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PubMed1993

Complement activation in patients with primary Sjögren's syndrome: an indicator of systemic disease.

Sixteen patients with primary Sjögren's syndrome, verified according to the Copenhagen criteria, were investigated for evidence of complement activation. Thirteen of the patients had intact functional activity of both the classical and alternative pathways, with normal concentrations of the complement proteins C1q, C1s, C3, C4 and the complement protein fragments C2a and C3d in the circulation. In contrast, three patients showed clear evidence of complement activation. Further investigation of these patients revealed manifestations of glomerulonephritis, vasculitis and primary biliary cirrhosis. Six months later, one patient developed a malignant non-Hodgkin lymphoma. We conclude that complement activation is generally not associated with primary Sjögren's syndrome. Evidence of complement activation in patients considered to have primary Sjögren's syndrome should raise the suspicion of concomitant systemic disease and/or extraglandular activity.

Aged↗
PubMed2002

Complement components and terminal complement complex in oesophageal smooth muscle of patients with achalasia.

This study investigates whether patients with achalasia exhibit autoimmune reactions with subsequent complement activation within oesophageal smooth muscle, vessels and neurones. Oesophageal muscular biopsies from 8 patients undergoing surgery for achalasia and from 6 patients operated for oesophageal cancer were investigated by immunofluorescence for the presence of the complement components C1q, C4, C3c, C3d, C9 and the C9 neoantigen of the terminal C5b-C9 complement complex. Tissues were also investigated for the expression of immunoglobulins (G,A,M) and of the antigens of rubella and varicella zoster viruses. In addition, sera of both patient groups were tested for the presence of autoantibodies against Auerbach's plexus. The terminal complement complex C5b-C9 was found within muscle cells from all patients with achalasia but in only one specimen from a patient with cancer. Two patients with achalasia also exhibited the terminal complement complex as well as IgM within ganglion cells. Muscle cells stained positive for the complement component C9 in all five patients with achalasia in whom this test was performed but in none of the control tissues. In addition, sera from four patients with achalasia contained antibodies against Auerbach's plexus. Studies for the complement components C1q, C4, C3c and for antigens of rubella and varicella zoster viruses revealed negative results in all patients and controls. The results of this study suggest that a complement activation is involved in the autoimmune pathogenesis of achalasia. However, the triggering mechanism of this phenomenon remains to be determined.

Adolescent↗
PubMed1988

Correlation of the activation of the fourth component of complement (C4) with disease activity in systemic lupus erythematosus.

Levels of C4d, a fragment of C4 generated during activation of the classical complement pathway, were measured in the plasma of 48 patients with systemic lupus erythematosus, 11 with inactive (group 1), 23 with mildly active (group 2), 14 with moderately/severely active disease (group 3), and 30 healthy subjects. Levels of C3d, C4, and C3 were also measured and the C4d/C4 and C3d/C3 ratios calculated. C4d levels correlated with the degree of disease activity, being higher in group 3 than in group 2, in group 2 than in group 1, and in group 1 than in controls. C4d/C4 gave a similar result. Activation indices of the common complement pathway, C3d and C3d/C3, also correlated with disease activity, but in a non-linear relationship, failing to discriminate between patient groups. C4 and C3 showed no correlation with disease activity. These results indicate that indices of C4 activation, C4d and C4d/C4, provide a laboratory measure of disease activity in lupus patients, for whom an objective assessment of the severity of the disease is not readily available.

Adult↗
PubMed1985

Reduced complement-mediated immune complex solubilization in leprosy patients.

The ability of sera from leprosy patients to solubilize immune precipitates in vitro through the complement system was studied. The solubilizing capacity of sera from patients who did not have any reactions during 2 years or more after starting chemotherapy was comparable with that of normal laboratory volunteers. On the other hand, sera from borderline tuberculoid and lepromatous leprosy patients in reaction had markedly decreased levels of solubilization. Their total and the alternative pathway haemolytic levels did not show a corresponding decrease. Although the circulating immune complexes and serum C3d of these patients came down after the subsidence of reaction, their solubilization remained consistently low during a 3 month follow-up period.

Antigen-Antibody Complex↗
PubMedDate not supplied

In vitro activation of human complement by polyacrilonitrile dialyzer membrane assayed by complement binding to bystander red cells.

Quantitation of complement activation by polyacrilonitrile (PAN) dialyzer membrane is complicated by the high adsorptive capacity of the membrane for fluid phase anaphylotoxins. Assays for these anaphylotoxins, therefore, underestimate the degree of complement activation produced by this membrane. Alternative methods of measuring in vitro complement activation by the PAN and Cuprophan membranes were explored by incubating normal human erythrocytes with the membranes in the presence of serum. This led to deposition of C3d on these "innocent bystander" red cells, and provided an independent parameter for measuring complement activation. The PAN membrane caused significantly more C3d deposition on red cells, and thus more complement activation than Cuprophan. The possible significance of complement activation by PAN membrane, in consideration of its property of binding the resultant anaphylotoxins, is discussed.

Acrylic Resins↗
PubMed2001

Complement C3b interactions studied with surface plasmon resonance technique.

The surface plasmon resonance (SPR) phenomenon is utilized in a number of new real time biosensors. In this study, we have used this technique to study interactions between the central complement component C3b and its multiple ligands by using the Biacore equipment. The SPR technique is particularly suitable for analysis of the alternative complement pathway (AP) because the inherent nature of the latter is to amplify deposition of C3b on various surfaces. C3b was coupled onto the sensor surface and the coupling efficiency was compared under various conditions on both polystyrene and carboxymethylated dextran surfaces. After enzymatic C3b coupling or standard amine C3b coupling, we analyzed and compared the binding of four C3b ligands to the surface: factor B, factor H, C5 and the soluble complement receptor 1 (sCR1, CD35). Binding of each ligand to C3b was detected when C3b had been coupled either enzymatically or using the amine coupling, but the half-lives of the interactions were found to vary depending on the coupling procedure. Factor H binds to C3b via three interaction sites. The target sites are exposed on the C3b, C3c and C3d fragments of C3, respectively. Therefore, we also tested by using the Biacore whether factor B, C5 and sCR1 bind to C3c and/or C3d. It was found that factor B bound to C3d, but not to C3c. On the other hand, both C5 and sCR1 bound to C3c, but not to C3d. In conclusion, this study shows that SPR is a powerful tool in analyzing and mapping the interactions of C3b with its multiple ligands.

Binding Sites↗
PubMed1998

A longitudinal study of C3, C3d and factor Ba in burn patients in Hong Kong Chinese.

A longitudinal study of serum C3, C3d and fragment Ba was carried out in 53 burn patients of Chinese origin whose total burn surface area ranged from I to 45%. Complement C3 was found to be activated on or before day 7 post-burn. The sharp increase in C3d suggested an acute inflammatory response. In addition factor Ba was increased in these patients, suggesting that the alternative pathway was also activated following thermal injuries. The fluctuations of C3, C3d and Factor Ba observed about 1 year after injury suggested chronic inflammation associated with long term of outcome of healing in the burn sites.

Adult↗
PubMed1998

Complement activation and regulator expression after anoxic injury of human endothelial cells.

Complement activation is involved in the ischemia-reperfusion injury of various organs, but the mechanisms leading to activation of the complement system are incompletely understood. In this study we show that EA.hy 926 human endothelial cells cultured under anoxic conditions (24 or 48 h) become activators of the homologous complement system. Flow cytometric analysis indicated that C1q, C3c, C3d, C4, C5, C9 components of complement are deposited on anoxic but not on normoxic cells after incubation with normal human serum. Cell membrane-associated regulators of complement, membrane cofactor protein (CD46), decay-accelerating factor (CD55) and protectin (CD59) were expressed on EA.hy 926 cells grown under normal oxygen tension. Under anoxic conditions the expression of protectin was clearly decreased, whereas the expression of CD46 and CD55 diminished only slightly. Our results suggest that anoxia can convert human endothelial cells to activators of the complement system. The diminished expression of protectin, CD46 and CD55 can sensitize the cells to complement-mediated damage. Activation of the complement system due to the anoxic injury of human endothelial cells might be an important triggering mechanism in the pathogenesis of ischemia-reperfusion injury of human heart.

Antigens, CD↗
PubMed1992

Complement activation during low-density lipoprotein apheresis.

Complement system activation was investigated in two girls with familial homozygous hypercholesterolemia undergoing two monthly sessions on LA15 or LA40 (Kaneka liposorber). We determined blood levels of C3c and C3a, leukocyte counts, and plasma levels of C3c and C3a in the extracorporeal circulation device at the start of the sessions and 15 and either 60 or 120 min into them. Sequential eluates were collected from LA40 at the end of the sessions (0.5M NaCl, 1M hydroxylamine). Anaphylatoxin C3a increased throughout, especially with LA40. As previously reported, C3a was trapped in the dextran column but was noticeably present in efferent plasma. Besides many proteins, nonnative complement fragments bearing C3a and C3d antigens were detected in almost all the eluates, suggesting possible in situ complement activation. Practically, complement activation induced by the first filter is a risk; long-term side effects may arise from this extracorporeal circulation device.

Blood Component Removal↗
PubMed1987

Burn wound sepsis may be promoted by a failure of local antibacterial host defenses.

Little attention has been focused on the local burn wound environment, even though burn wound sepsis is a common cause of death in the burn victim. To characterize the effect of the local burn wound environment on neutrophil function and metabolism, the opsonic activity of blister fluid specimens against Pseudomonas aeruginosa was measured as was the effect of blister fluid on control neutrophil oxygen consumption using preopsonized zymosan and f-met-leu-phe (FMLP) as stimuli. Blister fluid did not support the killing of P. aeruginosa by normal neutrophils as well as normal serum. Additionally, blister fluid inhibited zymosan-stimulated, but not FMLP-stimulated, neutrophil oxygen consumption. The inhibitory effect of blister fluid on zymosan-stimulated oxygen consumption correlated with the extent of complement activation, measured as C3d or C3AI (p less than 0.01). That blister fluid did not inhibit the FMLP-mediated respiratory burst supports the concept that the blister fluid inhibitory effect on the zymosan-mediated respiratory burst was mediated through the complement receptor. These findings that blister fluid can affect the bactericidal and metabolic activity of normal neutrophils support the concept that cellular function can be altered by the microenvironment in which the cells are bathed. This potential impairment of host defenses within the burn wound could predispose the burn victim to burn wound sepsis.

Adolescent↗
PubMed1991

Association of amyloid P component with complement proteins in neurologically diseased brain tissue.

Amyloid P component (AP) was detected in a number of lesions in human brain associated with chronic degenerative disease. These lesions included diffuse and consolidated amyloid deposits, cerebral amyloid angiopathy, neurofibrillary tangles, neuropil threads and complement activated oligodendroglia. The staining for AP generally paralleled that for complement proteins C4d and C3d, suggesting that AP may serve as an adjuvant for phagocytosis.

Alzheimer Disease↗
PubMed1986

Biocompatibility of different hemodialysis membranes: activation of complement and leukopenia.

The ability of three hollow-fiber dialyzers (Cuprophane [CU], polymethylmethacrylate [PMMA], and polyacrylonitrile [PAN]) to activate complement and to induce leukopenia was studied prospectively in six patients on long-term hemodialysis. CU membranes caused the most intense complement activation with C3a, C3d, and C5a levels peaking 15 min after beginning dialysis. Total white blood cell (WBC) counts dropped simultaneously by 76%, and the decrease in leukocytes was inversely correlated with the levels of C3a and C5a. In contrast, PMMA membranes led only to slight complement activation with an associated fall in WBC counts of 29%, and PAN membranes induced very little complement activation without leukopenia. In vitro studies involving incubation of normal human plasma with each of the three membranes corroborated these findings. The results suggest that the biocompatibility of PMMA and PAN dialyzers is superior to CU.

Acrylic Resins↗
PubMed1989

Absence of induction of IL-1 production in human monocytes by complement fragments.

The ability of C fragments to induce IL-1 production in human monocytes was examined by using various approaches to carefully exclude the role of contaminating endotoxin. The presence of IL-1 activity in monocyte supernatants and lysates was assayed by the augmentation of PHA-induced proliferation of murine thymocytes. SRBC were opsonized with IgM rabbit antibodies and various human C components to prepare EAC reagents that contained less than 25 pg LPS/ml of EAC at 5 x 10(8) cells/ml. EAC1q, EAC4b, EAC4b2aoxy, EAC4b2aoxy C3b, EAC4b2aoxyC3bi, and EAC4b2aoxyC3d all failed to induce IL-1 production when incubated at 10- to 100-fold excess with adherent human monocytes. Similarly, LPS-free purified C3a, C5a, and C5a des Arg all showed no IL-1-inducing activities at concentrations up to 25 micrograms/ml. However, the same C5a preparations were active on human monocytes in the induction of chemotaxis, and C3a and C5a both induced skin-blueing in guinea pigs. Fragment Ba and Bb preparations purified by gel filtration chromatography contained approximately 100 pg LPS/micrograms Ba or Bb. These Ba and Bb preparations at 10 and 50 micrograms/ml, respectively, induced IL-1 production in the presence of 5 micrograms/ml polymyxin B (PMB). However, Ba and Bb preparations purified by affinity chromatography and HPLC contained lower levels of endotoxin contamination and displayed IL-1-inducing activities at Ba and Bb concentrations of 50 and 100 micrograms/ml, respectively, that were almost completely inhibited by PMB. To explore further the role of contaminating endotoxin, a Bb preparation was adsorbed with PMB-4B in the presence of a dialyzable detergent to remove LPS bound to the Bb. This LPS-free Bb preparation failed to induce IL-1 production while maintaining intact enzymatic activities. These results indicate that various solid phase or soluble C fragments, including C3b, iC3b, C3d, C3a, C5a, Ba or Bb do not induce IL-1 production in human monocytes in the absence of contaminating endotoxin.

Antigen-Antibody Complex↗
PubMed1992

Evaluation of endometrial tissue specific complement activation in women with endometriosis.

OBJECTIVE: To determine if endometrial tissue specific complement (C) activation occurs in patients with endometriosis. DESIGN: Prospective. SETTING: University of Oklahoma Health Sciences Center, a tertiary care referral center. PATIENTS: Twenty-six women, 9 with endometriosis and 17 without endometriosis. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Uterine and ectopic endometria were evaluated by the immunofluorescence assay for the presence of activated products of the initial (C3d) and terminal (C5b-9) C pathway, C3 regulatory proteins (decay-accelerating factor and membrane cofactor protein), and terminal C regulatory proteins (clusterin and vitronectin). RESULTS: The initial (C3d) and terminal (C5b-9) C components were deposited on blood vessel walls in uterine and/or ectopic endometria of women with and without endometriosis. In the stromal compartment at both sites, C deposition was colocalized with terminal C inhibitors/cell-cell attachment factors, clusterin and vitronectin on elastic fibers. No specific staining for C proteins was detected on the glandular epithelium of uterine and ectopic endometrial tissues examined. Furthermore, intense staining of endometrial epithelium for C3 regulatory proteins, decay-accelerating factor, and membrane cofactor protein was noted on endometrial glands from women with and without endometriosis. CONCLUSIONS: Our findings demonstrate a lack of specific deposition of C in the glandular epithelial cells of endometria of women with endometriosis. The localization of C3 regulatory proteins, decay-accelerating factor, and membrane cofactor protein on glandular epithelium may suggest the involvement of intrinsic protective mechanisms on these cells from autologous C attack in vivo.

Adult↗
PubMed1989

Reduced numbers of complement receptor type 1 on erythrocytes are associated with increased levels of anticardiolipin antibodies. Findings in patients with systemic lupus erythematosus and the antiphospholipid syndrome.

In several diseases, including systemic lupus erythematosus (SLE) and autoimmune hemolytic anemias, the numbers of complement receptor type 1 (CR1) expressed on erythrocytes of patients are reduced. In patients with SLE, anticardiolipin antibodies (aCL) have been associated with positive results on direct antiglobulin tests. Because of these findings, we investigated whether the reduced expression of erythrocyte CR1 in 61 patients (53 with SLE and 8 with the antiphospholipid syndrome) might be associated with the presence of aCL. A negative correlation was observed between aCL levels and mean numbers of CR1 (rs = -0.43, P = 0.001), and a positive correlation was observed between aCL levels and the levels of erythrocyte C4d and C3d (rs = 0.33 and 0.41, P = 0.01 and 0.001, respectively), but no correlation of aCL levels with serum C4 levels was found. When the results were further analyzed according to the IgG or IgM class of aCL, levels of antibodies of both classes were negatively correlated with CR1 numbers, but only IgM aCL levels were correlated with erythrocyte C4d and C3d numbers. The levels of anti-double-stranded DNA antibodies showed no correlation with erythrocyte CR1, C4d, or C3d numbers but were negatively correlated with serum C4 levels (rs = -0.43, P = 0.002). These data suggest that aCL, or a closely related antibody specificity, may bind to erythrocytes and may be directly involved in the mechanism for reduction of erythrocyte CR1 expression in SLE patients.

Antibodies, Antinuclear↗
PubMed1994

Correlations of C1q- and C3d-bearing circulating immune complexes with immunopathological disease activity in lupus nephritis patients.

The serum levels of circulating immune complexes (CIC) measured by three different types of enzyme immunoassay (EIA) using monoclonal anti-C1q and antibodies and C1q as solid phase reagents were compared with clinical disease activity and immunohistological glomerular lesions in 29 SLE patients. Three types of CIC measured by these assays (anti-C1q CIC, anti-C3d CIC and C1q SP CIC) showed significantly higher levels in patients than in controls and were significantly associated with the clinical and serological disease activities. Anti-C1q CIC showed good correlation not only with mesangial IgG depositions (P < 0.01), but also with that of C1q (P < 0.05). C1q SP CIC also showed a weak correlation with mesangial C1q deposition (P < 0.05). Serum levels of anti-C3d CIC increased with the degree of mesangial IgG and complement depositions. Analysis of the clinical course of a patient with active SLE revealed a more rapid decrease of anti-C1q CIC and anti-C3d CIC along with the improvement of disease activity, including the mesangial lesion, than that of C1q SP CIC. According to these results, the CIC detected with assays using monoclonal antibodies against complement fragments, especially the anti-C1q assay, is likely to provide specific information regarding the clinical, serological and immunohistological disease activity in lupus nephritis.

Antigen-Antibody Complex↗
PubMedDate not supplied

The significance of red cell bound complement components in development of standards and quality assurance for the anti-complement components of antiglobulin sera.

Human red blood cells, sensitized with complement in vivo and by a variety of methods in vitro, (e.g. blood group antibody, low ionic strength, alternate pathway), were tested with a battery of anti-complement sera (anti-C3, -C3c, -C3d, -C4, -C4c). Red blood cells could be prepared by relatively simple methods to yield cells sensitized with C3 and C4, C3 but not C4, C4 but no C3, C3d with no C3c and C4d with no C4c. These cells are suitable for standarization and quality assurance of antiglobulin sera (AGS). Anti-C3d is necessary for optimal detection of sensitization of red blood cells by complement in vivo by the direct anti-globulin test (DAT). Anti-C3d may also be optimal for the indirect antiglobulin test (IAT) especially if incubation periods greater than one hour are employed. Potent anti-C4 and anti-C3 antisera made in the authors' laboratory resulted in numerous weakly positive antiglobulin tests when testing red blood cells from refrigerated clots (especially anti-C4) but red blood cells from refrigerated anticoagulated segments gave negative results. When red blood cells were incubated in normal serum at room temperature (as in the room temperature phase of a compatibility test), some positive results were again obtained with the potent anti-C4 and anti-C3 antisera. However, one commercial antiglobulin serum containing anti-complement antibodies that were at least as potent as any other commercial antiglobulin serum gave uniformly negative results under the above conditions. Anti-C4 antibodies may be omitted from anti-globulin sera without decreasing the efficacy of such antisera to be used in compatibility testing. Thus, positive results in the compatibility test due to detection of clinically insignificant cold antibodies in the IAT by the anti-complement antibodies in AGS, may be avoided if anti-C4 is omitted or is in low concentration and if the concentration of anti-C3d is carefully standardized. A higher concentration of anti-C3d could be used for compatibility tests if red blood cells from anticoagulated segments were used instead of those from clots and if a separate tube were used for the IAT at 37 C rather than using one tube for both room temperature and 37 C incubations.

Antibody Specificity↗
PubMed1986

Immunohistochemical study of the C5b-9 complex of complement in human kidneys.

The presence and localization of the C5b-9 neoantigens of the terminal complement sequence, of antigens expressed by cleavage fragments of C3, and of Factor H antigens have been studied by immunohistochemical techniques in morphologically normal adult human kidneys and in biopsy specimens from patients with a wide range of renal diseases with and without immune deposits. In morphologically normal kidneys, C5b-9 neoantigens were observed within all connective matrices (arteriolar media, glomerular basement membrane (GBM), mesangial matrix and tubular basement membrane). The C3d and C3g antigens of the C3dg, and C3bi cleavage fragments of C3 and Factor H antigens were found in similar locations. None of the matrices stained for immunoglobulins. Immunoelectron microscopy demonstrated that C3d, C3g, H antigens and the C5b-9 neoantigens were localized on membranous and vesicular structures embedded in the connective matrices. These structures represent cell membranes shed from adjacent cells as evidenced by their ultrastructural appearance and by the fact that those which were in close vicinity to pedicles within the GBM expressed the C3b receptor antigen, a specific marker for podocyte membranes. Formation of C5b-9 complexes in the shielded environment of connective matrices may explain their persistence over long periods of time in the absence of apparent immunopathological consequences. Biopsies from pathological kidneys were classified into three groups based on the pattern of glomerular staining with anti-C5b-9 antibodies. In the first group, a sparse mesangial labeling was seen, similar to that observed in normal kidneys. In the second group, abundant clusters of C5b-9 were seen in the same location as immune deposits. Activation of the complement system to completion could be documented in the absence of detectable C3 (C3c) antigen in glomeruli. Immunoelectron microscopy demonstrated that C5b-9 neoantigens were present on cell remnants in connective matrices in all specimens that were studied. Labeled cell remnants were present in large amounts in sclerotic matrices. C5b-9 neoantigens were constantly found on old and large immune deposits, and absent or occasionally present on recent and small immune deposits. In membranous nephropathy stage I, proteinuria appeared to be independent of the presence or absence of detectable C5b-9 neoantigens on immune deposits. Thus, the presence of C5b-9 neoantigens in pathological renal tissue does not have an univocal significance, and requires analysis of the localization of the antigens and appropriate controls in order to assess the potential role of C5b-9 in tissue damage.

Adult↗