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PubMed1975

Immunofluorescent investigations in cutaneous vasculitis. I. Histotopical demonstration of complement/complement factors.

Using an indirect double layer immunofluorescence method, fresh skin lesions of 10 patients with different forms of cutaneous vasculitis were tested for the occurrence of complement-factors C1q (C1), alpha2D(C3) and beta1F (C5). In contrast to the irregularly found complement fixing immunoglobulins IgG and IgM, complement could be regularly seen bound to the cutaneous vessel walls; mostly the C3-factor alpha2D. C1q was demonstrable, combined with IgG and/or IgM only in 2 cases. In 5 patients there was a non-homogenous, roddy fluorescenece of the epidermal basal membrane zone and the cutaneous vessels, when alpha2D or beta1F were tested. Our findings suggest that the "alternate pathway" beginning with C3-activation is followed in most cases, whereas a typical "immune complex vasculitis" is obviously rare. The constant occurrence of complement in the cutaneous vessel walls of vascultis lesions is consistent with the known chemotactic and destructive role of complement factors in experimental models of angiitis, but it may not necessarily involve a specific immunological process.

Antigen-Antibody Complex↗
PubMed1976

Separation of six bovine complement components and one inactivator (1, 2).

Six components (C1, C5, C6, C7, C8 and C9) of bovine complement and one inactivator (C3 in) could be separated from bovine serum. Bovine C1 was separated by precipitation at low molarity (0.03 M of relative salt concentration) other components by DEAE-cellulose chromatography using 0.005 M sodium phosphate buffer, pH 7.5, as a base for solvents having the relative salt concentration adjusted by addition of NaCl from 0.03 to 0.3 M. The separated bovine complement components could be tested using intermediates formed from sheep erythrocytes, rabbit hemolysin, guinea pig C1 and remaining human complement components. C2, C3 and C4 of bovine origin remained undetected either because of incompatibility with the intermediates used or interference of inhibitors or inactivators.

Animals↗
PubMed1989

Role of the thymus in natural tolerance to an autologous protein antigen.

C5-deficient mice grafted with thymus from C5-sufficient donors and immunized with C5 failed to make humoral antibody to C5, suggesting that the transfer of thymus had induced tolerance. Irradiated C5-deficient hosts repopulated with lymphoid cells from thymectomized C5-deficient mice grafted with C5-sufficient thymus also failed to respond to immunization with C5, thus showing that the state of tolerance can be adoptively transferred. These results demonstrate that natural tolerance to self-protein antigen is "learned" in the thymus.

Animals↗
PubMed1986

Complement activation in human lymph: modulation by the contact activation system and by leukocytes.

Complement components, their activation and the generation of C3a and C5a peptides were studied in human lymph used as a model of tissue fluid. Both, classical and alternative pathways could be activated by suitable agents such as immune aggregates or zymosan. C3 activation and C3a formation were marked while only 10-15% of the anyway low amount of C5 were converted during complement activation, yielding very low concentrations of C5a. Carboxypeptidase N activity was present in lymph and converted the peptides to their less (C5a) or not at all (C3a) active desArg derivatives. Contact activation of Hageman factor and kallikrein enhanced activation of the classical pathway up to C3 conversion. The search for additional processes apt to create efficient concentrations of C5a (desArg) in lymph led to the discovery that the presence of leukocytes in lymph greatly increases the release of C5a activity upon complement activation. This suggests a physiological role of leukocytes resident in tissues for the induction of inflammatory reactions.

Anaphylatoxins↗
PubMed1990

Neutrophil recruitment in the respiratory tract of a patient with plasma cell granuloma of the lung.

A 69-year-old woman had plasma cell granuloma of the left middle lobe of the lung. Her symptoms and roentgenologic findings improved with antibiotic treatment. Before treatment, the number of neutrophils and NCA were markedly increased in BAL fluid obtained from the affected region of the left lung and moderately increased in BAL fluid obtained from the nonaffected region of the right lung. The number of neutrophils, the NCA as well as the contents of C5 and C5a des Arg (neutrophil chemotactic factors) in the BAL fluids from both these regions decreased during treatment. These findings suggest that plasma cell granuloma was due to chronic immune and inflammatory reactions in the lung, that neutrophils are involved in development of the symptoms and signs of this disease, and that neutrophil chemotactic factors, including complement-derived factors, are important in neutrophil recruitment at the lesion and in nonaffected parts of the lung.

Aged↗
PubMed1991

Monoclonal antibodies as probes to investigate the molecular changes of C5 associated with the different stability of the molecule on sheep erythrocytes and Escherichia coli 0111:B4.

The fifth C component (C5) exhibits a different stability when bound to sheep E or Escherichia coli 0111:B4, being fairly stable on the bacterial intermediate sensitized E. coli 0111:B4 coated with C components up to C5 (BAC1-5) and extremely labile on the RBC intermediate sensitized sheep E coated with C components up to C5 (EAC1-5). We examined the possibility that molecular changes of membrane-bound C5 might be responsible for the different functional behavior of the two intermediates using mAb to C5 and sensitive immunoassays to detect bound C5. The decay of EAC1-5 over 30 min of incubation at 37 degrees C was associated with a significant drop in the reactivity of bound C5 with three of four mAb used. These results contrasted with those obtained with BAC1-5, which showed unchanged reactivity with all mAb tested over the same period of incubation. The effect of mAb on the activity of C5 was then investigated in an attempt to relate the change of the reactivity pattern of EAC1-5 with the functional modification of bound C5. MAb 1.5 and 1.6 were the only antibodies that interfered with the functional activity of C5, although through a different mechanism. In particular, mAb 1.5 was active both on fluid-phase and on membrane-bound C5 and is therefore likely to interact with the binding site for the late components on C5. Conversely, mAb 1.6 was only effective on fluid-phase C5 and acted by promoting a decay of BAC1-5 similar to the spontaneous decay of EAC1-5. We suggest that the bacterial outer membrane may protect C5 from functional decay and that mAb 1.6 interferes with the stabilizing effect of the bacteria in an as yet unclear manner.

Animals↗
PubMed2000

In vitro cleavage by asbestos fibers of the fifth component of human complement through free-radical generation and kallikrein activation.

Chrysotile and crocidolite fibers incubated in normal human plasma (NHP) generated from the C5 component of complement C5a-type fragments that stimulated polymorphonuclear leukocyte (PMN) chemotaxis. Absorption of NHP with antiserum against C5a totally abolished neutrophil chemotactic activity. Asbestos fibers also produced C5a small peptides in the presence of ethylene glycol bis(beta-aminoethyl ether) N,N,N'N'-tetraacetic acid (EGTA) but not ethylene diamine tetraacetic acid (EDTA). Activation of C5 was significantly inhibited when asbestos fibers were pretreated with iron chelators such as sodium dithionite (DTN), deferoxamine (DFX), or ascorbate (AA). Concentration-related inhibition of C5 activation was also observed when asbestos fibers were added concurrently to plasma in the presence of DFX, 1,3-dimethyl-2-thiourea (DMTU), a strong hydroxyl scavenger, or aprotinin (APR), a specific protease inhibitor. Further, chrysotile and crocidolite significantly increased plasma kallikrein activity. Data demonstrate that asbestos-induced C5 activation plays a role in inflammatory reactions characteristic of asbestosis through mechanisms involving iron ions, hydroxyl radicals, and oxidized C5-ike fragments. The ferrous ions present at the asbestos fiber surface trigger this activation and catalyze, via Fenton reaction, the production of hydroxyl radicals, which in turn convert native C5 to an oxidized C5-like form. This product is then cleaved by kallikrein, activated by the same asbestos fibers, yielding an oxidized C5a with the same functional properties as C5a.

Adult↗
PubMed1992

Bullous pemphigoid autoantibodies reactive with intracellular basal keratinocyte antigens: studies of subclass distribution and complement activation.

Using immunofluorescence (IF) and monoclonal antibodies (MoAbs) to IgG subclasses, terminal complement components, and S-protein/vitronectin, we have extended recent observations concerning reactivity of bullous pemphigoid autoantibodies with intracellular antigens located on the polar tips of basal human keratinocytes (HuK). Using three purified bullous pemphigoid IgG fractions, autoantibody reactivity with these intracellular antigens was present in all four IgG subclasses. When skin sections were used as substrate, an identical IgG subclass distribution of autoantibodies for each bullous pemphigoid IgG fraction was observed, but reactive with the basement membrane zone. All three bullous pemphigoid IgG preparations contained IgG subclass autoantibodies capable of complement fixation. Each IgG fraction resulted in fixation of all of the terminal complement components (C5, C6, C7, C8, and C9) and assembly of the membrane attack complex (MAC) on the polar tips of basal HuK. S-protein/vitronectin was not bound in a similar fashion. Normal IgG fractions yielded consistently negative reactions. Thus, bullous pemphigoid autoantibodies, fixed to polar tips of basal HuK, are found in all four IgG subclasses and will activate complement resulting in generation of MAC.

Antibodies, Monoclonal↗
PubMed1985

The cobra complement system: I. The alternative pathway of activation.

The complement system of the cobra snake is of particular interest because cobra venom contains cobra venom factor (CVF), a protein that is related to C3 and forms a stable C3 convertase with mammalian Factor B. We investigated the alternative pathway of cobra complement. Cobra plasma lysed erythrocytes in presence of Mg-EGTA of some mammalian species, but not cobra erythrocytes. The hemolytic activity was inhibited by EDTA and destroyed by heating. Preincubation of cobra plasma with alternative pathway activators (zymosan, inulin, lipopolysaccharide), with small nucleophiles (methylamine, hydrazine), or with chaotropes (KSCN) abrogated the hemolytic activity. The activity of cobra plasma was not affected by CVF. Cobra plasma also lysed EAC1423 cells in presence of EDTA but not EAC142 cells (prepared with sheep erythrocytes, rabbit antibody, and human complement proteins) indicating the presence of C5 in cobra plasma that is susceptible to activation by the human C5 convertase. These results indicate that the cobra has a complement system with an alternative pathway very similar to mammalian complement.

Animals↗
PubMed1978

Resistance and susceptibility of mice to bacterial infection: genetics of listeriosis.

A survey of various strains of mice showed distinct differences in resistance or susceptibility to Listeria monocytogenes. C57B1, related sublines, NZB, and SJL were resistant to Listeria, whereas BALB/c, CBA, A, DBA/1, C3H, LP.RIII, 129, and WB were susceptible. The gene(s) responsible for resistance and susceptibility to Listeria were studied in detail. C57BL6/6, B10.D2, and B10.A mice were 100 times more resistant than were BALB/c, CBA, and A. Resistance of the (C57B1/6 X BALB/C)F1 was intermediate between the two parents, suggesting partial penetration of a dominant gene. Backcross studies in which the (C57B1/6 X BALB/c)F1 were crossed with the susceptible BALB/c parent suggested that a single gene or group of linked genes were the major determinant of resistance, although the possibility that other genes exerted a modifying influence was not excluded. By using the backcross and various congenic and recombinant mice, linkage of the genes involved to the H-1, H-2, H-3, H-4, H-7, or H-8 loci, to the immunoglobulin allotype, to the Thy-1 gene, to the Hc gene specifying C5, or to coat color genes (B, c) was excluded. There was no difference in the response of males and females. In all studies, the powerful overriding influence of the C57B1 genome was evident.

Animals↗
PubMed1987

Granulomatous lung disease by Thermoactinomyces vulgaris antigen in C5 deficient and sufficient mice.

Hypersensitivity pneumonitis (HP) is a granulomatous lung disease with pulmonary lymphocytic infiltration supposed to be caused by type III and type IV allergic mechanisms. In type III allergy, compliment activation plays an important role. In this study, we adopted the intranasal administration of the ultrasonified Thermoactinomyces vulgaris(Tv) antigen to mice, which causes granulomatous lung lesions. We used C5 (the fifth component of compliment) deficient B10D2/oSnJ mice and C5 sufficient B10D2/nSn control mice for the above murine model of HP to see if late components of compliment (C5-9) are concerned in the granuloma formation of HP. The result was that both C5 deficient and sufficient mice formed histologically similar granulomatous lung lesions with lymphocytic infiltration. Our data indicate that C5 is not necessary for the granulomatous lung lesions of HP by the Tv antigen.

Actinomyces↗
PubMed1982

Bacterial and fungal infection in children with fulminant hepatic failure: possible role of opsonisation and complement deficiency.

Serious bacterial infection, including eight episodes of bacteraemia, developed in seven of 15 (47%) children with fulminant hepatic failure. Those with infections had a slightly higher leucocyte response than those who did not. Serum immunoglobulin concentrations were normal or raised in all patients. Opsonisation of heat-killed baker's yeast, functionally measured total haemolytic complement, C4, C5, total alternative pathway activity, factor B and D activity, and C3 concentrations were all significantly (p less than 0.005) reduced at presentation but returned to normal in those who survived. The severity of defects in yeast opsonisation, C4, and factor B activity at presentation were significantly correlated with the subsequent development of infection. In five patients bacteraemia occurred at a time when opsonisation and complement components were defective. Plasma infusions in vivo improved opsonisation in vitro and only one bacterial isolate was obtained within four days of such an infusion. Those patients who developed infection had received significantly (p less than 0.05) fewer plasma infusions than those who did not. Our findings suggest that both alternative and classical pathways of complement are defective in children with severe liver disease and may contribute to the susceptibility of such patients to infections. Plasma infusions might be useful in reducing the incidence of bacterial infection in such conditions.

Acute Disease↗
PubMed1976

Effects of granulocyte neutral proteases on complement components.

The proteolytic effects of collagenase and elastase from human granulocytes were investigated on the human complement components C3 and C5 in serum and with purified components. The conversion of C3 was analyzed with crossed immunoelectrophoresis as described by Ganrot, and the conversion of C5 was detected with immunoelectrophoresis according to Scheidegger's method. Collagenase converted C3 to C3b but had no detectable effect on C5. Elastase converted C3 to C3b and converted C5 to a C5b-like fragment. The proteolysis by collagenase and elastase in serum was not detectable until the molar ratio for enzyme to the protease inhibitors alpha1-antitrypsin and alpha2-macroglobulin was greater than 1.

Complement C3↗
PubMed1982

The pulmonary response of C5 sufficient and deficient mice to Pseudomonas aeruginosa.

Neutrophils have been shown to be important in the clearance of Pseudomonas aeruginosa from murine lungs. The mechanisms responsible for the neutrophil influx into the lungs, however, remain poorly defined. This study was undertaken to define the contribution to this inflammatory process by the C5 molecule or its fragments. Congenic C5 sufficient (B10.D2/nSn) and CS deficient (B10.D2/oSn) mice were challenged by intrapulmonary administration of Pseudomonas aeruginosa. Differences in survival of the 2 strains of mice were noted over a 6-day period. In addition, host response was assessed at 6-, 24-, and 48-h time points by histologic examination, analysis of cells from pulmonary lavage, analysis of cells in the peripheral blood and culture of the lungs and blood of challenged mice. Mortality was consistently higher in C5 deficient mice. Neutrophil accumulation within the lung was greater at the 6-h time point in the C5 sufficient mice, and greater at the 48-h time point in the C5 deficient mice as demonstrated by both lavage and histologic examination. Differences in neutrophil accumulation could not be explained by differing blood neutrophils concentrations in the mice before challenge, or a lack of mobilization of neutrophils into the peripheral circulation after challenge in the C5 deficient mice. An early lack of clearance of the bacteria from the lungs of the C5 deficient strain was documented. We conclude that the C5 molecule and its phlogistic fragments are important neutrophil chemotaxins in murine lungs exposed to Pseudomonas aeruginosa, and, quantitatively, may be the most important early stimulus for neutrophil accumulation in this model.

Animals↗
PubMed2004

(99m)Tc-labeled murine ior C5 monoclonal antibody in colorectal carcinoma patients: pharmacokinetics, biodistribution, absorbed radiation doses to normal organs and tissues and tumor localization.

Monoclonal Antibody (mAb) ior C5 is a murine IgG(1) that recognizes the tumor associated antigen (TAA) ior C2, a cell surface O-linked glycoprotein carbohydrate chain not present in most normal tissues and homogeneously expressed in the cytoplasm of normal colon epithelium and heterogeneously expressed in more than 83% of primary colorectal carcinomas. This study was designed to investigate the pharmacokinetics, biodistribution and the absorbed radiation doses of (99m)Tc-labeled mAb ior C5 antibody in colorectal tumor patients. Ten patients were administered 3 mg of anti-O-linked glycoprotein carbohydrate chain TAA ior C2 murine monoclonal antibody ior C5 radiolabeled with (99m)Tc activity of 1435.0 +/- 123 MBq by intravenous (i.v.) bolus infusion. Blood and urine samples were collected from 4 out of 10 patients at timed intervals from 10 min and up to 24 h after injection of the (99m)Tc-labeled mAb ior C5 for pharmacokinetic studies. Whole body images were taken in 5 out of 10 patients for quantitative normal organ biodistribution and dosimetry studies and planar anterior and posterior and SPECT images were taken in 5 out of 10 patients for tumor localization. Mean absorbed doses were estimated using the methods developed by the Medical Internal Radiation Dose (MIRD) committee. The effective dose equivalent (EDE) and effective dose (ED) were calculated as prescribed in International Commission on Radiological Protection (ICRP) publications 30 and 60. Plasma disappearance curves of (99m)Tc-labeled murine antibody ior C5 were best fit by a two-compartment model in all patients with (t(1/2alpha)) of 4.32 +/- 2.18 h and (t(1/2beta) of 32.6 +/- 3.82 h. Among the main target organs, accumulation of the radiolabeled antibody was found in liver (9.38 +/- 0.80%), heart (8.92 +/- 0.94%) and spleen (1.37 +/- 0.30%) at 5 min post-administration. These values were reduced at 24 h to (5.91 +/- 0.73%) and (0.62 +/- 0.22%), respectively, for the heart and spleen and increased to (9.78 +/- 1.99%) for liver. Estimates of radiation absorbed dose to normal organs in rad/mCi administered were: whole body, 0.0181 +/- 0.0017; heart wall, 0.0768 +/- 0.0090; kidneys, 0.0530 +/- 0.0260; liver, 0.0565 +/- 0.0109 and spleen, 0.0540 +/- 0.0128. The effective dose equivalent and effective dose estimates for adults were 0.0314 +/- 0.0031 and 0.0249 +/- 0.0027 rem/mCi administered. This feasibility study indicates that the O-linked glycoprotein carbohydrate chain TAA ior C2 is expressed in primary and metastatic colorectal carcinomas and shows very limited expression in normal adult tissues. The very good pattern of biodistribution of (99m)Tc-labeled mAb ior C5 in patients will allow imaging of colorectal carcinoma lesions.

Aged↗
PubMed1979

Factors promoting colony stimulating activity (CSA) production in macrophages and epithelial cells.

The regulation of colony stimulating activity (CSA) release from CSA producing cells is a poorly understood process. Using freshly isolated mouse peritoneal cells and a continuous line of mouse thymic epithelial cells a precise and reproducible method of short term culture was developed to study this phenomenon. Serum, endotoxin, lithium, and cyclic GMP stimulated CSA release from both cell types. Particles such as zymosan, inulin, latex, and iron filings stimulated CSA release from mouse peritoneal cells but not from thymic epthelial cells. Theophylline and cyclic AMP inhibited CSA release from both cell types. Trypsin activated guinea pig C3 and C5 did not stimulate CSA release. Cycloheximide, an inhibitor of protein synthesis, completely inhibited CSA release. We believe these findings may reflect mechanisms of in vivo regulation of CSA release.

Animals↗
PubMed1976

Arthritis associated with intestinal-bypass procedure for morbid obesity. Complement activation and characterization of circulating cryoproteins.

Five patients were studied after intestinal-bypass operations for morbid obesity to determine if the arthritis observed in three of these patients was associated with circulating cryoproteins. Only serum from the three patients with acute arthritis contained cryoprotein complexes. The complexes comprised IgG, IgM, IgA, complement components C3, C4, C5 and IgG antibody against Escherichia coli and Bacillus fragilis. The C3-activator fragment of the properdin complex was identified in fresh serum samples obtained from two of the three patients with circulating cryoprotein complexes and arthritis. These observations suggest that systemically absorbed intestinal bacterial antigens may lead to (or contribute to) the formation of circulating cryoprotein complexes. Circulating cryoprotein complexes activated both the classical and alternate complement pathways and may be important in the pathogenesis of the arthritis associated with the intestinal-bypass procedure for morbid obesity.

Adult↗
PubMed1975

Complement factors in gingival crevice material from healthy and inflamed gingiva in humans.

The presence and levels of complement factors C3, C4, C5, and C3 proactivator, were determined by electroimmuno assay in gingival cervice material from five individuals with healthy gingiva and from six patients with chronically inflamed gingiva. Higher concentrations of C3 and C4 were found in samples from chronically inflamed gingiva when compared to those healthy gingiva. The amount of C3 in material from healthy as well as from inflamed gingiva was related to that in plasma, when the albumin in plasma and gingival crevice material was used as a reference. The same was found for C4 in samples from healthy gingiva but in those from inflamed gingiva, the values were significantly lower when related to plasma levels. C5 could not be found in material from healthy gingiva but was present in material from inflamed gingiva. C3 proactivator was present in material from inflamed gingiva in the converted form. No C3 proactivator was found in material from healthy gingiva with the methods used. Analysis of C3 in samples from inflamed gingiva, using crossed immunoelectrophoresis, showed that C3 was converted in these samples. The results indicate that the complement system may be activated in gingival crevice material from inflamed gingiva.

Adult↗