hydroxylamine.

Treatment of highly purified preparations of the third component of complement (C3) with 0.5M hydroxylamine at 20 degrees C for 15 to 30 minutes, followed by acidification, resulted in dissociation of a peptide from the C3 molecule. The isolated fragment (molecular weight, 7600) resembled enzymatically liberated anaphylatoxin (C3a) with respect to size, charge, amino acid composition, and biological activity. Its capacity to contract smooth muscle was inhibitable by antihistamines; it also produced tachyphylaxis and desensitization of the guinea pig ileum to C3a. Thus native C3 probably contains an esterlike bond and hydroxylamine-liberated anaphylatoxin may represent one of the polypeptide chains of the C3 molecule.

Amino Acids↗
PubMed1989

Purification of chicken C3 and a structural and functional characterization.

A major plasma protein from chicken, analogous to mammalian complement component C3, was purified by the removal of plasminogen, precipitation with polyethyleneglycol, and ion-exchange chromatography. Purification was guided by a rabbit antiserum specific to chicken C3. The yield of native C3 was 27%, and purity and functional activity was assessed by SDS-PAGE, immunoprecipitation techniques, and the ability of the purified C3 to restore the haemolytic activity of C3-depleted chicken serum. Monoclonal antibodies were raised against purified chicken C3. These antibodies were characterized and used to prepare an immunosorbent column to deplete chicken plasma specifically of C3. Chicken C3 has a mol.wt of 185,000-195,000 and a two-chain structure with an alpha chain (118,000) and beta chain (68,000). Complement activation leads to changes in the electrophoretic mobility of chicken C3 and to a decrease in mol.wt to 144,000 corresponding to the release of a 15,000 C3a and a 34,000 C3d/C3dg fragment. Chicken C3 exists in multiple molecular forms with pI values of 6.4-6.6. A genetic polymorphism of chicken C3 based on electrophoretic mobility has not yet been detected after analysis of more than 500 individuals. The function of chicken C3 is dependent on a reactive thioester because treatment of purified chicken C3 with methylamine causes functional inactivation of C3.

Animals↗
PubMed1976

Partial characterization of human C5a anaphylatoxin. I. Chemical description of the carbohydrate and polypeptide prtions of human C5a.

Human C5a was isolated from complement-activated serum and was characterized for protein and carbohydrate content. The purified C5a was judged to be homogeneous by both polyacrylamide gel electrophoresis and immunologic techniques. The polypeptide moiety of C5a contains 73 amino acid residues which represent a m.w. of 8,200. Analysis of the carbohydrate moiety in C5a indicated 4 moles of glucosamine, 3 to 4 moles os sialic acid, 4 moles of mannose and 2 moles of galactose. The total carbohydrate content in C5a, therefore, amounts to approximately 25% of the apparent m.w. of the anaphylatoxin molecule. The protein and carbohydrate portions of C5a together equal a m.w. of approximately 11,000 which is considerably less than the 15 to 16,000 indicated by physical measurements. Human C5a contains a COOH-terminal arginine which is essential for anaphylatoxin activity and a sequence of Gln-Leu-Gly-Arg-COOH at the COOH-terminus which compares favorably with that of human C3a (Gly-Leu-Ala-Arg-COOH). Additional similarities between the C3a and C5a molecules include length of the polypeptide chain, number of disulfide bonds and an absence of tryptophan residues. A major chemical difference does exist between these two human anaphylatoxins, namely that carbohydrate is associated with C5a but is absent in the C3a molecule. The partial NH2-terminal sequence of C5a was determined as NH2-Thr-Leu-Glx-Lys-Ile-Glx-Glx-Ile-Ala- and direct comparison with the known sequence of human C3a shows little homology.

Amino Acid Sequence↗
PubMedDate not supplied

[Modification of complement components under the effect of cationic proteins from leukocytes from donors and leukemia patients].

Cation proteins (CP) were isolated from leukocytes by means of ion exchange chromatography. Enzyme immunoassay showed that these cation proteins modified C3 component of complement in vitro. CP obtained from healthy volunteers decreased the content of C3 purified by affinity chromatography and C3 of blood serum; however, content of C3.H2O op C3b-like form and C3a-fragment were not altered. Effect of CP isolated from leukocytes of patients with chronic myeloleukemia and chronic lympholeukemia on C3 component was less distinct as compared with that of healthy volunteers. At the same time, content of C3b-like form was increased the presence of CP from patients with myeloleukemia and of C3a-fragment--in the presence of the proteins from patients with lympholeukemia. Excess of physiologically active C3 fragments, developed under conditions of these diseases, may contribute to a decrease in unspecific body resistance.

Blood Proteins↗
PubMed1977

Synthetic peptides with the biological activities and specificity of human C3a anaphylatoxin.

Two peptides identical to the COOH-terminal sequence of human C3a anaphylatoxin and two analogs were synthesized by the solid-phase method and tested for biological activity. The synthetic COOH-terminal octapeptide, C3a-(70-77) or Ala-Ser-His-Leu-Gly-Leu-Ala-Arg, caused contraction of guinea pig ileum and uterus, release of vasoactive amines from rat mast cells, and increased vascular permeability in guinea pig and human skin. On a molar basis, the synthetic octapeptide possessed 1-2% of the biological activities of C3a and specifically desensitized smooth muscle to stimulation by C3a. Like natural C3a, the synthetic C3a=(70-77) was inactivated by digestion with carboxypeptidase B [peptidyl-L-lysine(-L-arginine) hydrolase, EC 3.4.12.3], which removed the essential COOH-terminal arginine. A synthetic nonapeptide [C3a-(70-77)-Gly], containing a glycyl instead of an arginyl COOH terminus, was approximately 1% as active as the octapeptide when assayed with smooth muscle. The COOH-terminal 13-residue peptide of C3a, C3a-(65-77), was equal in activity to C3a=(70-77); similarly, C3a-(65-77)-Gly expressed the same activity as C3a-(70-77)Gly. It is concluded that both the biological specificity and the activity of human C3a anaphylatoxin are determined by eight or fewer residues located at the COOH terminus of the natural protein. However, expression of full activity requires additional groups and the secondary conformational integrity of the C3a molecule.

Amino Acid Sequence↗
PubMed2000

Guinea pig C3 specific rabbit single chain Fv antibodies from bone marrow, spleen and blood derived phage libraries.

We constructed combinatorial immunoglobulin libraries from the whole rabbit antibody repertoire of bone marrow, spleen and peripheral blood of a rabbit immunized with guinea pig complement protein C3. By means of the phage display technology we selected guinea pig C3 specific single chain Fv (scFv) antibodies from each of the libraries. None of the scFv antibodies cross reacted with guinea pig C3a, human C3 or rat C3. The frequency of bone marrow derived C3 positive clones was much higher as compared to blood or spleen derived clones. Additionally bone marrow and spleen derived clones show higher diversity than clones, obtained from blood, as determined by fingerprint analysis with the restriction enzyme AluI. Dissociation rate constants for all scFvs were similar, indicating that the source of the scFvs had no influence on affinities. The antibody fragments were used to analyze complement activation during xenotransplantation. Several blood or bone marrow derived scFvs bound to C3 located on rat liver endothelium after hyperacute rejection of a heterotopically transplanted rat liver into guinea pig. These data demonstrate that monoclonal rabbit scFvs can be easily generated from recombinant phage display libraries, constructed from spleen, blood or bone marrow. The selected guinea pig C3 specific scFvs appear to be useful to detect complement activation during xenotransplantation in guinea pigs.

Amino Acid Sequence↗