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PubMed2001

Complement component C3 is not required for full expression of immune complex glomerulonephritis in MRL/lpr mice.

Complement activation and tissue deposition of complement fragments occur during disease progression in lupus nephritis. Genetic deficiency of some complement components (e.g., Factor B) and infusion of complement inhibitors (e.g., Crry, anti-C5 Ab) protect against inflammatory renal disease. Paradoxically, genetic deficiencies of early components of the classical complement pathway (e.g., C1q, C4, and C2) are associated with an increased incidence of lupus in humans and lupus-like disease in murine knockout strains. Complement protein C3 is the converging point for activation of all three complement pathways and thus plays a critical role in biologic processes mediated by complement activation. To define the role of C3 in lupus nephritis, mice rendered C3 deficient by targeted deletion were backcrossed for eight generations to MRL/lpr mice, a mouse strain that spontaneously develops lupus-like disease. We derived homozygous knockout (C3(-/-)), heterozygous (C3(+/-)), and C3 wild-type (C3(+/+)) MRL/lpr mice. Serum levels of autoantibodies and circulating immune complexes were similar among the three groups. However, there was earlier and significantly greater albuminuria in the C3(-/-) mice compared with the other two groups. Glomerular IgG deposition was also significantly greater in the C3(-/-) mice than in the other two groups, although overall pathologic renal scores were similar. These results indicate that C3 and/or activation of C3 is not required for full expression of immune complex renal disease in MRL/lpr mice and may in fact play a beneficial role via clearance of immune complexes.

Albuminuria↗
PubMedDate not supplied

Some humoral immunological aspects of the rheumatoid arthritis correlated with the ultrastructural changes of the rheumatoid synovial fluid.

We performed serologic and synovial investigations in rheumatoid (Latex 1/1280, 1/640, negative and Waaler Rose 1/1024, 1/512, negative), non-rheumatoid and control lots. The immunological results were correlated with ultrastructural changes found in the synovial fluid (SF) at the same titres of rheumatoid factor (RF). The pathologic values of the circulating immune complexes (CIC) (mean = 108.05 U), IgM (mean = 420 UI/ml), IgG (mean = 355.36 UI/ml), and anti-collagen II antibodies (mean = 558.6 U) were present at high titres of RF (Latex 1/1280, Waaler Rose 1/1024). These cases had also major ultrastructural changes of the nucleus and cytoplasm. We inferred from this the implication of the immune factors in the etiology and pathology of the Rheumatoid Arthritis (RA). The high, titres of RF were correlated with pathologic values of the C-reactive-protein (CRP) (mean = 13.31 mg%) and alpha-1-acid glycoprotein (A-1-GA) (mean = 158.3 mg%). The decline of the complement fraction C3 from the synovial fluid in RA confirms the immune character of the rheumatoid synovitis and may be useful in the diagnosis process. The significantly lower concentrations of the protease inhibitors alpha-1-anti-trypsin (A-1-AT) (mean = 165.1 mg%) and alpha-2-macroglobulin (A-2-M) (mean = 129.6 mg%) in synovial fluid suggest a diminution of the anti-proteasic activity due to local immune conflict.

Antigen-Antibody Complex↗
PubMed1992

A trypsin-like serine protease activity on activated human B cells and various B cell lines.

We have studied the trypsin-like serine protease activity of human tonsillar B lymphocytes. The lysate of the low-density, in vivo activated B cells as well as the lysate of cells stimulated with anti-human IgM F(ab')2 show elevated trypsin-like serine protease activity compared to the resting subset as monitored by the cleavage of Tos-Gly-Pro-Arg-pNA. The cleavage is sensitive to N-tosyl-L-lysyl-chloromethyl ketone and benzamidine but not to iodoacetamide. Experiments with intact cells give similar results. The finding that the intact cells hydrolyze the substrate, while their supernatant does not, suggests that the protease activity is cell membrane associated. It is possible that C3 is a substrate of the enzyme since the activated B cells cleave C3, whereas the resting B cells do not, and also C3 inhibits the enzyme-substrate reaction. In addition to the ex vivo B cells, we studied the serine protease activity of certain well-characterized B cell lines. The results show a correlation between the phenotype and the enzyme expression of the cell lines. BL41, an Epstein-Barr virus (EBV)-negative Burkitt lymphoma line, with a resting phenotype, has low activity, while its EBV genome-carrying convertants E95-A-BL41, E95-C-BL41, EHR-A-BL41 and BL41/95 that have the phenotype of activated B cells, have high proteolytic activity. The lymphoblastoid cell line WW-1-LCL which has the phenotype of an immunoblast, has the highest serine protease activity. On the basis of the above data, we suggest that a rather tight correlation exists between the degree of activation and the appearance of serine protease(s) on the surface of human B cells.

B-Lymphocytes↗
PubMedDate not supplied

Assessment of heparin binding to the AN69 ST hemodialysis membrane: I. Preclinical studies.

The AN69 ST membrane was designed to render the surface of the native polyacrylonitrile polymer less cationic. This was achieved by layering the membrane with the polycationic biopolymer polyethyleneimine. This new membrane is able to bind heparin to its surface, through electrical interactions, without altering the reactivity of the sulfonate groups of the membrane, regularly distributed in the membrane bulk. The kinetics of unfractionated or low-molecular-weight heparins were studied in vitro and in vivo in sheep. Encouraging results were obtained indicating that heparin-coated hemodialyzers are potent anticoagulants. Priming the AN69 ST membrane-equipped hemodialyzer with heparin, as in regular hemodialysis, could allow drastic reduction of heparin consumption in hemodialysis.

Acrylic Resins↗
PubMed1985

A possible self-regulating mechanism mediated by C3b-acceptor-bound C3b generated by stimulated macrophages.

Macrophages have been shown to produce C3 and to bear Fc receptors (FcR), and besides the various C3 receptors, they possess C3b acceptors (C3bA) as well as surface proteases capable of cleaving C3. Using the immune adherence method, we demonstrated that the amount of covalently fixed (i.e., C3bA-bound) C3b is markedly increased upon cell stimulation by phorbol myristate acetate or aggregated IgG, even in the absence of C3. The enhancement of nascent C3b (C3bx) binding to C3bA on these cells could be reversed by inhibiting the process at different stages, using either cycloheximide, phenyl-methyl-sulphonyl-fluoride, salycil hydroxamic acid, or methylamine. On the basis of our present results and earlier results, we propose a self-regulatory mechanism by which activated, C3-producing macrophages cleave C3 by their surface proteases. C3bx generated in this way fixes covalently to C3bA of the producer cells, resulting in the inhibition of FcR on these cells.

Animals↗
PubMed1993

Analysis of clinical and laboratory profile in Indian childhood systemic lupus erythematosus and its comparison with SLE in adults.

Data on the clinical and laboratory profiles of 83 children with SLE have been analysed and compared with data on 187 adults with the disease. The clinical features of childhood SLE are similar to those seen in adults, although clinical and laboratory parameters reflect propensity to a more severe form of the disease in the juvenile age group. However, in comparison to descriptions of childhood lupus from developed countries, in India the female-to-male ratio in this age group parallels that in adults. Renal involvement is noted to be more common, whereas gastro-intestinal and haematological abnormalities are less common. Interestingly, leucopenia, lymphopenia and nephritic type of renal involvement are commonly seen in boys with SLE, but these features are non-existent in men.

Adolescent↗
PubMedDate not supplied

Complement activation in renal disease.

Perturbation of the serum complement system in glomerulonephritis can be the result of classical pathway activation by immune complexes or of C3 activation by the C3-C5 convertase stabilized by the C3 nephritic factor. Low C3 levels can also be the result of diminished C3 synthesis and possibly, in certain circumstances, of C3 convertases deposited on capillary walls. In glomerulonephritis the complement profile is helpful in diagnosis, in following the course of therapy and in providing insights into pathogenesis. Complement profiles must be interpreted recognizing that a pattern resembling classical pathway activation can be produced by idiopathic nephrotic syndrome, that hypogammaglobulinemia can reduce Clq levels, and that a primary deficiency of factor H or I or both, will secondarily produce subnormal levels of C3 and factor B. With these caveats, the complement profiles typical of systemic lupus erythematosus, membranoproliferative glomerulonephritis, acute glomerulonephritis, acquired Cl inhibitor deficiency, and hypocomplementemic vasculitis syndrome are described.

Antigen-Antibody Complex↗
PubMed1984

On the potential role of trypsin and trypsin inhibitors in acute pancreatitis.

The protective role of alpha 2-macroglobulin, alpha 1-antitrypsin and Aprotinin against trypsin-induced effects on C3 and kininogen was studied in a human in vitro model. When human cationic trypsin was added to human serum or plasma, there was a gradual saturation of alpha 2-macroglobulin and later of alpha 1-antitrypsin. When alpha 2-macroglobulin was 70% saturated, there was a prompt cleavage of both C3 and kininogen, in spite of 80% free and active alpha 1-antitrypsin. These biochemical changes and antiprotease levels are identical to our findings in patients with acute pancreatitis, especially in their peritoneal exudate. Very high concentrations of Aprotinin, 5-15 times higher than ever used clinically, blocked the cleavage of both C3 and kininogen, while doses commonly used clinically were without significant effect. The clinical implications are: A trypsin-induced activation of both the complement and kinin system with clinical consequence is possible in patients with acute pancreatitis because of very low alpha 2-macroglobulin levels. Aprotinin in adequate doses, 5-15 times higher than ever used clinically, seems to protect against activation of two systems.

Acute Disease↗
PubMed1993

Protease-antiprotease levels and whole-blood chemiluminescence in acute peritonitis.

Whole-blood chemiluminescence and levels of leukocyte proteases and plasma protease inhibitors were studied in 43 patients with acute, generalized peritonitis. An almost three-fold increase in whole-blood chemiluminescence was found in acute peritonitis, which may indicate activation or "priming" of the leukocytes by blood-borne factors. High levels of leukocyte elastase and neutrophil proteinase 4(3) were found in plasma and peritoneal exudate. Patients with sepsis had higher plasma levels of both proteases than other patients. Large variations in the plasma levels among patients decreased their sensitivity as markers of infectious complications during the postoperative period. The plasma levels of the protease inhibitors followed three different patterns of reaction. The acute phase proteins alpha 1-proteinase inhibitor and C1-inactivator, increased during the first week of disease, to normalise later in its course. alpha 2-macroglobulin, antithrombin III and alpha 2-antiplasmin were all decreased from onset and normalised later in the course, while secretory leukocyte protease inhibitor showed a slow decrease throughout the course of disease. In peritonitis exudate, the levels of the main protease inhibitors, alpha 1-Proteinase Inhibitor and alpha 2-Macroglobulin, were decreased, probably due to complexation and subsequent elimination, as a part of the defense against liberated leukocyte proteases. The immunoreactive and especially functional levels of the protease inhibitors alpha 2-Antiplasmin, Antithrombin III and C1-Inactivator were also decreased in the exudate, indicating an increased turn-over of these proteins through activation of the cascade systems and/or break-down by leukocyte proteases. In contrast to the other inhibitors, secretory leukocyte protease inhibitor showed higher levels in exudate than in plasma, and unexpectedly high exudate/plasma-quotients were seen in cases with colonic perforations. Degradation of complement factor 3 (C3) and decreased "opsonic capacity" were found in exudate. The "opsonic capacity" could be correlated to the levels of leukocyte proteases in the exudate, which indicates that degradation of complement factor 3 may have been at least partly due to the action of leukocyte proteases. Further depletion of complement factors in exudates of long-standing peritonitis or abscesses may create a vicious circle of deficient opsonisation and clearance of bacteria, as earlier reported for chronic pleural exudates.

Acute Disease↗
PubMed1992

Dissociation of primary antigen-antibody bonds is essential for complement mediated solubilization of immune precipitates.

The role of dissociation of primary antigen-antibody bonds in the solubilization of immune complexes (IC) has been investigated using photo-affinity crosslinked IC comprising NAP15-BSA and murine monoclonal anti-DNP antibodies. Non-covalently linked IC were solubilized rapidly when incubated with normal human serum (NHS), whereas covalently-linked IC were solubilized poorly or not at all. The rate and extent of complement activation produced by incubating covalently-linked and non-covalently linked IC with NHS was similar as assessed by the production of the C1s:C1-inhibitor, C3:properdin and C5b-9 complexes and the anaphylatoxins C4a and C3a. Thus, the inability of serum to solubilize photo-affinity crosslinked IC must be due to failure of dissociation of primary antigen-antibody bonds.

Animals↗
PubMed1996

Synthesis of classical pathway complement components by chondrocytes.

Using immunohistochemical studies, C1q, C1s, C4 and C2 were detected in chondrocytes in normal human articular cartilage and macroscopically normal articular cartilage from the inferior surfaces of hip joints of patients with osteoarthritis. Using reverse-transcribed polymerase chain reaction (RT-PCR), mRNA for C1q, C1s, C4 and C2 was also detected in RNA extracted from articular cartilage. C1r, C3, C1-inhibitor, C4-binding protein and factor I were not detected by either technique. Articular chondrocytes cultured in vitro synthesized C1r, C1s, C4, C2, C3 and C1-inhibitor but not C1q, C4-binding protein or factor I, as assessed by enzyme-linked immunosorbent assay (ELISA) and Northern blot analysis. Thus cultured articular chondrocytes have a complement profile that is similar to that of cultured human fibroblasts rather than that of articular chondrocytes in vivo. Complement synthesis in cultured chondrocytes was modulated by the cytokines interleukin-1 beta (IL-1 beta), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), showing that cytokines can probably regulate complement synthesis in intact cartilage. The possible roles of local synthesis of complement components by chondrocytes in matrix turnover and the regulation chondrocyte function are discussed.

Base Sequence↗
PubMed1992

[Activation of complement and serial changes of anaphylatoxin (C3a, C5a) in patients for open-heart surgery using a membrane oxygenator].

Activation of complement and serum changes in anaphylatoxin (C3a and C5a) were studied in 8 patients who underwent open-heart surgery using a membrane oxygenator. C1 esterase inhibitor (C1-EI), C3, C5, CH50, C3a and C5a were measured serially at 7 points. C1-EI, C3, and C5 were measured by single radial immunodiffusion, CH50 by Mayer's method, and C3a and C5a by radioimmunoassay. Levels of C1-EI, C3 and C5 decreased significantly from 10 min after initiation to 120 min after the end of CPB compared with base line values. Degree of activation of complement increased in proportion to duration of CPB. Significant decreases of C3 and C5 continued until first postoperative day. Level of C3a increased significantly 10 min after initiation of CPB, and gradually increased till immediately after the end of CPB, when the level was maximum (4625 +/- 560 ng.ml-1) among 7 points. Level of C3a decreased gradually till 120 min after end of CPB. C5a was not detected during whole course. No patient showed respiratory distress of pulmonary edema. In conclusion, membrane oxygenator activated classical pathway of complement at 10 min after initiation of CPB. C3a increased significantly from 10 min after initiation of CPB to 120 min after end of CPB, but C5a was not detected at all during the whole course. The significant activation of complement continued till first postoperative day.

Aged↗
PubMed1998

Complement-mediated killing of microtumors in vitro.

Complement-mediated lysis of cancer cells growing in three-dimensional aggregates involves factors that are not associated with the killing of cells in suspension. We have used multicellular tumor spheroids established from breast carcinoma (T47D) and ovarian teratocarcinoma (PA-1) cell lines as models to study complement-mediated destruction of micrometastases and small solid tumors. We found that significant killing of microtumors treated with an antitumor antibody and a specific monoclonal antibody (YTH53.1) against the complement lysis inhibitor protectin (CD59) started to occur after a 1 to 2-hour lag phase. After an overnight incubation, the microtumors became totally infiltrated by the YTH53.1 monoclonal antibody and C1q, whereas C3 and C5b-9 penetrated as a frontier to the peripheral cell layers. A 51Cr release assay showed that during a 24-hour pulsed treatment with complement, 33% of cells in the spheroids were killed, and the average tumor volume decreased by 28%. According to propidium iodide staining, complement exposure resulted in killing and peeling off of the outermost tumor cells.

Antibodies, Monoclonal↗
PubMed1977

[Anticomplement activity of a polyanion: pentosan sulfuric polyester. III. Mechanism of functional inactivation of the different properdin and complement system fractions].

In vitro, the drug pentosan-poly-sulfoester (PPS) changes the electrophoretic migration of different proteins from the complement and properdin systems, such as native C3 (beta 1C globulin), C3c (beta-1A globulin), C3d (alpha-2D globulin), C1s inactivator (ClsINA), Clq and properdin factor B (B). Their more anodal migration is the consequence of a molecular alteration and persists after prolonged dialysis. These structural changes, yet undefined, explain the loss of functional activity of these proteins, and the anticomplementary activity of this drug. Moreover, PPS is able to block the alternate pathway activation by its action on properdin factor B (C3 proactivator). In fact, in presence of PPS, the activators of the properdin systems such as C3 nephritic factor are inactive. These altered mobilities are also responsible for the overestimation in the antigenic concentration of B (+ 45%), C4 (+27%) and C3/C3c (+ 14%), found in human serum containing 50 mg/ml of PPS. PPS has an original action upon the complement and properdin systems, which allows its clinical use as a potent inhibitor of the humoral mediators of inflammation.

Binding Sites↗
PubMed1981

Large scale isolation of functionally active components of the human complement system.

In the present work a scheme is presented for the isolation of multiple components of human complement in a functionally and biochemically pure state and with full hemolytic activity. These preparative procedures allow high recovery of milligram and gram quantities of particular complement components from a large pool (2-11 liters) of fresh EDTA plasma in no more than four chromatographic steps. Many components (C3bINA, C5, C3, C1EI, C4, and C9) are recovered functionally pure or highly purified following the first chromatographic step employing DEAE-Sephacel and may be utilized as reagents with no further purification. Prior to anion exchange, individual units of plasma are treated with inhibitors of complement activation and serum proteases, the pooled plasma is fractionated with polyethylene glycol, depleted of plasminogen on Sepharose-lysine, and rapidly ultrafiltered to low ionic strength and high protein concentration. The high degree of resolution of the components on DEAE-Sephacel subsequently obtained is demonstrated by the functional recovery and purification in a representative experiment as indicated (in their order of elution) for the following proteins: C3bINA (24%, 18-fold), C2 (74%, 12-fold), C7 (87%, 14-fold), factor B (55%, 8.7-fold),, C8 (50%, 16-fold), C6 (82%, 25-fold), beta 1H (39%, 12-fold), C5 (62%, 111-fold), C3 (99%, 64-fold), C1EI (42%, 135-fold), C9 (80%, 297-fold), and c4 (78%, 164-fold). Other components separated by these procedures include C1q and C4 binding protein. Additional steps described, which demonstrate the utility and effectiveness of this preparative scheme, have allowed isolation of C3, C5, and C7 as pure components with full hemolytic activity as judged by functional, immunochemical, and physicochemical criteria. C8, also isolated as a homogeneous protein, was recovered with partial hemolytic activity. All these components were recovered in high yield and in the purification as indicated: C3 (61%, 103-fold), C5 (24% 1350-fold), C7 (19%, 2260-fold), and C8 (32%, 547-fold). Complement components C6, beta 1H, factor B, and C2 in addition to C3bINA, C1EI, C4, and C9 are recovered partially purified with good activity and are amenable to further purification.

Complement C3↗
PubMed1981

Isolation and characterization of a low molecular weight complement inhibitor present in normal human serum.

Normal human serum and urine were found to contain a low molecular weight complement inhibitor (LMWI). LMWI was separated from serum by dialysis in membrane tubing or through an Amicon PM10, and then concentrated on an Amicon UM05 membrane. On Bio-Gel P-2 filtration, LMWI was eluted just after the column calibration marker, stachyose hydrate (6666 . 6 daltons), and was estimated to be 500 daltons. Both pathways of complement activation were susceptible to modulation by LMWI. Addition of LMWI reduced the haemolysis of sheep erythrocytes sensitized with antibody, rabbit erythrocytes and guinea-pig erythrocytes bearing human C3 and C4. Formation of EAC142 from EAC14 and guinea-pig C2 was blocked, indicating a failure to generate the classical pathway C3 convertase: however, the lysis of preformed EAC142 was not suppressed. Conversion of factor B and C3 did not occur when LMWI was present during zymosan activation of serum. This indicates that the inhibitor either prevented, or acted at a step prior to, the cleavage of factor B by factor D. LMWI did not prevent formation of erythrocyte C567 intermediates nor their subsequent lysis by C8 and C9. Thus, serum contains a 500-dalton inhibitor which modulates the activities of both complement pathways at an early step in each of the activation sequences. LMWI may serve as a regulator of the inflammatory process by suppressing C3 convertase formation and generation of complement-derived, biologically reactive molecules.

Blood↗