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PubMed1985

Circulating immune complexes in patients with cystic fibrosis in relation to clinical features.

Immune complexes have been previously reported in the serum of patients with cystic fibrosis. This study was undertaken to relate the finding of complexes with the clinical features of the disease. Immune complexes detected by the 125I-C1q binding assay were found in the sera of 17/60 (28%) of patients with cystic fibrosis (CF). There was no association between the finding of raised levels of immune complexes and duration of chest symptoms, duration of daily sputum production, age, sex, weight, atopy, the presence or absence of malabsorption, pneumothorax, diabetes, Aspergillus precipitins or specific bacterial pathogens in the sputum. There was however a correlation between the finding of increasing circulating immune complexes and decrease in the respiratory function; forced expiratory volume in 1 sec (P less than 0.001) and forced vital capacity (P less than 0.005); also with weight (P less than 0.02). It is possible that the finding of immune complexes, at low levels, in cystic fibrosis are the result of tissue damage rather than its cause.

Adolescent↗
PubMed2000

[Acquired angioneurotic edema. Clinical and biological characteristics in 9 patients].

OBJECTIVE: Angioneurotic edema (AE) is a rare but severe disease. Hereditary AE is the more well-known form. The acquired form is exceptional: the symptoms are the same but there are some biologic and treatment differences. We investigated the clinical and biochemical features in nine patients with acquired angioneurotic edema (AAE). PATIENTS AND METHODS: Four of the patients with type I AAE presented an accelerated metabolism of C1Inh, associated with a hematology disease. Their C4, C1q and C1Inh plasma levels were low. Four patients had type II AAE associated with an autoantibody to C1Inh. Their C1Inh plasma levels were normal or low but the functional levels were low in all four. One patient had AAE induced by oral contraceptives. The C1Inh plasma level was normal but the functional level was very low; there were no autoantibodies. Symptoms resolved when oral contraceptives were withdrawn and the C1Inh level returned to normal. DISCUSSION: Treatment of AAE is a difficult matter. For type I AAE, it consists in treating the associated disease. For type II AAE, the treatment goal is to lower the autoantibody level. Management of these diseases requires close collaboration between clinicians and biologists.

Adult↗
PubMed1981

C1q binding activity in the sera of patients with chronic lung diseases.

Sera from patients with chronic lung diseases were tested for the presence of immune complexes (ICs) by the 125I-C1q-binding assay. Contrary to earlier reports, modification of the test system by addition of heparin decreased rather than increased the ability of the test to discriminate between control and pathological sera. Using the unmodified system, elevated C1q-binding activity (C1qBA) was found in patients with asthma (18%), chronic bronchitis (18%), sarcoidosis (18%), fibrosing alveolitis (50%), bronchogenic carcinoma (52%) and bronchiectasis (67%). Studies with the reducing agent 2-mercaptoethanol (2-ME) suggested a role for IgM rheumatoid factor (RF) and/or IgG-containing complexes in the C1q-reactive material of sera from patients with bronchiectasis and bronchogenic carcinoma. In the latter two groups, C1qBA was found to correlate with serum levels of IgG and IgA but not with C3 and C4. A weak condition between levels of C-reactive protein (CRP) and C1qBA was found in the bronchogenic carcinoma group. Carcinoembryonic antigen (CEA) levels were elevated in all groups studied but no correlation with C1qBA was demonstrated, suggesting that CEA and CEA-ICs, if present, do not have an influence on the C1qBA of such sera. The results indicate that elevated serum C1qBA is a concomitant of both chronic inflammatory and neoplastic diseases of the lung but the extent of any similarity in the non-immunoglobulin components of the immune complexes in the respective conditions remains unknown.

Adolescent↗
PubMed1983

Chronic liver disease: the detection and characterization of circulating immune complexes.

Circulating immune complexes containing IgG, IgM and hepatitis B surface antigen (HBsAg) in sera from groups of patients with various liver diseases were detected by both the C1q and conglutinin solid phase assays. Elevated levels of antigen non-specific immune complexes were observed in sera from all groups and complexes containing IgG were present to a greater extent than were IgM-containing complexes. Higher levels of complexes were generally obtained using the conglutinin assay than the C1q assay and the two assays were shown to preferentially bind complexes of different size ranges and antigen-antibody ratios. Only sera from HBsAg-positive patients had complexes containing HBsAg, and although serum HBsAg titres and levels of HBsAg-containing complexes were correlated, the correlation coefficient was low. The mean levels of immune complexes and the frequency of positive sera varied between different disease categories, but there was little correlation between levels of the three types of complexes detected by the two tests. Assay of immune complexes in sequential serum samples from an individual patient revealed considerable variation in the levels of the three complex types, demonstrating that the measurement of complexes in single serum samples is of limited value in assessing the potential significance of circulating immune complexes in hepatitis B.

Antigen-Antibody Complex↗
PubMed1996

Biotinylation of proteins via amino groups can induce binding to U937 cells, HL-60 cells, monocytes and granulocytes.

The use of biotinylated ligands for the flow cytometric detection of cell surface receptors has become a popular alternative to radioreceptor assays. Although the biotinylation of a protein is a relatively mild chemical reaction several reports have mentioned the fact that the number and location of biotin moieties coupled to amino groups of a protein can alter its physicochemical properties and impair biological activity. In the present study we show for a variety of biotinylated functionally unaltered ligands that biotinylation by N-hydroxysuccinimide (NHS) esters of biotin can induce a binding to cell surfaces, which is not specific for the respective unlabelled ligand. C1q, C1 inhibitor (C1-INH), alpha 1-antitrypsin (AT), ovalbumin (OV), transferrin and soybean trypsin inhibitor (STI) were labelled with S-NHS-LC-biotin and activated C1s (C1s) with NHS-biotin. Biotinylation of C1q, C1s and C1-INH exerted negligible effects on biological function, antigenicity or electrophoretic mobility but when labelled and unlabelled proteins were assayed for binding to monocytic U937 cells, promyelocytic HL-60 cells, monocytes and granulocytes, a remarkable binding was observed for biotinylated C1q, C1-INH and C1s. In contrast, no binding was observed when we used unlabelled C1q, C1s and C1-INH and employed specific antibodies, alpha-mouse-FITC or alpha-rabbit-FITC for detection. Increasing molar ratios of biotin-to-protein (B : P) for biotinylated AT, OV and STI evoked increased fluorescence intensities of the cells. Most importantly the unlabelled ligands did not compete for cell binding with their biotinylated derivatives, with the exception of transferrin. Preincubation of the cells with an excess of free d-biotin did not reduce binding of biotinylated proteins, thus excluding a potential involvement of biotin receptors. Hydrophobic interaction chromatography revealed a remarkable increase in hydrophobicity of the biotinylated proteins compared to their unlabelled counterparts, suggesting that the biotinylation-induced binding is due to increased hydrophobicity. Our findings indicate that biotinylation by the common amino acid esterification method may be critical for proteins if they are to be used as ligands for receptor binding studies.

Amino Acids↗
PubMed2005

Humoral heart rejection (severe allograft dysfunction with no signs of cellular rejection or ischemia): incidence, management, and the value of C4d for diagnosis.

Severe allograft dysfunction after heart transplant (HT), without ischemia or evidence of cellular rejection upon endomyocardial biopsy (EMB), is a rare but potentially fatal condition that suggests humoral rejection (HR). Its incidence, and the methods of choice for its diagnosis and management, remain uncertain. We retrospectively studied 445 HT patients (April 1991-December 2003) to determine incidence of HR diagnosed by clinical and conventional histopathological criteria. We used immunofluorescence (IF) techniques to test archived frozen EMB issue for IgM, IgG, C1q, C3, fibrin and C4d. Twelve patients (2.7%) fulfilled the criteria for HR after a mean time post-HT of 21.3 +/- 24.7 months (range: 2-72 months). Patients were treated with high doses of steroids and plasmapheresis, with successful recovery in 11 cases. IF studies using classical markers were mainly negative for the six patients with enough EMB tissue for testing. All six patients showed positivity for C4d during the HR episode but not before or after. Humoral rejection was observed in less than 3% of HT patients. Plasmapheresis treatment was highly effective. Classical IF tests were not useful for diagnosis, but C4d appears to be useful both for confirmation of diagnosis and for monitoring response to treatment.

Adult↗
PubMed1991

Automated turbidimetry of rheumatoid factor without heat inactivation of serum.

We describe an improved turbidimetric procedure for rheumatoid factor measurement in human serum. Heat-aggregated human IgG is used as antigen. Interference produced by the complement component C1q, which required a previous heat pretreatment of sera, is avoided by the addition of the chemical inhibitor, poly(vinyl sulphonic acid). This inhibitor eliminates C1q interference without affecting the attachment of rheumatoid factor to the Fc part of IgG, thus permitting full automation of the assay. After studying the reactivity of different heat-aggregated IgG preparations, we optimized the procedure for preparing the antigen in order to attain maximal reactivity: IgG was heated at 63 degrees C until the absorbance at 340 nm of a 1/10 dilution of the antigen lay between 0.65 and 0.95 absorbance units. The study of antigen stability showed a maximum aggregation two weeks after preparation. The antigen was then stable and could be used in the assay. The standard curve extends from 30 to 500 x 10(3) IU/l. Intra- and inter-assay CV were less than 5.5%. Relative analytical sensitivity and specificity were 98.3% and 95.2%, respectively. The results agreed well with those obtained by the non-improved turbidimetric procedure (r = 0.996) and with nephelometry values on the Behring nephelometer analyser (r = 0.964). The correlation with an enzyme immunoassay was also good (r = 0.923).

Complement C1q↗
PubMed1987

Subunit interactions in the first component of complement, C1.

Interactions between C1q and other subunits of C1 were analyzed by sucrose gradient ultracentrifugation. A zone of dilute, radioiodine labelled C1q was sedimented through uniform concentrations of either C1r2C1s2, C1r2, C1r2 or C1s(2). The dissociation constants were found to be 3 x 10(-9) M and 6 x 10(-9) M for C1r2C1s2 and C1r2 binding respectively. Hill coefficients of 1 indicated no cooperativity in these bindings. Positive cooperativity was found in binding of C1s to C1q. Dissociation constants of 2 x 10(-6) M and 5 x 10(-8) M were obtained form computer modelling of a two step binding mechanism. No interaction was detected between C1q and activated C1r2. The data indicate that most of the interactions between C1q and C1r2C1s2 originates from a strong binding to the C1r2 moiety of the zymogen complex. This interaction is lost upon activation of C1r2.

Binding Sites↗
PubMed1996

Human autoantibodies against Clq: lack of cross reactivity with the collectins mannan-binding protein, lung surfactant protein A and bovine conglutinin.

The collectins, a group of humoral C-type lectins, have globular and collagen-like regions and share structural features with the complement protein C1q. The question was asked if autoantibodies to the collagen-like region of C1q (anti-C1qCLR) might cross-react with collectins, such as mannan-binding protein (MBP), lung surfactant protein A (SP-A) and bovine conglutinin (BK). Anti-C1qCLR antibodies of the systemic lupus erythematosus (SLE) type and anti-C1qCLR antibodies of the hypocomplementemic urticarial vasculitis syndrome (HUVS) type were investigated. Cross-absorption and elution experiments combined with antibody detection by enzyme-linked immunosorbent assay (ELISA) and immunoblot analysis gave no evidence of cross-reactive anti-C1qCLR antibodies. However, one serum with HUVS type anti-C1qCLR antibodies contained anti-MBP antibodies that were cross-reactive with SP-A. Judging from results of ELISA inhibition experiments and immunoblot analysis, four SLE sera contained antibodies to native BK, while two sera with HUVS type anti-C1qCLR antibodies contained antibodies to epitopes of denatured BK. This might imply that autoimmunity to collagen-like structures is not restricted to C1qCLR in HUVS and HUVS/SLE overlap syndromes.

Animals↗
PubMed2003

Autoantibodies and lymphoproliferative diseases in acquired C1-inhibitor deficiencies.

Angioedema due to acquired C1-inhibitor (C1-INH) deficiency (also referred to as "acquired angioedema") is a rare, life-threatening disease with poorly defined etiology, therapy, and prognosis. To define the profile of acquired C1-INH deficiency and to facilitate the clinical approach to these patients, we report on 23 patients with acquired C1-INH deficiency followed for up to 24 years (median, 8 yr), and review the literature. We measured C1-INH activity with chromogenic assay and detected autoantibodies to C1-INH by enzyme-linked immunosorbent assay (ELISA). Median age at onset of angioedema was 57 years (range, 39-75 yr). All patients had C1-INH function and C4 antigen below 50% of normal. C1q was reduced in 17 patients. Autoantibodies to C1-INH were present in 17 patients. Long-term prophylaxis of attacks with danazol was effective in 2 of 6 patients, and with tranexamic acid, in 12 of 13 patients. Therapy with C1-INH plasma concentrate was necessary in 12 patients: 9 had rapid positive response and 3 became progressively resistant. Associated diseases at the last follow-up were non-Hodgkin lymphomas (3 patients), chronic lymphocytic leukemia (1 patient), breast cancer (1 patient), monoclonal gammopathies of uncertain significance (13 patients). In 4 patients no pathologic condition could be demonstrated. Compared with the general population, patients with acquired C1-INH deficiency present higher risk for B-cell malignancies, but not for progression of monoclonal gammopathies of uncertain significance to malignancy. Antifibrinolytic agents are more effective than attenuated androgens in long-term prophylaxis. Patients with acquired C1-INH deficiency may be resistant to replacement therapy with C1-INH plasma concentrate.

Aged↗
PubMed1983

Presence of circulating macromolecular IgA in patients with hematuria due to primary IgA nephropathy.

The relation between renal histologic features and the presence of circulating immune complexes was studied in 50 patients with hematuria. Primary IgA nephropathy was found in 25 patients, and various other forms of glomerulopathy were seen in the remaining 25 patients. Circulating immune complexes were detected with the 125I-C1q-binding assay, the conglutinin-binding assay, and the anti-IgA inhibition binding assay, the latter detecting specifically IgA-containing immune complex-like material. The 125I-C1q-binding assay gave negative findings for all patients except one. With the conglutinin-binding assay, immune complexes were found in a similar frequency for patients with and without IgA nephropathy. However, the anti-IgA inhibition binding assay gave positive results only in patients with primary IgA nephropathy (68 percent) and in none of the other patients. Sucrose density ultracentrifugation, as well as experiments in which the anti-IgA inhibition binding assay was performed with and without pretreatment of serum with polyethylene glycol, showed the presumed IgA immune complexes to have intermediate sedimentation coefficients (11 to 21S). The presence and level of this macromolecular IgA in the circulation correlated significantly (p less than 0.001) with the presence of hematuria in patients who had this clinical manifestation intermittently. Furthermore, a significant correlation (r = 0.69, p less than 0.0001) was found between the degree of hematuria and the degree of positive findings of the anti-IgA inhibition binding assay. This study shows that in patients presenting with hematuria, a positive finding on the anti-IgA inhibition binding assay is restricted to patients with primary IgA nephropathy and therefore could be of diagnostic value.

Binding Sites, Antibody↗
PubMed1979

Evaluation of the C1q solid-phase binding assay for immune complexes. A clinical and laboratory study.

The solid-phase C1q binding assay for circulating immune complexes has been evaluated. The assay provides a rapid, sensitive (detecting as little as 1 microgram of aggregated IgG) and reproducible procedure for the detection of immune complexes in biological fluids. Using artificially prepared immune complexes, the assay detects complexes at four-times antigen-excess. Gel filtration over Sepharose 6B showed that these complexes were distributed over a range of molecular weights from greater than 4 x 10(6) to 300,000 daltons. Using radiolabelled anti-BSA, antigen (BSA) could be detected in these complexes. Screening of gel-filtered SLE showed that the assay detects complexes of both high and low molecular weight, but does not detect all complexes in the SLE sera. Clinical studies showed that immune complexes are frequently found in the sera of patients with SLE and measurement of the concentrations of complexes provides a more sensitive index of disease activity than either serum C3 or C4 concentrations or DNA binding capacity. In patients with RA concentrations of immune complexes were generally higher in synovial fluid than serum, although a patient with systemic rheumatoid disease with hypocomplementaemia had an extremely high level of circulating immune complexes. The assay only infrequently detects circulating immune complexes in glomerulonephritis and in renal transplant recipients. It is concluded that the assay provides a useful clinical tool, but detects only a limited species of immune complexes. It can be used in the detection of antigens in complexes.

Antigen-Antibody Complex↗
PubMedDate not supplied

High levels of antibodies against Clq are associated with disease activity and nephritis but not with other organ manifestations in SLE patients.

OBJECTIVE: Serum concentration of antibodies to C1q (C1qAb) has been reported to be elevated in a high percentage of patients with systemic lupus erythematosus (SLE). The associations of high C1qAb levels with different clinical manifestations and the activity of the disease, however, are not definitely understood. METHODS: We measured the levels of IgG type C1qAb in the sera of 137 patients with SLE using an ELISA method. RESULTS: Serum concentrations of C1qAb were found to be higher (p < 0.0001) in SLE patients than in healthy controls. High titer (> 66 AU/ml) C1qAb was found in 40/137 (29.2%) SLE patients, and 4/192 (2.1%) healthy controls (p < 0.0001). A strong negative correlation (R = -0.4, p < 0.0001) between the age of the patients and the C1qAb titers could be detected. C1qAb levels in clinically active SLE patients significantly (p < 0.0001) exceeded those measured in the sera of patients in the inactive stage of the disease. A significant positive correlation was detected between C1qAb levels and the laboratory activity markers (anti-DNA, low C3 level) of the disease. We found a significant negative correlation between levels of C1qAb and a negative acute phase protein, alpha2-HS-glycoprotein. Renal involvement was present in 11/40 (27.5%) and 11/97 (11%) of the patients with high and low titers of C1qAb, respectively (p = 0.038). The prevalence of other organ manifestations was, however, the same in the patients with or without high titer C1qAb. CONCLUSION: These findings indicate that C1qAb measurement is a useful method for detecting the activity of SLE and predicting renal manifestations, but not other organ involvement in the disease.

Adult↗
PubMed2006

A dominant complement fixation pathway for pneumococcal polysaccharides initiated by SIGN-R1 interacting with C1q.

The intricate system of serum complement proteins provides resistance to infection. A pivotal step in the complement pathway is the assembly of a C3 convertase, which digests the C3 complement component to form microbial binding C3 fragments recognized by leukocytes. The spleen and C3 provide resistance against blood-borne S. pneumoniae infection. To better understand the mechanisms involved, we studied SIGN-R1, a lectin that captures microbial polysaccharides in spleen. Surprisingly, conditional SIGN-R1 knockout mice developed deficits in C3 catabolism when given S. pneumoniae or its capsular polysaccharide intravenously. There were marked reductions in proteolysis of serum C3, deposition of C3 on organisms within SIGN-R1(+) spleen macrophages, and formation of C3 ligands. We found that SIGN-R1 directly bound the complement C1 subcomponent, C1q, and assembled a C3 convertase, but without the traditional requirement for either antibody or factor B. The transmembrane lectin SIGN-R1 therefore contributes to innate resistance by an unusual C3 activation pathway.

Animals↗
PubMed1988

Identification and partial characterization of human platelet C1q binding sites.

We recently showed that human blood platelets bind the complement component, C1q, and mAb directed against lymphoblastoid C1q receptors in a specific and saturable manner. To identify and further characterize platelet C1q binding sites, human platelets were washed, solubilized in Triton X-100 and either subjected to SDS-PAGE and Western blotting by using monoclonal (II1/D1) and polyclonal antibodies recognizing C1qR on lymphoblastoid cells, or applied to a C1q-Sepharose affinity column under low ionic strength conditions (20 mM NaCl). Adherent proteins were eluted with buffer containing 300 mM NaCl. Western blotting with monoclonal and polyclonal antibodies directed against C1qR showed exclusive reactivity with a 67,000 m.w. protein possessing intrachain disulfide bonds. SDS-PAGE of C1q-Sepharose eluates also revealed the presence of a 67,000 protein which was accompanied to varying degrees by a 94,000 constituent. Because similar m.w., 125I-labeled proteins were recovered from C1q-Sepharose columns to which lysed, surface-labeled platelets had been applied, both 94,000 and 67,000 components appear to be platelet membrane constituents. The 94,000 and 67,000 species, however, appear to be antigenically distinct. The 94,000 protein was immunoprecipitated by polyclonal antibodies against platelet membrane glycoprotein IIIa but not polyclonal antibodies against C1qR, whereas the 67,000 protein was immunoprecipitated exclusively by the polyclonal anti-C1qR antibody. The 67,000 protein thus appears to represent platelet C1q binding sites resembling C1qR on lymphoblastoid cells.

Antibodies, Monoclonal↗
PubMed2005

Biological activity of bevacizumab, a humanized anti-VEGF antibody in vitro.

Bevacizumab (Avastin, Genentech) is a humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF), a critical angiogenic factor involved in both physiological and pathological conditions. It has been recently approved by the US FDA as a first-line therapy for widespread metastatic colorectal cancer. This report is a detailed biological characterization of bevacizumab in a variety of in vitro models. It is shown that bevacizumab potently neutralizes VEGF and blocks its signal transduction through both the VEGFR-1 and VEGFR-2 receptors, as demonstrated by the inhibition of VEGF-induced cell proliferation, survival, permeability, nitric oxide production, as well as migration and tissue factor production. Although bevacizumab retains the ability to bind to human Fcgamma receptors and complement protein C1q, it does not demonstrate cell or complement-mediated cytotoxicity in either VEGF producing or targeting cells. Thus the mechanism of anti-tumor activity of bevacizumab is most likely due to its anti-angiogenesis effect through binding and neutralization of secreted VEGF.

Antibodies, Monoclonal↗
PubMed1992

Purification and characterization of LPS-free porins isolated from Salmonella minnesota.

Porins of Salmonella minnesota, R595, were purified by anion exchange chromatography and subsequently isolated in their monomeric form by chromatofocusing. Two forms of porin could be isolated, both with an apparent molecular mass of 37,000, but of differing isoelectric points (pI 4.6 versus pI of 4.9). Porins with pI 4.9 did not contain any detectable LPS, but porins with pI 4.6 were found to contain trace amounts of LPS (1.3 x 10(-4) micrograms LPS/1 microgram porin) as measured using a highly sensitive limulus assay. Unlike the LPS-associated porins the monomeric porins were biologically inert with regard to pore formation, but they were still able to bind C1q, a subcomponent of the first component of complement.

Bacterial Outer Membrane Proteins↗