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PubMed1986

C3 activation by a new factor B-dependent enzyme detected in culture supernatant from guinea-pig peritoneal macrophages.

Culture supernatants (c.s.) collected from thioglycollate-elicited macrophages were concentrated and incubated with purified C3. In this reaction mixture loss of haemolytic C3 according to classical enzyme kinetics was observed. As revealed by SDS-PAGE, c.s.-catalysed fragmentation of the C3 alpha-chain occurred. The cleavage products were identified by size and function as C3a and C3b. The apparent molecular weight of this C3-activating enzyme in c.s. was approximately 220,000 according to ultracentrifugation studies. This large enzyme showed the following characteristics: it had no activity against C5; it was inhibited by EDTA; Mg2+ was required for its optimal function; its half-life at 37 degrees was approximately 35 min; it was completely inhibited by anti-B IgG. Thus, we were able to detect a C3-activating enzyme in c.s. containing B but differing otherwise from a preformed C3 convertase of the alternative pathway. The exact component composition of this new enzyme is under further investigation.

Animals↗
PubMed1976

Relationship between the C5 peptides chemotactic for leukocytes and tumor cells.

A reciprocal relationship has been demonstrated between the generation of the leukotactic and the tumor cell chemotactic peptides from C5. Trypsin-produced C5 leukotactic peptides can be converted into tumor cell chemotactic factors by treatment with tumor cell extracts or by incubation with the alpha-globulin chemotactic factor inactivator (CFI) isolated from human serum. A similar CFI isolated from rat serum can, like the alpha-globulin CFI from human serum, generate the tumor cell chemotactic factor from the whole human serum. These results suggest that the tumor cell chemotactic factor derives from the same portion of the C5 molecule as the leukotactic peptide. Furthermore, it appears that the critical change may be cleavage of the amino-terminal portion of the leukotactic peptide. In addition, it has been shown that most normal tissues contain an enzyme-like material that is able to generate in normal human serum a factor chemotactic for tumor cells. The implications of these findings are discussed.

Alpha-Globulins↗
PubMed1977

C3 and C5-cleaving properdin enzymes formed on zymosan incubated with human serum: the decay and the regeneration of the enzymes.

Incubation os zymosan (Z) with normal human serum led to the formation of ZXhu, which had the abilities to cleave C3 and C5. Kinetic studies on ZXhu formation revealed that the amount of inactivated C5 by ZXhu, when expressed in site-forming unit (SFU), was much greater than that of inactivated C3. When ZXhu having limited C3 and C5-cleaving was incubated at 37 degrees C it decayed with a first order reaction completely in 120 min. At any stage of decay of ZXhu, the activities could be restored by the addition of both B and D, but not by the addition of B or D alone. Not D but B could be bound to the completely decayed ZXhu, and activation of bound B by D led to the regeneration of ZXhu.

Beta-Globulins↗
PubMed1986

Presence of chemotactic peptides other than C5a anaphylatoxin in scales of psoriasis and sterile pustular dermatoses.

A unique leukocyte chemotactic factor of around 12 kD molecular weight has been suggested to be responsible for the mechanisms involved in transepidermal migration of leukocytes observed in psoriasis and related sterile pustular dermatoses. Although we confirmed with radioimmunoassay the presence of a C5-cleavage product in the chemotactic fractions from psoriatic scale extract eluted by gel filtration HPLC, the neutrophil chemotactic activity demonstrated in the peak fraction was only partially inhibited by rabbit antiserum to human C5a, whereas that noted in the peak fraction, prepared from zymosan activated serum, was totally abrogated by the same treatment. Similarly the chemotactic fraction prepared from the scale extracts of other related pustular dermatoses were only partially inhibited with anti-C5a antiserum. These findings suggest that chemotactic peptides other than C5a also play a role in the transepidermal migration of leukocytes in these dermatoses.

Animals↗
PubMed1989

A properdin dependent nephritic factor slowly activating C3, C5, and C9 in membranoproliferative glomerulonephritis, types I and III.

The IgG fraction of serum from patients with membranoproliferative glomerulonephritis (MPGN) types I and III was found to contain a nephritic factor (NFI/III) which differed from that usually present in MPGN type II and partial lipodystrophy (NFII) in that it converts C5 and C9 as well as C3, is dependent on properdin for its activity, and requires an incubation period of several hours rather than 30 min for its demonstration. C3 conversion occurred in the absence of an intact classical pathway. This nephritic factor was found in patients with reduced serum levels of terminal components and its activity, like that of the nephritic factor in MPGN type II, correlated with the serum C3 level indicating that these nephritic factors play a large role in producing hypocomplementemia. Although potentially nephritogenic because of its ability to activate the terminal pathway, the presence of this nephritic factor did not clearly correlate with clinical course.

Complement Activation↗
PubMed2001

Serum proteins modified by neutrophil-derived oxidants as mediators of neutrophil stimulation.

Reactive oxygen intermediates (ROI) released during inflammation may act as important mediators of neutrophil effector functions. The objective of this investigation was to evaluate the influence of ROI generation on neutrophil adhesion molecule regulation and degranulation. Induction of the neutrophil oxidative burst via Fcgamma receptor cross-linking was accompanied by up-regulation of neutrophil surface CD11b, CD35, and CD66b only in the presence of selected serum proteins, such as purified human C4, C5, or human serum albumin (HSA). Scavenging of ROI attenuated protein-dependent receptor regulations. Moreover, exogenous hydrogen peroxide was effective to increase neutrophil CD11b expression in a protein-dependent way. HSA exposed to neutrophil-derived ROI displayed signs of oxidative modification in terms of carbonyl formation. Such modified HSA transferred to resting neutrophils bound readily to the cell surface and effected receptor modulation as well as cellular spreading. In contrast, neither native HSA nor HSA protected against oxidation by the tocopherol analog Trolox exhibited agonistic properties. In conclusion, we demonstrate that neutrophil-derived ROI modify selected serum proteins, which, in turn, act as proinflammatory mediators of neutrophil stimulation.

Blood Proteins↗
PubMed1987

Psoriasis and leukocyte chemotaxis.

Transepidermal migration of leukocytes, with resultant formation of microscopic or macroscopic sterile subcorneal pustules is a phenomenon characteristically noted in psoriasis and related sterile pustular dermatoses. It is natural to assume the presence of potent neutrophil chemotactic substances in the subcorneal portion of the lesional epidermis, because this location is the target of the in vivo leukocyte chemotaxis. In fact, crude psoriasis scale extracts show remarkably high neutrophil chemotactic and activating properties as compared with those of other non-psoriatic inflammatory dermatoses. We isolated a psoriatic leukotactic factor (PLF) having a molecular mass of around 12 kD, distinct from those common to other inflammatory changes involving the skin or those released by bacteria. Further analysis of PLF identified C5 cleavage fragments, together with other chemotactic peptides, such as those derived from monocytes. Likewise, potent low-molecular-mass chemotactic factors, including cell membrane lipid derived chemotactic factor, e.g. leukotriene B4, are also increased in psoriatic lesions, as in other nonpsoriatic inflammatory dermatoses. However, their activity to stimulate the generation of oxygen radicals in neutrophils was found to be much weaker than that of PLF. The peripheral blood leukocytes from active psoriatic patients show enhanced function in chemotaxis, phagocytosis, active oxygen production, and enzyme release; patients' sera contain substances such as anaphylatoxins that activate leukocyte function. Further research is required for clearer understanding of the series of events resulting in the leukocyte chemotaxis, as well as for the elucidation of the background immunoregulatory mechanisms.

Cell Movement↗
PubMed1977

The SC5b-7 complex: formation, isolation, properties, and subunit composition.

Activation of C in C8-depleted serum results in the formation of a soluble complex containing C5, C6, and C7. The complex has an electrophoretic mobility of an alpha-globulin, an s-rate of 18.5S, and a m.w. of 668,000 daltons. This complex was isolated and upon SDS polyacrylamide gel electrophoresis it was found to contain, in addition to C5b, C6 and C7, an 88,000 dalton glycoprotein. The protein was identified as the band V protein of the soluble C5b-9 complex. It is referred to as SIIIs-protein, or S-protein. Since the S-protein does not bind to C5b-6, it is concluded that it is incorporated during the fusion of C5b-6 with C7. The SC5b-7 complex exhibits the same neoantigen as the SC5b-9 complex, but compared to the C5b-6 complex it appears to contain an additionally qualitatively distinct neoantigen.

Animals↗
PubMed1995

Substrate specificities of the protease of mouse serum Ra-reactive factor.

Ra-reactive factor (RaRF) is a serum bactericidal factor whose function seems to be to activate C in a manner similar to that of C1, but with activation triggered by binding to bacterial polysaccharides instead of to immune complexes. It is composed of multiple polysaccharide-binding subunits associated with a novel serine protease, and its overall structural organization is similar to that of C1. This similarity extends to the serine protease component, which shares a similar modular construction and about 40% sequence identity with the C1r and C1s subcomponents of C1. In this study, we examined the substrate specificity of mouse RaRF by assaying its ability to cleave C components C3, C4, and C5, and its activity against the murine C4 isotype, sex-limited protein. Our results revealed that RaRF preferentially cleaves the C4 alpha-chain with specific activities 20- to 100-fold greater than either human or murine C1s, and that RaRF also cleaves the C3 alpha-chain, but with a lower efficiency than C4 alpha. We also found that RaRF is much less sensitive than C1s to mutations near the proteolytic site and that the two proteases show different reactivities against synthetic substrates. Hence, although the RaRF protease and C1s have similar structures and play similar roles in C activation, they also display clear differences in substrate range and in the details of their substrate recognition mechanisms. Finally, we found that RaRF does not cleave sex-limited protein even at a level 100-fold higher than necessary for C4 cleavage.

Amino Acid Sequence↗
PubMed1975

The role of C3 as an opsonin in the early stages of infection.

In order to investigate the role of C3 in host defense in vivo, normal AKR/J mice, genetically deficient in C5, were depleted of serum C3 by the injection of purified cobra venom factor (CoVF). Concurrent with their C3 depletion, their serum opsonizing activity decreased to a level less than 20% of normal. When these mice were challenged with an intraperitoneal injection of pneumococci 2 hr after the CoVF treatment, the LD50 was from 30 to 80 times lower than the LD50 in saline-treated control animals. When the CoVF was given only 6 hr after the pneumococcal challenge, the LD50 was the same as in the control mice. If the pneumococci were first preopsonized in vitro and then injected into CoVF-treated animals, the LD50 was the same as that in control animals. These experiments demonstrate that C3 plays a significant role in vivo in the host's defense against infection and that a major part of that role is through its action as an opsonin. Furthermore, these experiments demonstrate that the role of C3 is most significant during the early stages of bacterial invasion.

Animals↗
PubMed1986

Bactericidal-activities of human polymorphonuclear leukocyte proteins against Escherichia coli O111:B4 coated with C5 or C8.

The postnuclear supernatant of disrupted polymorphonuclear leukocytes exhibited bactericidal activity on Escherichia coli O111:B4 coated with immunoglobulin M antibodies and C5 or C8 but not on C3- or C7-coated bacteria. To characterize this antimicrobial activity further, granules obtained from the postnuclear supernatant were extracted with sodium acetate (pH 4) and the soluble extract was subsequently fractionated through carboxymethyl cellulose and Sephacryl S-200. Over 90% of the activity present in the starting material was recovered in the soluble granule extract. Kinetic and dose-response analyses of the bacterial activity of the polymorphonuclear leukocyte extract on BAC1-5 and BAC1-8 revealed different susceptibilities to killing of these two bacterial intermediates; they also differed for their susceptibilities to killing at 37 degrees C and at room temperature. The suggestion raised by these data, that BAC1-5 and BAC1-8 could be killed by different bactericidal factors, was confirmed by the findings that separate fractions of the soluble granule extract obtained by carboxymethyl cellulose and Sephacryl S-200 chromatography exhibited specific activity on either BAC1-5 or BAC1-8, whereas other fractions were active on both intermediates.

Blood Bactericidal Activity↗
PubMed1985

[Homozygotic C5 deficiency disclosed by purulent Neisseria meningitidis meningitis].

The complement system functions to protect the individual against infectious agents. Deficiencies of the late-acting complement proteins C5-C8 are associated with an increased susceptibility to Neisseria infection. This paper describes a deficiency in C5 in a Caucasoid family from the north of France that was revealed by the occurrence of a N. meningitidis meningitis in the homozygous C5-deficient propositus.

Adult↗
PubMed1989

Cessation of neutrophil influx in C5a-induced acute experimental arthritis is associated with loss of chemoattractant activity from the joint space.

Neutrophil emigration is a critical component of the inflammatory process and is generally thought to play a role in host defense as well as in the tissue injury that often accompanies inflammation. Most inflammatory reactions exhibit a sequence of emigrating cell types, thus clearly demonstrating that the neutrophil influx eventually ceases and that the neutrophils are then removed from the lesion. It has been our premise that in order to understand the processes that lead to the progressive inflammatory reactions that underly so many disease processes, it is important to determine the mechanism by which the "normal" inflammatory response resolves. The purpose of this study was to identify the time of cessation of neutrophil influx in experimental arthritis induced by the injection of C5 fragments (C5f) and to investigate mechanisms underlying the cessation process. The migration of i.v. delivery pulses to inflamed joints was assessed by lavage of the joint space and by external scintigraphy. We found no evidence for the development of inhibitory systems against chemotactic factors or "desensitization" of the inflamed site, because a second injection of C5f into joints which had been injected previously with C5f resulted in enhancement rather than inhibition of migration. Neither was evidence found for altered tissue barriers to migration or for desensitization of neutrophils as possible explanations for cessation of influx. The major mechanism appeared to be a loss of chemoattractant activity in the joint space between 2 h and 6 h after C5f injection which was detected by transfer into a fresh joint. Radiolabeled C5a des-Arg had a t1/2 of disappearance from the joint of less than 1 h, which suggested that the transferred chemoattractant must, in part, have been due to the generation of new chemotaxins by C5f injection. These observations suggest that continued generation of chemoattractants or failure of their subsequent removal may be mechanisms leading to persistent neutrophil influx in chronic inflammation.

Acute Disease↗
PubMed1992

Bactericidal activity of C9-deficient human serum.

Escherichia coli B/SM, strain 1-1, was killed dose dependently by human hereditary C9-deficient serum (C9DHS), which was shown to contain no C9 Ag by an ELISA method. On the other hand, human hereditary C7-deficient serum did not kill the bacteria under similar conditions. The bactericidal activity of C9DHS was inhibited by rabbit anti-C5 antibody but not by murine anti-C9 mAb. The anti-C9 antibody decreased the bactericidal activity of normal human serum (NHS) to the level of that with C9DHS. Sheep anti-human lysozyme antibody did not affect the bactericidal activity of C9DHS or NHS even when added at more than twice the concentration required to block the serum lysozyme activity on Micrococcus luteus. After treatment with C9DHS and washing, surviving Escherichia coli were killed by C9, but not by lysozyme, transferrin, or both. Other strains of E. coli (K12 W3110, C600, and NIHJ) and Salmonella typhimurium (strain NCTC 74), all maintained in the laboratory, were also killed by C9DHS. However, pathogenic strains recently isolated from patients with traveler's diarrhea and some strains of S. typhimurium were resistant to both C9DHS and NHS, at least at the serum concentration tested. A concentration of 0.1 M Tris did not increase the susceptibility of serum-resistant strains of bacteria to C9DHS, but made one strain of S. typhimurium tested susceptible to NHS, but not to C9DHS. These results clearly showed that C9DHS kills bacteria that are sensitive to NHS through activation of C up to the step of C8 in the same way that C9-deficient C serum lyzed sensitized erythrocytes.

Blood Bactericidal Activity↗
PubMed1998

Cytokine regulation of the acute-phase protein levels in multiple myeloma.

BACKGROUND: Interleukin (IL) 6 has an important role in the regulation of acute-phase proteins (APPs) during an acute-phase response. We studied IL-6 and other cytokines to determine if they regulate serum APP levels in the same way under the condition of the aberrant, long-lasting 'acute-phase response' that occurs in patients with chronic inflammation and cancer. METHODS: Serum levels of nine positive APPs [CRP, SAA, C1-INH, Bf, C5, C8, C9, alpha 1-acidic glycoprotein (AGP) and haptoglobin] and two negative APPs [transferrin and alpha 2-HS glycoprotein (AHSG)] were measured using immunochemical methods in 59 multiple myeloma patients and in 72 healthy control subjects. Serum IL-6 and tumour necrosis factor (TNF) alpha levels were determined by bioassays. RESULTS: IL-6 was negatively correlated with five out of nine (C1-INH, C8, C9, AGP and haptoglobin) positive APPs but positively correlated with C-reactive protein (CRP). When patients with high and low IL-6 serum concentration were compared, CRP levels were higher, AGP and haptoglobin levels were lower in the high- than in the low-L-6 group, whereas no significant difference between the two groups was found in levels of the other positive and negative APPs. TNF-alpha levels were negatively correlated with transferrin and AHSG levels. No difference in the levels of positive APPs was observed between patients with low and high TNF-alpha serum concentration. By contrast, levels of both transferrin and AHSG were significantly lower in the high- than in the low-TNF-alpha group. CONCLUSIONS: These findings indicate that, except for regulation of the negative APPs by TNF-alpha, the mechanism of APP regulation is different under the conditions of the short-term and the chronic, long-lasting 'acute-phase reaction'.

Acute-Phase Proteins↗
PubMed2002

Eculizumab (Alexion).

Eculizumab (5G1.1), a humanized monoclonal antibody that prevents the cleavage of human complement component C5 into its pro-inflammatory components, is under development by Alexion as a potential treatment for several chronic inflammatory diseases, including rheumatoid arthritis (RA) and nephritis [190673], [292328]. In January 2002, a phase IIb trial was initiated for RA [437814]. This trial was ongoing in April 2002, at which time, eculizumab was also in phase II trials for the treatment of membranous nephritis and lupus nephritis, and in earlier stage clinical trials for dermatomyositis and pemphigoid [446377]. The company is also developing a single-chain version of this antibody, pexelizumab, for use in acute cardiovascular indications [188760]. In October 2000, eculizumab was granted Orphan Drug status by the FDA for the treatment of dermatomyositis [385057]. In February 2002, the product received Orphan Drug designation for its use in patients with membranous nephritis [440583]. In September 2001, analysts at US Bancorp Piper Jaffray predicted eculizumab's launch for dermatomyositis and pemphigus in 2003, RA and nephritis in 2004, and chronic heart failure (CHF) after 2006 [426537]. In March 2002, analysts at US Bancorp Piper Jaffray predicted that the product would have peak worldwide sales in RA of US $175 million and US $400 million for nephritis. Sales for the RA indication are predicted to reach US $35 million in 2006, rising to US $110 million in 2008, and US $10 million in 2006, rising to US $50 million in 2008, in the US and the rest of the world, respectively. For the nephritis/other indication(s), sales are pegged at US $50 million in 2006, rising to US $200 million in 2008, and US $15 million in 2006, rising to US $100 million in 2008, again in the US and the rest of the world, respectively [446992].

Animals↗