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PubMed1989

Activation of the complement system in primary sclerosing cholangitis.

Recent evidence, including the presence of circulating immune complexes, suggests that abnormalities of humoral immunity may be important in the pathogenesis of primary sclerosing cholangitis. The aim of the present study was to determine whether activation of the complement system is present in patients with this disease, as this would be supportive evidence of a role for circulating immune complexes in primary sclerosing cholangitis. Plasma complement fragments C3d and C4d, and serum C3 and C4, their respective parent molecules, have been assayed. Both C3d and C4d were elevated in patients with primary sclerosing cholangitis compared with patients with extrahepatic obstructive cholestasis and normal controls (p less than 0.01 in all instances). C3 was elevated in both patient groups, in whom it was similar, compared with normal controls (p less than 0.001 in both cases), whereas C4 was similar in all groups. Elevated levels of circulating immune complexes were identified in 21 of 24 (88%) patients with primary sclerosing cholangitis, but in none of the normal controls. These findings support the hypothesis that in primary sclerosing cholangitis circulating immune complexes are associated with activation of complement via the classical pathway.

Adult↗
PubMed2000

Complement activation in the brain after experimental intracerebral hemorrhage.

OBJECT: Brain edema formation following intracerebral hemorrhage (ICH) appears to be partly related to erythrocyte lysis and hemoglobin release. Erythrocyte lysis may be mediated by the complement cascade, which then triggers parenchymal injury. In this study the authors examine whether the complement cascade is activated after ICH and whether inhibition of complement attenuates brain edema around the hematoma. METHODS: This study was divided into three parts. In the first part, 100 microl of autologous blood was infused into the rats' right basal ganglia, and the animals were killed at 24 and 72 hours after intracerebral infusion. Their brains were tested for complement factors C9, C3d, and clusterin (a naturally occurring complement inhibitor) by using immunohistochemical analysis. In the second part of the study, the rats were killed at 24 or 72 hours after injection of 100 microl of blood. The C9 and clusterin proteins were quantitated using Western blot analysis. In the third part, the rats received either 100 microl of blood or 100 microl of blood plus 10 microg of N-acetylheparin (a complement activation inhibitor). Then they were killed 24 or 72 hours later for measurement of brain water and ion contents. It was demonstrated on Western blot analysis that there had been a sixfold increase in C9 around the hematoma 24 hours after the infusion of 100 microl of autologous blood. Marked perihematomal C9 immunoreactivity was detected at 72 hours. Clusterin also increased after ICH and was expressed in neurons 72 hours later. The addition of N-acetylheparin significantly reduced brain edema formation in the ipsilateral basal ganglia at 24 hours (78.5 +/- 0.5% compared with 81.6 +/- 0.8% in control animals, p < 0.001) and at 72 hours (80.9 +/- 2.2% compared with 83.6 +/- 0.9% in control animals, p < 0.05) after ICH. CONCLUSIONS: It was found that ICH causes complement activation in the brain. Activation of complement and the formation of membrane attack complex contributes to brain edema formation after ICH. Blocking the complement cascade could be an important step in the therapy for ICH.

Animals↗
PubMed1988

Complements in diabetes mellitus: activation of complement system evidenced by C3d elevation in IDDM.

To characterize insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) in terms of the complement system, some components of the system as well as the related substances and indices were studied. CH50, C3, C4 and C3bINA significantly increased in both IDDM and NIDDM compared with non-diabetic healthy controls. ACH50 was also elevated in NIDDM, whereas it was similar in IDDM and controls. Besides, the serum concentration of C3d, a breakdown product of C3, was higher in IDDM than in NIDDM and healthy controls, but that in NIDDM did not differ significantly from the control. B1Hg1 was not different among IDDM, NIDDM and non-diabetic controls. These observations suggested that there is a high level of complements in both types of diabetes mellitus, but the complement activation seems to be much enhanced in IDDM compared with NIDDM.

Complement Activation↗
PubMed1994

Protection of thyroid cancer cells by complement-regulatory factors.

BACKGROUND: Clinical and experimental studies have suggested that complement activation may play a role in tumor cytotoxicity. Little information is available concerning the presence of complement activation and the localization of complement-regulatory factors in cells or tissues of malignant tumors. The aim of the present study was to examine, using immunohistochemistry and immunoelectron microscopy, whether the complement system is activated in tissues of thyroid carcinoma and whether thyroid carcinoma cells are protected from cell lysis by in situ complement activation. METHODS: Fresh tissues were obtained by thyroidectomy from 15 patients with papillary carcinomas, 7 with follicular carcinomas, and 5 with follicular adenomas. In addition, five specimens of histologically normal thyroid tissue and five specimens of chronically inflamed tissue adjacent to thyroid neoplasms were studied. Immunohistochemical and immunoelectron microscopic localization of complement components, C3d and C5b-9, and the complement-regulatory factors, such as s-protein, decay-accelerating factor (CD55), membrane cofactor protein (CD46), complement receptor types 1 (CD35) and 2 (CD21), and protectin (CD59), were examined in these tissues. RESULTS: The staining patterns of C3d, C5b-9, and s-protein were positive and homogeneous in the nonneoplastic and most neoplastic thyroid tissues. Immunoelectron microscopy showed these antigens were localized mainly on the subepithelial and vascular basement membranes and attached to the cell surface of thyroid follicular cells. Decay-accelerating factor (CD55) was present homogeneously on the basement membranes, on the basal cell border of the thyroid follicular cells, and often on the luminal surface of carcinoma cells. Both membrane cofactor protein (CD46) and protectin (CD59) were expressed strongly on the cell surface of almost all benign and malignant thyroid follicular cells. Membrane cofactor protein was expressed on both the basal and lateral membrane, showing cell-to-cell interaction, but rarely on the luminal surface, whereas protectin was expressed strongly on the luminal surface and often on the basal cell border but rarely on the lateral membrane. Neither complement receptor type 1 (CD35) nor complement receptor type 2 (CD21) was expressed on any thyroid follicular cells. CONCLUSIONS: The present study confirmed the presence of complement activation with subsequent deposition of C3d and C5b-9 complexes in thyroid carcinomas. It also indicated that thyroid carcinoma cells are protected from cell lysis because of complement activation in multiple phases by complete coverage of the entire cell membrane surface with complement-regulatory factors. These findings were similar to those found in nonneoplastic thyroid follicular cells.

Adenoma↗
PubMedDate not supplied

Growth control of activated, synchronized murine B cells by the C3d fragment of human complement.

Three restriction points control the cell cycle of activated B lymphocytes. The first occurs directly after mitosis and is controlled by the occupancy of surface-bound immunoglobulin. The second is observed approximately 4 h after mitosis in the G1 phase of the cycle, that is, before DNA replication, and is controlled by growth factors that are produced by macrophages which we have previously classified as alpha-type factors. The third restriction point occurs in the G2 phase, 2-4 h before mitosis, and is controlled by beta-type growth factors probably produced by helper T lymphocytes. The third component of complement, C3, has long been implicated in the control of B-cell responses. C3 is secreted by monocytes and macrophages. We have found recently that crosslinked, but not soluble, human C3 stimulates activated, but not resting, murine B cells to thymidine uptake. Here we investigate the role of C3b and C3d in the progression of the cell cycle of activated, synchronized murine B cells. We find that crosslinked C3d replaces the action of alpha-factors within the cell cycle of these cells and allows entry into S phase. In contrast, soluble C3d inhibits the action of alpha-factors. This implies that a C3d-specific receptor, probably the murine analogue to the human complement receptor CR2, is a growth factor receptor on activated B cells that will give the cell a growth-positive signal when it is crosslinked, while occupancy by the soluble form of C3d will result in inhibition of the action of alpha-factors or of crosslinked C3b or C3d. A stretch of weak homology between the cDNA sequence of murine C3d and those of murine growth factors indicates that an insulin-like growth factor could be the active principle of C3d that controls the cell cycle of activated B cells.

Animals↗
PubMed1991

Epstein Barr virus/complement C3d receptor is an interferon alpha receptor.

Interferon alpha contains a sequence motif similar to the complement receptor type two (CR2/CD21) binding site on complement fragment C3d. Antibodies against a peptide with the CR2 binding sequence on C3d react with a peptide carrying the IFN alpha CR2 binding motif (residues 92-99) and with recombinant IFN alpha. The IFN alpha-derived peptide, as well as recombinant IFN alpha, inhibits C3bi/C3d interaction with CR2 on the Burkitt lymphoma Raji. The direct interaction of IFN alpha and CR2 is inhibited by polyclonal anti-IFN alpha, anti-CR2 and anti-C3d peptide antibodies as well as by C3bi/C3d, EBV coat protein gp350/220 and IFN but not by IFN gamma. [125I]IFN alpha binding to Raji cells is inhibited by polyclonal anti-IFN alpha and anti-CR2 antibodies, by peptides with the CR2 binding motif and partially by C3bi/C3d. Monoclonal anti-CR2 antibody HB5, but not OKB-7, blocks IFN alpha binding to Raji cells. CR2 or CR2-like molecules may therefore be the major IFN alpha receptors on B lymphocytes.

Amino Acid Sequence↗
PubMed1978

Quantitation of serum complement components and plasma C3d in patients with malignant lymphoma: relation to the stage of the tumor and circulating immune complexes.

Total hemolytic complement activity (CH 50) and complement component levels were measured in 27 patients with Hodgkin's disease and 31 patients with non-Hodgkin malignant lymphoma. CH 50 values were higher than normal in almost all the patients. Increased levels of serum C4, C3 and factor B were observed in 62%, 31% and 19% of these patients, respectively. However, plasma concentration of C3d, a breakdown product of C3, was elevated in 29% of the cases. The hypercatabolism of C3 was not closely associated with the presence of circulating immune complexes, as assessed by the C1q binding assay, nor with the presence of general symptoms in the patients. On the contrary, it appeared to be in relation with the extent of the malignant disease.

Adolescent↗
PubMed1985

A synthetic nonapeptide corresponding to the NH2-terminal sequence of C3d-K causes leukocytosis in rabbits.

Numerous biologically active fragments have been described that are derived from the C3 molecule. Recently, a polypeptide (Mr 41,000) generated from the alpha chain of human iC3b by limited proteolysis with plasma kallikrein was shown to exhibit several biological functions. This C3-derived cleavage product, C3d-K, suppresses mitogen- and antigen-induced proliferation of human T-lymphocytes and induces leukocytosis in rabbits. We have identified and synthesized a portion of C3d-K that is associated with the leukocytosis phenomenon. A nonapeptide corresponding to the amino-terminal nine residues of C3d-K was synthesized using conventional Merrifield solid-phase peptide chemistry; the structure of this peptide is Thr-Leu-Asp-Pro-Glu-Arg-Leu-Gly-Arg (TLDPERLGR). At a final concentration of 4 X 10(-6) M, both the nonapeptide and the des-Arg octapeptide (TLDPERLG) were capable of inducing leukocytosis in rabbits. Additionally, both peptides enhance vascular permeability when injected in guinea pig skin. These activities are similar to those previously attributed to a C3 fragment identified as C3e by Ghebrehiwet and Müller-Eberhard (Ghebrehiwet, B., and Müller-Eberhard, H.J. (1979) J. Immunol. 123, 616-621). We conclude that the nonapeptide TLDPERLGR represents the active center of the C3-derived leukocytosis factors C3e and C3d-K. This active synthetic analogue of C3d-K should prove valuable in elucidating the mechanism of action for complement-dependent leukocyte mobilization in vivo.

Amino Acid Sequence↗
PubMed1983

Partial characterization of physiologically generated C3 components expressing C3d but not C3c epitopes.

Techniques for the quantification of C3d are shown to estimate the sum of 4 different plasma protein components possessing C3d but not C3c epitopes. All 4 components were C3-derived polypeptides as shown by activating serum containing 125I-labelled C3, isolating the anti-C3d reactive material in 14% PEG supernatant, followed by analysis on SDS-PAGE and autoradiography. Identical results were obtained by radiolabelling 14% PEG plasma supernatants followed by analysis of the anti-C3d reactive material. The components are referred to as d1, d1', d2 and d3 based on their relative electrophoretic mobilities (alpha 1, alpha 1, alpha 2 and alpha 2 respectively) judged by crossed immunoelectrophoresis. Their apparent molecular weights by SDS-PAGE were 129K (d1), 110K (d1'), 46K (d3) and 45K (d2). The possibility that one or more of the C3d containing components represented a complex of a C3 fragment with another plasma protein was investigated. The role of these components in the scheme of the physiological breakdown of C3 and the importance of the individual C3d components as indicators of complement activation in clinical materials is discussed. It is proposed that the 45K d2 component represents a final physiological breakdown product of C3 in human serum.

Antigen-Antibody Reactions↗
PubMed1984

Detection of IgA class circulating immune complexes bound to anti-C3d antibody in patients with IgA nephropathy.

IgA class circulating immune complexes (CIC) were detected by solid-phase fluorescent enzyme immunoassay of F(ab')2 anti-C3d antibody in the serum of 52 patients with IgA nephropathy. Conglutinin (Kg) binding IgA class CIC were also measured, and results by these assays were compared. Kg binding IgA class CIC and anti-C3d binding IgA class CIC were detected in 27% and 44%, respectively, of the patients with IgA nephropathy. Either or both of the two were found in 65% of the patients. There was no significant correlation between IgA class CIC detected by these methods and serum IgA. Although all samples with a very high level of anti-C3d binding IgA class CIC did not also have a very high level of Kg binding IgA class CIC, there was a slight quantitative correlation between the 2 assays. Ultracentrifugation analysis showed that anti-C3d binding IgA class CIC were of various sizes between polymeric (21 S) and monomeric IgA (7 S), whereas Kg binding IgA class CIC were mostly monomeric IgA (8 S) with a minor component of heavy fractions (14 S). Both IgA class CIC fixed iC3b and IgA class CIC fixed C3d are present in IgA nephropathy. These observations suggest that the different types of complement bound to IgA class CIC have different roles in IgA nephropathy.

Antigen-Antibody Complex↗
PubMed1988

Blood-membrane interactions during haemodialysis with cellulose and synthetic membranes.

Haemodialysis is associated with transient leucopenia, hypoxia and activation of the patient's complement system, mediated by blood-membrane contact. Changes in white blood cell counts, blood gases (PaO2 and PaCO2), carbon monoxide diffusing capacity (DLCO) and complement activation (C3d and C3a) were measured pre-treatment and during dialysis. The degree of complement activation, leucopenia and changes in DLCO were influenced by membrane type; these changes were most marked for cellulosic membranes and were much reduced for synthetic membranes. A significant relationship between the degree of leucopenia and the magnitude of change in DLCO during dialysis was demonstrated.

Acrylic Resins↗
PubMed2000

Activated microglial cells and complement factors are unrelated to cortical Lewy bodies.

Inflammatory mechanisms have been demonstrated in Alzheimer's disease (AD) but their presence in other neurodegenerative disorders is not well documented. Complement factors and activated microglia have been reported in the substantia nigra of Parkinson's disease (PD). In the present study we investigated the cingulate gyrus of 25 autopsied patients with clinically and neuropathologically well-documented PD, with or without dementia, for the presence of (activated) microglial cells and their relation with Lewy body (LB)-bearing neurons. In addition, we studied the presence of complement factors in LBs. Of the 25 patient, 15 were clinically demented, fulfilling criteria for dementia with LBs (DLB); 7 also fulfilled CERAD morphological criteria for probable or definite Alzheimer type of dementia. Microglia clustering was seen around congophilic plaques with or without tau pathology. Microglial cells were not associated with LB-bearing neurons or noncongophilic plaques. The cortex of DLB patients without AD plaques did not show more microglial cells than the cortex of non-demented controls. The number of microglia was the lowest in young control patients who died immediately after trauma. Complement factor C3d was occasionally seen in diffusely ubiquinated neurons but late complement factors were not detected in these neurons. Double staining for complement and alpha-synuclein was negative, suggesting the absence of complement in LBs. In contrast, AD plaques in the same sections showed complement factors C3c, C3d, C1q and C5-9. In conclusion, we have found no evidence that inflammatory mechanism are involved in LB formation in cerebral cortex.

Aged↗
PubMed1985

Quantification of the C3d split products of human complement by a sensitive enzyme-linked immunosorbent assay.

A double-antibody biotin-avidin enzyme-linked immunosorbent assay (ELISA) for quantification of the C3d split products is described. Polyethylene glycol 6000 was used to precipitate large C3 molecules, and the C3d-containing supernatant was used in the assay. C3d was measured in ethylenediaminetetraacetic acid plasma from 40 healthy blood donors, and the normal range was defined. Twenty-two patients were tested, and 12 of these had increased levels of C3d. No correlation was observed between total C3 and C3d in these patients. There was a close correlation between C3d measured by this method and by the double-decker rocket immunoelectrophoresis method. The C3d ELISA method is very sensitive, easy to perform, and time-saving and economical compared with most C3d methods already described. A procedure to define the lower detection limit and examine the reliability of an ELISA method in general is discussed.

Antigen-Antibody Reactions↗
PubMed1988

Immune reactive C3d on the surface of myelin sheaths in neuropathy.

Immunofluorescence studies of sural nerve demonstrated immune reactive C3d and IgM on the surface of myelin sheaths in seven patients with neuropathy and an anti-myelin-associated glycoprotein (MAG) IgM M-protein. Similar deposits of C3d and sometimes IgM were found in four of six patients with acute or chronic inflammatory demyelinating polyneuropathy and in three of six patients with vasculitic neuropathy (including one with acquired immunodeficiency syndrome (AIDS)). C3d was not found in 80 patients with other peripheral nerve disorders except for two with metachromatic leukodystrophy. None of the C3d deposits contained immune reactive C3c implying substantial degradation of C3b. C3d is a sensitive index of complement activation in nerve and may be useful in classification of neuropathies.

Antibodies, Monoclonal↗
PubMed1987

The gene encoding decay-accelerating factor (DAF) is located in the complement-regulatory locus on the long arm of chromosome 1.

Delay-accelerating factor (DAF) protects host cells from complement-mediated damage by regulating the activation of C3 convertases on host cell surfaces. Using a panel of hamster-human somatic cell hybrids, the DAF gene was mapped to human chromosome 1. In situ hybridization studies using human metaphase cells further localized the gene to bands 1q31-41, with the largest cluster of grains at 1q32. This establishes the close linkage of the DAF gene to genes for four other proteins (C3b/C4b receptor or complement receptor 1, C3d receptor or complement receptor 2, factor H, and C4-binding protein) that share 60-amino-acid homologous repeats as well as complement-regulatory or -receptor activity, thereby enlarging the complement-regulatory gene family on the long arm of human chromosome 1.

CD55 Antigens↗