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PubMed1999

Complement activation and expression of membrane regulators in the middle ear mucosa in otitis media with effusion.

The aetiopathogenesis of chronic otitis media with effusion (OME) in children is not yet fully understood. OME is characterized by metaplasia of the epithelium and accumulation of sticky, glue-like effusion in the middle ear containing different mediators of inflammation, including activation fragments of the complement system. Here we examined whether the fluid phase complement activation is reflected in the middle ear mucosa and how the mucosa is protected against the cytolytic activity of complement. Mucosal biopsies from 18 middle ears of children with a history of chronic OME were taken. The biopsies were analysed by immunofluorescence microscopy after staining for complement fragments iC3b/C3c, C3d and C9, and regulators membrane cofactor protein (MCP; CD46), decay-accelerating factor (DAF; CD55) and protectin (CD59). There was a strong staining for iC3b/C3c, and a weaker one for C3d and C9 on the surface of the middle ear epithelial cells of OME patients but not in controls without OME. MCP was expressed on the hyperplastic three to four outer cell layers of the epithelium, while CD59 was expressed throughout the middle ear mucosa. The results suggest a strong ongoing complement activation and consequent inflammation in the middle ear cavity. Unrestricted complement damage of the epithelial lining is prevented by the strong expression of MCP and CD59.

Antigens, CD↗

PubMed2003

Mycobacteria, an environmental enhancer of lupus nephritis in a mouse model of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by the production of antibodies directed against self antigens. Immune complex glomerulonephritis (GN) is one of the most serious complications of this disorder and can lead to potentially fatal renal failure. The aetiology of SLE is complex and multifactorial, characterized by interacting environmental and genetic factors. Here we examine the nature of the renal pathology in mycobacteria-treated non-obese diabetic (NOD) mice, in order to assess its suitability as a model for studying the aetiopathogenesis of, and possible treatment options for, lupus nephritis (LN) in humans. Both global and segmental proliferative lesions, characterized by increased mesangial matrix and cellularity, were demonstrated on light microscopy, and lesions varied in severity from very mild mesangiopathic GN through to obliteration of capillary lumina and glomerular sclerosis. Mixed isotype immune complexes (IC) consisting of immunoglobulin G (IgG), IgM, IgA and complement C3c were detected using direct immunofluorescence. They were deposited in multiple sites within the glomeruli, as confirmed by electron microscopy. The GN seen in mycobacteria-treated NOD mice therefore strongly resembles the pathology seen in human LN, including mesangiopathic, mesangiocapillary and membranous subclasses of LN. The development of spontaneous mixed isotype IC in the glomeruli of some senescent NOD mice suggests that mycobacterial exposure is accelerating, rather than inducing, the development of GN in this model.

Animals↗

PubMed1998

High-dose intravenous immunoglobulin treatment activates complement in vivo.

Several complement modulating effects of high-dose intravenous immunoglobulins (IVIG) have been proposed from in vitro studies and experimental animal models. However, the in vivo effects of IVIG on plasma complement in humans are yet not known. We have investigated the in vivo effects of IVIG on complement in seven women with unexplained recurrent spontaneous abortion who were without evidence of autoimmune disease. Samples were obtained before and after the very first infusion of IVIG. There was a marked increase in immunoglobulin G (IgG) from (median and range) 12.4 (9.4-15.9) to 26.8 (22.4-30.0) g/l but no change in immunoglobulin A (IgA) or immunoglobulin M (IgM). A significantly increased complement activation was demonstrated using neoepitope-specific enzyme immunoassays to the activation products C3bc (median increased from 9.8 to 31.2 AU/ml), Bb (0.66-1.66 g/ml), C5a (10.5-12.7 ng/ml), and TCC (0.81-2.19 AU/ml) (P = 0.015 for all). There were no changes in antigenic concentrations of individual complement components or regulators (C1q, C4, C3, C1-inhibitor, C4b-binding protein) and no decrease in complement haemolytic activity (classical and alternative CH50), which were all within the normal range. The classical pathway activation products C1rs/C1-inhibitor complexes, C4bc and C4d were elevated in all patients before IVIG treatment and did not change significantly during treatment. In conclusion, IVIG induced a significant activation of complement in vivo.

Abortion, Habitual↗

PubMed1999

Complement haemolytic activity (classical and alternative pathways), C3, C4 and factor B titres in healthy children.

Values of complement lytic activity of classical and alternative pathways, assessed by measuring the time required to lyse 50% of target red blood cells, and the concentration of complement components C3, C4 and factor B were estimated in the sera of 103 healthy children aged 3 to 14 y. Age-dependent variations were seen in the C3 and factor B concentrations, but not in C4, with the highest values found among 5-6-y-old children. Variations in classical and alternative lytic activity were not detected in this group of children, although the values are significantly different from our previously published data on adults, using the same kinetic assay (1). We also evaluated the relationship between the lytic activity of the classical (CPT) and alternative pathways (APT) and the levels of complement components. There were significant correlations between: APT and factor B, APT and C3, C3 and C4, C3 and factor B, and C4 and factor B concentrations. The normal ranges measured here can be used in the initial screening of Brazilian children presenting diseases involving the complement system. This study also contributes to a better understanding of the complement system ontogeny.

Adolescent↗

PubMed2003

Immunologic and other biological parameters as a function of smoking status and of residence in areas differing in terms of air pollution.

In the industrial region of La Louvière (Belgium), healthy persons, presenting at a consultation of preventive medicine, showed differences as a function of smoking and of residence in one of four areas differing in sources of emissions, population density and green zones. Smokers had significantly (P</=0.05) more leukocytes microl(-1), neutrophils microl(-1), CD3+ lymphocytes (lys) microl(-1), CD4+ lys microl(-1), CD25+ lys microl(-1), higher CD4/CD8 ratio's and higher carcino-embryonic antigen serum levels but significantly lower IgG immunoglobulin and serum carotene levels than non-smokers. Compared to persons living in the 'Peripheral area', and after correction for sex, smoking status and age, persons living in the more polluted areas showed significantly more CD3+CD56+ lys microl(-1). Although about the same mean value for the CD4/CD8 ratio was found for the more polluted areas, a higher percentage of their residents showed a ratio that was either <1 or >/=2.25, significantly so for the Power Station-Landfill area. A non-significant but consistent trend towards higher lymphocyte and CD8 lys counts and higher complement C3c serum levels further suggested an association between residence in a more polluted area and immunologic features. The number of CD3+CD56+ lys microl(-1), reported to be increased in cancer patients, showed a negative correlation with the CD4/CD8 ratio (r(2)=0.132, P<0.0001).

Adult↗

PubMed1998

Helicobacter pylori urease significantly reduces opsonization by human complement.

The role of Helicobacter pylori urease in opsonization by human complement was investigated. H. pylori wild type strain N6 and isogenic mutants lacking either the large urease subunit (UreB) or an accessory urease protein (UreG) were incubated with different sera. C3b bound to the bacteria was measured by specific staining and flow cytometry. As compared with opsonization of N6 and the UreG-lacking mutant, opsonization of the UreB-lacking mutant was significantly increased after incubation with sera from both H. pylori uninfected (P<.001) or infected (P<.05) persons. However, when sera from uninfected persons were used, effective opsonization of this mutant proved to be dependent mainly on the classical pathway of complement activation. Irrespective of the serum used, opsonization values were very low after selective inactivation of the classical or the alternative pathway. Reduced opsonization of the urease-expressing strains could, to some extent, result from degradation of bound C3b.

Bacterial Proteins↗

PubMed1990

Identification of specific serum proteins synthesized de novo by monolayer cultures of glandular cells of gestational endometrium.

Monolayer cell cultures (n = 3) of glandular epithelium of gestational endometrium obtained from three apparently healthy women undergoing elective termination of pregnancy (7-9 weeks gestation) were established. De novo synthesis of eight serum proteins (albumin, alpha 1-antitrypsin, ceruloplasmin, beta-lipoprotein, alpha 2-macroglobulin, fibronectin and complement factors C3 and C4) was demonstrated by the incorporation of radiolabelled substrate ([35S]methionine) employing autoradiography (AR) in combination with crossed immunoelectrophoresis (XIE), referred to as ARXIE, and line immunoelectrophoresis (LIE), referred to as ARLIE. By contrast, there was no evidence for de novo synthesis of IgA, haptoglobin and orosomucoid. Our findings suggest that the gestational endometrium may contribute to the production of several proteins considered to be synthesized and secreted mainly by the liver and reticulo-endothelial system. The simple techniques used here to identify the de novo synthesis of human serum proteins could be applied to investigate protein synthesis by a wide range of tissues and cells.

Blood Proteins↗

PubMed1996

Human nasal epithelium adsorbs complement C3-related fragments and expresses cell membrane complement regulatory proteins.

Recent evidence suggests that complement is activated in human nasal airways in inflammatory states. Activated complement protects the nasal mucosa against microorganisms, but also has the potential to lyse the host's normal cells. Complement-mediated cell lysis depends on adsorption of complement to the cell membrane and on uninterrupted activation of the complement cascade upon the same cell membrane. In the present study, the authors investigated first whether key complement components, C3-related fragments, are adsorbed to nasal epithelial cell membrane. Second, we investigated whether nasal epithelium expresses cell membrane complement regulatory proteins that are known as interruptors of complement activation. Studies were done using fresh nasal mucosa obtained at turbinectomies from allergic rhinitis and vasomotor rhinitis patients. In addition, in order to establish an in vitro model, studies were also done using primary cell cultures of nasal epithelium. We have found that complement C3-related fragments are present on cell membranes of fresh nasal epithelium and that C3-related fragments are adsorbed to the epithelial cell membrane in nasal mucosa tissue segments and in cell cultures that were incubated with autologous serum. Adsorption of C3-related fragments to the cell membrane of cultured nasal epithelial cells was found by flow cytometry analysis to be concentration-dependent. In addition, we found that nasal epithelium in fresh tissue and in cell culture express three cell membrane complement regulatory proteins: membrane cofactor protein (MCP, CD46), decay-accelerating factor (DAF, CD55), and CD59. Our findings in fresh nasal epithelium suggest that complement activation may occur upon the nasal epithelial cell membrane during inflammation in vivo and that nasal epithelium might regulate this complement activation. Our in vitro cell culture model will allow further investigations of complement activation and regulation upon the human nasal epithelial cell membrane.

Adolescent↗

PubMed1998

High-level endothelial expression of human CD59 prolongs heart function in an ex vivo model of xenograft rejection.

BACKGROUND: Hyperacute rejection of discordant xenografts is dependent on activation of the complement system of the recipient. Transgenic expression of recipient complement regulatory factors in donor tissue has proved to be a promising approach to dealing with hyperacute rejection, although the relationship between the level of complement regulatory factor expression and the degree of protection is not well established. Here, we examine this relationship using CD59 transgenic mouse hearts in an ex vivo model of xenograft rejection. METHODS: The level of expression of CD59 in two lines of transgenic mice, in which CD59 is expressed under the control of either the murine H2Kb (MHC class I) promoter (line CA-17) or the endothelium-specific human intercellular adhesion molecule-2 promoter (line 237-7), was compared by immunohistochemistry and flow cytometry. Hearts from both groups and wild-type controls were perfused ex vivo with human plasma, and mean heart work for each group was compared over a 60-min period. RESULTS: CD59 expression on cardiac endothelial cells isolated from homozygous CA-17 mice was 25- to 30-fold lower than that on cardiac endothelial cells from heterozygous 237-7 mice. CA-17 hearts perfused with 6% human plasma exhibited a reduction in deposition of the membrane attack complex, but not a prolongation of function, compared with nontransgenic mouse hearts. In contrast, 237-7 hearts showed significantly prolonged function during perfusion with 20% plasma. CONCLUSIONS: High-level endothelial-specific expression of CD59 was effective in prolonging the function of mouse hearts perfused with 20% human plasma, whereas low-level, broader expression did not provide protection from 6% plasma.

Animals↗

PubMed1983

In vitro complement binding in human skin cells with altered differentiation.

Exposure of cytoskeletal intermediate-sized filaments (ISF) of various cell populations in normal human skin to normal human serum (NHS) results in the deposition of C3 upon these structures; this phenomenon most likely occurs antibody-independently, is initiated by Clq binding to ISF, and is followed by the activation of the classical complement pathway. In the present study we investigated the cytoplasmic C3-binding properties of skin cells undergoing altered differentiation. Incubation of cryostat skin sections of dermal melanocytic nevi with NHS and, subsequently, with fluorescein isothiocyanate-conjugated rabbit antihuman C3 resulted in a bright cytoplasmic staining of the vast majority of nevus cells. Immunoelectron microscopic studies demonstrated that ISF within nevus cells represented the only cytoplasmic C3-binding structures. In contrast, ISF within melanoma cells, basal cell carcinoma cells, and keratinocytes constituting psoriatic lesions lacked C3-binding properties. We propose that changes in structure and subunit protein composition of ISF in certain cells undergoing altered differentiation results in a decrease or loss of their C3-binding capacity.

Basal Cell Carcinoma↗

PubMed1990

The level of mannan-binding protein regulates the binding of complement-derived opsonins to mannan and zymosan at low serum concentrations.

When sera diluted to 5% in a buffer containing calcium and magnesium were incubated with mannan-coated ELISA plates, C4 fragments, properdin and factor B were bound to the plates as well as the expected opsonic C3 fragments, C3b and C3bi. The calcium-dependent lectin mannan-binding protein, which is structurally similar to C1q, was also shown to bind in this assay and analysis of sera from 179 healthy blood donors revealed that the binding levels of all these proteins were highly significantly correlated. Results obtained with a previously described C3b opsonic assay using zymosan also correlated with the mannan-binding levels. When the sera were diluted to 5% in the presence of Mg-EGTA there was no detectable binding of complement proteins to the mannan surface, confirming that no alternative pathway activation occurred at this serum concentration. When sera were diluted to 5% in a buffer containing EDTA in order to study immunoglobulin binding in the absence of complement activation, the levels of bound IgG1, IgG2, IgG3, IgA and IgM antibodies were found to be completely unrelated to the C3bi binding levels previously observed. The results suggest that in this experimental system using low concentrations of serum, mannan-binding protein initiates an antibody-independent mechanism of cleavage of the classical pathway component C4, which subsequently regulates the degree of cleavage of C3 and recruitment of alternative pathway proteins.

Carrier Proteins↗

PubMed1995

Complement receptor expression and activation of the complement cascade on B lymphocytes from patients with systemic lupus erythematosus (SLE).

It has previously been reported that the expression of the complement receptors, CR1 on erythrocytes and blood leucocytes and CR2 on B cells, is reduced in patients with SLE, and that the reduced expression of CR1 on erythrocytes is related to disease activity. We have earlier demonstrated that normal B cells are capable of activating the alternative pathway (AP) of complement in a CR2-dependent fashion. In this study we have investigated whether disturbances in this activity may be related to the altered phenotype of SLE B cells. Flow cytometry was used to measure expression of complement receptors and regulatory proteins on B cells from SLE patients, as well as the deposition of C3 fragments occurring in vivo or after in vitro AP activation. We have confirmed, for a proportion of the patients studied, reduced expression of CR1 and CR2 on B cells, and shown a consistency between low CR2 expression and reduced in vitro AP activation in the presence of homologous, normal serum. In addition, the B cells, like erythrocytes, bear raised levels of in vivo-deposited C3dg, but not C3b fragments, compared with normal B cells. The erythrocytes from SLE patients were unable to inhibit in vitro AP activation by B cells in homologous serum. Finally, we demonstrated an inverse relationship between SLE disease activity index (SLEDAI) and the expression of complement receptor 2 (CR2) on SLE B cells. Thus, determination of CR2 on B cells may emerge as an additional laboratory tool in the assessment of SLE activity.

Adult↗

PubMed2006

Hypocomplementemic urticarial vasculitis: a rare presentation of systemic lupus erythematosus.

BACKGROUND: Urticarial vasculitis is a small-vessel vasculitis, presenting clinically as persistent urticarial skin lesions and microscopically as leucocytoclastic vasculitis. Hypocomplementemic urticarial vasculitis syndrome (HUVS) is a distinct type of urticarial vasculitis with multiorgan involvement, whose etiology and link with other diseases are still unknown. Some authors have suggested that HUVS can be accompanied by systemic lupus erythematosus (SLE), and others believe that it is a rare subtype of SLE. Urticarial vasculitis is seen in 7-8% of SLE, while 50% of HUVS patients are diagnosed with SLE. OBSERVATIONS AND RESULTS: We report a case of HUVS associated with SLE with fatal outcome unresponsive to the combination of systemic corticosteroids and azathioprine. CONCLUSIONS: SLE and HUVS share both clinical and laboratory features and are probably not separate entities. It is mostly likely that HUVS and SLE fall into the same spectrum of autoimmune diseases. HUVS is probably a subset of SLE. As both diseases can fatally, it should be kept in mind that the overlap of SLE and HUVS may exhibit a relatively rapid progression and poor prognosis.

Adrenal Cortex Hormones↗

PubMed1993

Effects of a streptococcal lipoteichoic acid on complement activation in vitro.

This study describes activation of serum complement by lipoteichoic acid (LTA) from Streptococcus mutans OMZ 176, while in solution. Serum from 16 healthy students was taken. Test samples were incubated with increasing doses (1-5,000 micrograms/ml) of LTA or lipopolysaccharide (LPS) from Escherichia coli 0111:B4 for 1 h at 37 degrees C; then assayed for degradation of C3, C4 or factor B by crossed immunoelectrophoresis. Each preparation caused a significant (p < 0.05) dose-dependent conversion of C3. The response curves obtained were not statistically different. LPS was a stronger activator of the alternative pathway than LTA, as judged from analysis of C3 degradation in the presence of Mg2+/EGTA, and from their effects on factor B cleavage. LTA caused, however, pronounced alterations in the shape of C4 precipitation in the gels. Functional (hemolytic) assays showed that, when tested at 200 micrograms/ml, LTA and LPS triggered significant (p < 0.05) consumptions of both classical and alternative pathway proteins. LPS was a significantly (p < 0.05) stronger activator than LTA. Apparently, the C3 degradation found for this LTA involved the alternative pathway to a small extent; thus some other mechanism of fluid-phase C3 cleavage seemed also to be operative.

Complement Activation↗

PubMed1991

A functionally active complement system is present in uterine secretion of the mouse prior to implantation.

Sephadex beads were placed carefully in the uterus on days 2 and 3 and left for 6 to 8 h to absorb uterine secretion. The beads were then removed with volatile silicon oil and mounted on small pieces of nitrocellulose paper. Immuno-staining of these bead blots showed they contained the complement components C1q, C3, C4, and C5. We demonstrated that complement component C3 in the uterine secretion could be activated and deposited on model immune complexes, and also that antibody-coated erythrocytes were lysed in utero, that is, a membrane attack complex was produced. Thus, the mouse uterine secretion at the preimplantation stage contains a functionally active complement system.

Animals↗

PubMed1985

Subnormal sensitivity of neutrophils to complement split product C5a in rheumatoid arthritis: relation to complement catabolism and disease extent.

The capacity of circulating neutrophils for activation by complement was studied in outpatients with classical or definite rheumatoid arthritis during treatment with dextropropoxyphene only. Analysis of dose-response in the Boyden chamber assay of chemotaxis showed that sensitivity to the potent, complement derived anaphylatoxin, C5a, was markedly decreased, especially in those patients with few joints involved. In contrast, peak response to C5a was within the normal range. Increased complement 3c split products in plasma of the patients suggested involvement of complement cascade reactions. Subnormal sensitivity of neutrophils to phlogistic mediators released by complement may tend to limit their recruitment and potentially tissue destroying secretion locally in rheumatoid arthritis.

Adult↗

PubMed1992

A long-term immunological study of childhood onset systemic lupus erythematosus.

Immunological dysregulation is an important cause of the development of systemic lupus erythematosus (SLE). Serological evaluation has been useful in the clinical management of patients and as a prognostic indicator. Sixteen patients who developed SLE as children were followed up for more than three years and immunological data collected. The results showed that (a) complement C3 concentration was lower in the active stage of SLE, especially during a major clinical exacerbation, but rarely preceded a major flare up. The concentration was often normal during the mildly to moderately active stage. In contrast, a low complement C4 concentration often preceded a major clinical exacerbation and could be of longer duration, sometimes persisting regardless of disease activity. (b) A T cell subset distribution study showed persistently low CD4 positive T cells in the peripheral blood of patients with SLE during the long term follow up, strongly suggesting that the intrinsic defect is mainly localised in T helper/inducer cells. These abnormal cellular defects did not tend to return to normal even in long term remission. (c) The persistently higher serum interleukin 2 and interleukin 2 receptor concentrations in SLE strongly suggested that the T cells were preactivated in vivo and that these phenomena might persist even in remission. (d) The best single parameter for predicting active SLE was anti-dsDNA. It was highly correlated with disease activity in most patients, and the asymptomatic increase of anti-dsDNA (greater than or equal to 60 U/ml, radioimmunoassay) was often followed by a major clinical exacerbation, especially in patients with a simultaneously low complement C4 concentration, suggesting that it might be an important warning sign of a major flare up. High dose steroids are indicated in this group of patients.

Adolescent↗

PubMed1997

Methotrexate in patients with moderate systemic lupus erythematosus (exclusion of renal and central nervous system disease).

OBJECTIVES: Methotrexate (MTX) has been used in several autoimmune diseases. Apart from its use in rheumatoid arthritis, MTX has been assessed in small studies in patients with vasculitis, uveitis, and inflammatory bowel disease. The aim of this study was to evaluate the efficacy of MTX in a particular group of patients with systemic lupus erythematosus (SLE). PATIENTS: In an open prospective study 22 patients fulfilling the ACR criteria for SLE were included. Patients had one or more of the following manifestations; active non-destructive polyarthritis, dermatitis, vasculitis of the skin, pleuritis. All patients had been treated with corticosteroids for at least six months without achieving remission. Sixteen patients were taking antimalarial drugs in addition to corticosteroids, which were stopped at the beginning of the trial. Patients with renal and central nervous involvement were excluded from the study. All patients received MTX orally at a dose of 15 mg/week over six months. Corticosteroids were continued. As additional medication only indomethacin up to 100 mg/day was permitted if used before the start of the study. The outcome was evaluated using the SLE disease activity index (SLEDAI). RESULTS: Disease activity was evaluated after six months of MTX treatment. All patients completed the study period. The SLEDAI decreased significantly from mean (SD) 12.2 (3.99) to 4 (3.75) (p = 0.001). The prednisolone dose was reduced from a mean (SD) of 17.4 (12.8) at the beginning to 8.8 (5.36) mg/day at the end point of the study (p = 0.01). MTX was well tolerated. Four patients complained of general malaise. Two patients had transient increases in liver enzymes. In no case did MTX have to be stopped. CONCLUSIONS: In an open prospective study methotrexate was used in SLE patients with particular clinical characteristics. MTX was shown to be effective in reducing disease activity and sparing the dose of corticosteroids. Further controlled studies are necessary.

Adult↗