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PubMed1986

Enhanced binding and degradation of the C1q subcomponent of complement by thioglycollate-stimulated guinea pig peritoneal macrophages.

Expression of C1q receptors on the plasma membrane of thioglycollate-stimulated guinea pig peritoneal exudate macrophages increased 1.54 times as compared to unstimulated controls. A Scatchard plot of the binding of 125I-C1q to the cells revealed that the binding is a result of an increase in the number of receptors and not to an increased affinity of the receptors. Thioglycollate-activated macrophages were found to be 1.6 times more active than nonactivated macrophages in the binding of 125I-C1q at 4 degrees C. The enhanced binding of 125I-C1q by activated peritoneal macrophages was reflected in an increase in the amount of 125I-C1q degraded by these cells as compared to resident peritoneal macrophages. This suggests that stimulation of phagocytic cells leads to an increase in the expression of C1q receptors and to a concomitant increase in the uptake and degradation of C1q.

Animals↗
PubMed1989

Molecular basis of complement activation in ischemic myocardium: identification of specific molecules of mitochondrial origin that bind human C1q and fix complement.

Mitochondria may be a source of molecules that activate complement during ischemic injury to myocardium, providing therewith a stimulus for infiltration of polymorphonuclear leukocytes. To identify specific molecules that activate the classical complement pathway, detergent lysates of canine cardiac mitochondria were fractionated by polyacrylamide gel electrophoresis and transferred electrophoretically to nitrocellulose paper (NCP). The NCP replicas of the gels were incubated with isolated C1q and fresh sera as a source of complement, washed briefly, and overlaid with sensitized sheep erythrocytes (RBC) in agarose. A cluster of four to six molecules between 45 and 53 kDa as well as four others, 34, 30, 26, and 23 kDa, consumed complement thereby preventing complement-mediated lysis of sensitized sheep RBC in the agarose overlay. Additional molecules reactive with C1 were identified by their ability to bind isolated human C1q and to serve as assembly sites for later acting complement components. Sites of localization of complement were demonstrated by incubating NCP replicas of fractionated mitochondria with antisera specific for C1q, C3, C5, and C9, followed by peroxidase-conjugated anti-immunoglobulin and substrate. A total of 12 C1q binding molecules ranging in size from 67 kDa to 23 kDa, which can fix later acting complement components, were identified. At least two of these reacted with antisera prepared against canine cardiac lymph collected in the first 3-4 hours after a 45-minute coronary artery occlusion. These studies present direct evidence that specific molecules, released from subcellular fractions of myocardial cells rich in mitochondria, can activate the complement cascade.

Animals↗
PubMed1978

The asparagine-linked sugar chains of subcomponent C1q of the first component of human complement.

Human C1q, a subcomponent of the first component of complement, contains six asparagine-linked sugar chains in 1 molecule. The sugar chains are exclusively located in the COOH-terminal globular region which is composed of 330 amino acid residues. The sugar chains were liberated from the polypeptide portion by hydrazinolysis, and their structures were studied by the combination of sequential exoglycosidase digestion and methylation analysis. Based on the results, the structures NeuAcalpha2 leads to 6Galbeta1 leads to 4GlcNAcbeta1 leads to 2Manalpha1 leads to 6(+/- NeuAcalpha2 leads to 6Galbeta1 leads to 4GlcNAcbeta1 leads to 2Manalpha1 leads to 3)Manbeta1 leads to 4GlcNAcbeta1 leads to 4(+/-Fucalpha1 leads to 6)GlcNAc were confirmed.

Asparagine↗
PubMed2000

The role of complement in B cell activation and tolerance.

It is becoming well accepted that innate immunity serves as a natural adjuvant in enhancing and directing the adaptive immune response. In this review, I have discussed how the complement system, a major mediator of innate immunity, links the two systems. The recent availability of knockout mice bearing selective deficiencies in the critical complement proteins and receptors has allowed formal demonstration of the importance of complement in enhancement of humoral immunity. Characterization of the mice has also uncovered mechanisms for maintaining survival of activated B cells within the lymphoid compartment. For example, co-ligation of the CD21/CD19/Tapa-1 receptor with the BCR not only reduces the threshold for B cell follicular survival but provides a unique signal for survival in the germinal centers. In addition complement receptors are critical for localization of antigen and C3d ligand to FDCs for maintenance of long-term B cell memory. A surprise that has come from analysis of the deficient mice is that complement is also important in negative selection of B lymphocytes. This observation provides new insight to a long-standing enigma that the major predisposing factor in lupus is deficiency in complement C1q or C4. The seeming contradiction of dual role for complement in both B cell activation and tolerance is reconciled by the hypothesis that natural IgM provides a mechanism to selectively identify self-antigens that are highly conserved and cross-react with microbial ones such as DNA and nuclear proteins. Thus, the importance of complement in tolerance to self-antigens is restricted to those self-antigens that are evolutionary conserved, and they are identified by natural antibody. The future should hold further surprises as to the intricate interactions between the complement system and acquired immunity.

Adjuvants, Immunologic↗
PubMed1988

Chromatographic and electrophoretic studies of immune complexes in non-A, non-B hepatitis.

Immune complexes isolated from two patients with chronic non-A, non-B hepatitis, one patient with acute non-A, non-B hepatitis and one patient with juvenile rheumatoid arthritis were examined by means of a combined chromatographic and electrophoretic method. Both analyses showed the presence of complexes consisting of IgG, IgM, complement c1q factor and albumin; no antigen constituents were detected. The IgG-to-IgM ratio varied from 1:1 to 4:1, suggesting that one could be dealing with complexes of both IgG-IgM and IgG-IgG types. Moreover, the detectable presence of c1q factor might indicate that such complexes were capable of activating complement.

Antigen-Antibody Complex↗
PubMed1983

Analysis of cell populations in crescentic glomerulonephritis.

The cell types present in the crescents were studied in 5 human patients with crescentic glomerulonephritis: two cases of systemic lupus erythematosus, one case of hemolytic uremic syndrome and two cases of rapidly progressive glomerulonephritis. Frozen sections of renal biopsies were studied by immunofluorescence, using murine monoclonal antibodies (orthoclones) against specific antigens on the membrane of human peripheral blood cells, and by histochemical methods. Monocytes (OKM1+, OKIa+ cells) but no lymphocytes (OKT+ cells), were detected in the crescentic glomeruli. Subsets of T lymphocytes (inducer-helper and cytotoxic-suppressor) were detected in the interstitium. Non-specific esterase-positive cells were observed in the glomeruli and in small numbers in the crescents. Fibrinogen deposits were present in the crescents of four of the five cases studied. No immunoglobulins (IgG, IgM, IgA) or complement (C1q, C3) deposits were detected in the crescents. Fibrinogen, immunoglobulins and complement were present in the glomerular tufts.

Antibodies, Monoclonal↗
PubMed1985

[Effect of the C1q subcomponent of complement on thrombocyte adhesion and spreading].

In vitro experiments have shown that C1q at a concentration of 8-250 mkg/ml produced a 1.5-2-fold increase in platelet adhesion to glass. Low doses (4-60 mkg/ml) enhanced platelet splitting 2-3-fold. C1q did not cause platelet aggregation or change ADP-, adrenalin- and thrombin-induced aggregation. C1q participation in the induction of immune response is suggested.

Blood Platelets↗
PubMed1991

Failure to detect deposition of complement and immunoglobulin in allergen-induced late-phase skin reaction in atopic subjects.

There still remains some controversy regarding the possible role of immune complexes in the pathogenesis of the late-phase skin reaction (LPSR). To assess this, skin biopsies were obtained from LPSR induced in atopic human subjects 6, 24 and 48 h after allergen challenge. Cryostat sections were stained by direct immunofluorescence for the presence of fibrinogen, immunoglobulin classes IgM and IgG and for the complement components C1q and C3c. Complement components were observed in only two of the 29 biopsies studied. In both instances, only C3c was detected. One of these subjects also had unequivocal IgG staining at 6 h. IgM staining was detected in two out of 10 subjects at 6 h but no significant deposition of immunoglobulins could be found at 24 or 48 h. Fibrinogen deposition was observed in about half of the biopsies at each time-point. This study suggests that substantial complement and immunoglobulin deposition are not overt features of the allergen-induced LPSR, although the presence of small amounts of immune complexes, below the sensitivity of the method employed cannot be excluded. Fibrin deposition occurs in the LPSR but does not appear to be a prerequisite for LPSR development.

Allergens↗
PubMed1981

C1q binding and complement activation by capsular and cell wall components of S. pneumoniae type XIX.

Cell wall components (purified cell walls, teichoic acid and residual cell walls) from S. pneumoniae type XIX showed antibody independent C1q binding capacity, as assessed by C1q deviation test, with teichoic acid being the most efficient. Specific capsular substance did not bind C1q. All substances tested produced C1 activation in normal human serum, but not in hypo-gamma-globulinemic serum. Thus, teichoic acid showed high C1q binding capacity but did not activate C1 in the absence of antibodies. Teichoic acid was an effective activator of alternative pathway. Specific capsular substance did not activate the alternative pathway in C1q deficient serum or in Mg2+ -EGTA chelated normal serum.

Cell Wall↗
PubMed1985

Segmental flexibility of the C1q subcomponent of human complement and its possible role in the immune response.

Fluorescence polarization techniques were used to study the rotational dynamics of the C1q subcomponent of human complement. C1q was covalently labeled with dansyl (DNS) chloride. Digestion of either C1q-DNS4.0 or C1q-DNS1.8 conjugates with pepsin showed that about 75% of the DNS probes were attached to the C1q globular heads and that the remainder were on the collagen-like stalk (peptic fragment). C1q-DNS conjugates readily agglutinated IgG-coated latex beads and combined with C1r2C1s2 to form hemolytically active 16 S C1-DNS. Both C1q-DNS and C1-DNS samples displayed steady-state rotational correlation time and fluorescence lifetime transitions near 48 degrees C. Hydrodynamic studies showed that C1q formed soluble aggregates near the transition temperature. In contrast, stalk samples with a DNS probe apparently attached to the large central fibril showed no thermal transitions or aggregation even when heated above 50 degrees C. Nanosecond fluorescence depolarization measurements detected restricted flexible motions of the C1q heads with an associated rotational correlation time, phi s, of about 25 ns. The C1q anisotropy decay was dominated, however, by a long component, phi L, of perhaps 1000 ns. Except for probe wiggle, the stalk-DNS anisotropy profile was essentially flat. The rapid rotations associated with phi s could represent restricted twisting motions of the arm-head segments or wobbling motions of the heads themselves. Such motions may facilitate binding of the C1q heads to immune complexes. Straightforward diffusion calculations indicated that phi L could represent either global tumbling of the entire C1q molecule or wagging motions of the individual arm-head segments, as suggested by electron micrographs. Upon binding of the C1q heads to an activator, some of the C1q segments may be held in a slightly more open or more closed conformation, which in turn may trigger activation of the C1 proenzymes. In conclusion, we suggest a plausible triggering mechanism for C1 activation that is compatible with the flexible properties of its subcomponents.

Complement Activating Enzymes↗
PubMed1979

Identification of a collagen-like antigen different from C1Q component of complement in serum.

The problem of the proportions of hydroxyproline proteins in serum linked to collagen and to the C1Q component of complement was examined. The C1Q component from human and bovine serum, and acid soluble calf skin collagen were purified. Antibodies to soluble collagen were prepared. With these antibodies we found by immunoelectrophoresis that in serum two distinct antigens exist: one reacts with antiserum to C1Q and the other reacts with antiserum to collagen. The collagen-like antigen may be precipitated by sodium chloride 4.3 mol/1.

Animals↗
PubMed1984

Rapid three-step purification procedure for isolation of the C1q component of human complement and its use in a solid-phase C1q binding assay.

A new procedure for the isolation of the C1q subcomponent of complement from human sera has been devised. The 3-step protocol employs DEAE Sephadex A-50, hydroxyapatite and Sephacryl S-200 chromatographies and can be performed within 9 h. It yields immunoglobulin-free homogeneous C1q protein with about 80% recovery. The isolated C1q protein is biologically active and may be used for the detection of circulating immune complexes in sera by the solid-phase C1q binding assay.

Antigen-Antibody Complex↗
PubMed1994

Synthetic polysulfated hyaluronic acid is a potent inhibitor for tumor necrosis factor production.

Based on the premise that naturally occurring glycosaminoglycans could serve as building blocks for synthesizing nontoxic drugs for suppression of tumor necrosis factor (TNF) production by inflammatory cells, we have chemically modified hyaluronic acid (HA) and tested its effects in blocking TNF-alpha and TNF-beta production in vitro. HA was chosen mainly for its structural simplicity, nonimmunogenicity, and readiness for chemical modifications. When HA was chemically polysulfated to a sulfate/hexosamine molar ratio of 3.9, the sulfated HAs was shown to be a potent inhibitor of TNF-alpha production in lipopolysaccharide (LPS)- or interferon-gamma-activated THP-1 cells. For example, a concentration of HAs as low as 10 ng/ml reduced TNF-alpha production in LPS-activated THP-1 cells more than 50%, whereas achieving a similar extent of reduction required 50 micrograms/ml native HA. By decreasing the extent of polysulfation, the inhibitory effect of HAs on TNF-alpha production was diminished. Other chemical modifications, including deacetylation, thiolation, or reduction of the carboxylic groups, could not increase the efficacy of HA in suppression of TNF-alpha production. Naturally polysulfated glycosaminoglycans, such as chondroitin sulfates, keratan sulfate, heparan sulfate, and heparin, failed to inhibit TNF-alpha production. HAs also restricted TNF-beta (lymphotoxin) secretion in an Epstein-Barr virus-transformed B cell line, Roha-9, which constitutively produces TNF-beta. HAs had no inhibitory effect on the proliferation of THP-1 or Roha-9 cells, which would account for the reduced TNF-alpha or TNF-beta production. Furthermore, time-course metabolic labeling studies revealed that HAs could not restrict overall protein synthesis and secretion in THP-1 cells. However, HAs increased complement C1q secretion in THP-1 in a dose-dependent manner, but it had no effect on biosynthesis of complement C1 inhibitor, factor D, and Fc gamma receptor type II (Fc gamma RII). These results indicate that HA, selectively restricts the production of TNF-alpha, TNF-beta, and probably several other protein species.

Cell Division↗
PubMed2000

Administration of IgG Fc fragments prevents glomerular injury in experimental immune complex nephritis.

Most human nephritis is due to glomerular deposition and/or formation of immune complexes (IC). In cultured mesangial cells, Fc receptor stimulation induces proliferation, matrix synthesis, and release of several mediators implicated in the initiation and progression of glomerular injury. Since Ig Fc fragments in vitro modified these phenomena, we studied the effects of systemic administration of IgG Fc fragments on the evolution of experimental IC nephritis. Fc fragment injection (1 mg/day i.p.) to rats with ongoing nephritis (proteinuria 20-50 mg/24 h vs 9 +/- 0.2 mg/24 h in controls) markedly ameliorates proteinuria, renal function, and morphological renal lesions. This was accompanied by a reduction in the renal synthesis of chemokines (monocyte chemoattractant protein-1, IFN-inducible protein-10, and cytokine-induced neutrophil chemoattractant-1), matrix proteins, and growth factors (platelet-derived growth factor, and TGF-beta), and in the activity of transcription factors. The treatment did not affect the glomerular deposition of IgG IC and complement C1q. In contrast, a decrease in the renal expression and production of C3 was observed without changes in serum complement levels. In vitro, very low complement consumption and no C3b covalent interaction were observed with Fc fragments, confirming that they did not modify systemic complement activity. These results indicate that the administration of Fc fragments prevents the development of glomerular damage in an aggressive model of proliferative glomerulonephritis through mechanisms involving a reduced local generation of complement, chemokines and growth factors. Modulation of IC-mesangial cell interaction by Fc fragment administration could represent a new approach to the treatment of severe immune nephritis.

Animals↗
PubMed1999

IL-2 receptor-targeted cytolytic IL-2/Fc fusion protein treatment blocks diabetogenic autoimmunity in nonobese diabetic mice.

High affinity IL-2R5 is present on recently activated but not on resting or memory T cells. Selective targeting of T cells bearing high affinity IL-2R is an attractive therapy for many T cell-dependent cytopathic disease processes. A variety of rodent mAbs directed against the alpha-chain of the IL-2R, as well as IL-2 fusion toxins, have been used in animals and humans to achieve selective immunosuppression. Here we report on the development of a novel IL-2R targeting agent, a cytolytic chimeric IL-2/Fc fusion protein. This immunoligand binds specifically and with high affinity to IL-2R and is structurally capable of recruiting host Ab-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity activities. The Ig component ensures an extended circulating t1/2 of 25 h following systemic administration. To subsequently explore the mechanisms of the antidiabetogenic effects of IL-2/Fc, we have mutated the FcR binding and complement C1q binding (Fc-/-) domains of the Fc fragment to render the Fc unable to direct Ab-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity activities. In a model of passive transfer of diabetes in nonobese diabetic mice, lytic IL-2/Fc, but not nonlytic IL-2/Fc-/-, exhibited striking antidiabetogenic effects. Together with the negligible potential of IL-2/Fc for immunogenicity, this finding forecasts that cytolytic IL-2/Fc may offer a new therapeutic approach for selective targeting of auto and alloimmune T cells.

Adoptive Transfer↗
PubMed1990

Proteolysis of the heavy chain of major histocompatibility complex class I antigens by complement component C1s.

The major histocompatibility complex (MHC) class I antigens contain a light chain, beta 2-microglobulin, non-covalently associated to the transmembrane heavy alpha-chain carrying the allotypic determinants. Since the C1q complement component is known to associate with beta 2-microglobulin, and we recently found that activated C1s complement was capable of cleaving beta 2-microglobulin, we decided to investigate the proteolytic activity of C1 complement towards the heavy chain of class I antigens. Our results demonstrate that human C1s complement cleaves the heavy chain of human class I antigens into at least two fragments, with apparent molecular weights of 22,000 and 24,000 g/mol on sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), under both reducing and non-reducing conditions. The cleavage of the heavy chain is inhibited by the presence of C1 esterase inhibitor. The molecular weights of the fragments are in agreement with the cleavage located in the area between the disulphide loops of the alpha 2-and alpha 3-domains of the heavy chain. In addition human C1s complement is able to cleave H-2 antigens from mouse in a similar fashion but not rat MHC class I antigen or mouse MHC class II antigen (I-Ad). Mouse MHC class I antigen-specific determinants could also be detected in supernatant from mouse spleen cells incubated with C1r and C1s. These results indicate the presence in the body fluids of a non-membrane-bound soluble form of the alpha 1-and alpha 2-domains which represent the binding site for antigenic peptides.

Animals↗
PubMedDate not supplied

[Detection of immune complexes in idiopathic thrombopenia].

In 206 sera from the patients with different haematological disorders including 45 sera from patients with idiopathic thrombocytopenia, immune complexes were searched for, using the method of inhibition of latex-IgG agglutination by rheumatoid factor (RF) and C1q complement component. In the group of patients in 27 cases (13%) presence of endogenous RF was found. The sera of 149 patients (72.5%) inhibited RF and C1q. With the exception of sera from patients with thrombocytopenia, all the remaining ones either inhibited RF and C1q or contained endogenous RF. In the sera of patients with idiopathic thrombocytopenia the inhibitory factors were found in 46.5% and endogenous RF in 22.5%. In 12 patients in this group selected on clinical grounds the levels of immune complexes were investigated before and during 2 weeks after splenectomy. Apart from some changes immediately after this operation no significant differences were observed in the levels of immune complexes during this brief follow-up.

Adolescent↗
PubMed1992

Effect of Pseudomonas aeruginosa elastase and alkaline protease on serum complement and isolated components C1q and C3.

The present study was undertaken to examine and compare the direct effect of two Pseudomonas enzymes, elastase and alkaline protease, on the serum hemolytic complement as a whole, and on the two recognition molecules of complement, C1q and C3 in particular. The results of our study show that incubation of serum with 0-50 micrograms/ml elastase or protease (60 min, 37 degrees C) resulted in a dose-dependent depletion of hemolytic complement with the protease being 3-4 times more efficient than elastase. Incubation of highly purified C3 (20 hr, 37 degrees C) with protease (2% w/w) resulted in the conversion of the 190-kDa molecule to a 120-kDa fragment. When analyzed by SDS-PAGE under reducing conditions, the 120-kDa piece yielded three distinct bands: an intact 75-kDa beta-chain and two alpha-chain pieces of approximately 41- and 26-kDa. NH2-terminal end sequence analysis localized the 26-kDa fragment within the cysteine-rich 41-kDa, COOH-terminal piece. This in turn suggests that the 70-kDa fragment which is not accounted for on SDS-PAGE is derived from the NH2-terminal end of the alpha-chain molecule which is completely degraded into small fragments. While the degradation pattern obtained with elastase is similar to that of protease, the latter enzyme was found to be more efficient. Exposure of C1q (0-5 hr, 37 degrees C) to protease or elastase on the other hand appears to reveal preferential sensitivity of the 28-kDa A-chain and 24-kDa C-chain, of the C1q molecule, with the protease being more potent than the elastase. Since both C1q and physiologic fragments of C3 (C3b, iC3b, and C3dg) are important opsonins of varying efficiencies, degradation of these molecules by Pseudomonas enzymes may, in part, facilitate the survival and proliferation of the organism in plasma. Furthermore, degradation of the key recognition molecules of complement, C1q and C3, would enhance the virulence of this organism by aborting complement-mediated bacterial killing. In addition the results imply that during Pseudomonas bacteremia, PaAP may be a much more destructive enzyme than PaE with regards to C3 and C1q but combined, the synergistic effect may overwhelm not only the proteins of the complement system, but other proteins of the humoral immune defense system as well.

Amino Acid Sequence↗