An appraisal of third complement component (C3) and breakdown product (C3d) in erythema nodosum leprosum (ENL).
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Adult↗
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Results for “Complement C3d”
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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↗
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↗
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↗
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↗
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↗
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↗
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↗
C3 complement components & their breakdown product (C3d) in patients of thromboangiitis obliterans.
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Adult↗
Serum or plasma levels of C3, factor H and C3d in patients with amebic liver abscess.
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Complement Activation↗
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↗
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↗
Diabetes and autonomic neuropathy: an immunological association?
Lymphocytic infiltration of autonomic ganglia found at autopsy and a strong clinical association with iritis suggests that diabetic autonomic neuropathy might have an immunological basis. We measured levels of circulating immune complexes, complement (C3, C4), complement breakdown products (C3d), and insulin antibodies in diabetics with autonomic neuropathy and a history of iritis (n = 17), compared to diabetics of similar age and duration with autonomic neuropathy but no history of iritis (n = 20), and with uncomplicated insulin-dependent diabetics (n = 23), together with normal controls (n = 26). We found higher levels of circulating immune complexes in patients with autonomic neuropathy (irrespective of iritis) compared to normal controls, and differences in C3d levels suggesting complement activation. C4 levels were unexpectedly normal in the diabetics with autonomic neuropathy, in contrast to the uncomplicated insulin-dependent diabetic controls. Insulin antibody levels showed no difference between the three groups of diabetics. These findings suggest that immunological mechanisms may be implicated in the aetiology of diabetic autonomic neuropathy and that further studies are indicated.
Adult↗
Pathways to complement activation during cardiopulmonary bypass.
Complement activation was assessed in 34 patients undergoing cardiopulmonary bypass. Arterial concentrations of complement fragments Ba and C3d rose in all patients, the increase in Ba preceding that of C3d. At the same time as complement fragments were being generated the arterial neutrophil count fell. These findings suggest (a) that complement activation is initiated by the alternative pathway during cardiopulmonary bypass and (b) that complement activation mediates loss of neutrophils during bypass. Complement mediated loss of neutrophils during the analogous setting of haemodialysis is the result of leucosequestration in the pulmonary vasculature. During cardiopulmonary bypass the lungs are out of circuit, so that activated leucocytes may sequester in other target organs. This may be an aetiological factor in the multi-organ failure occasionally seen after uneventful cardiopulmonary bypass.
Adult↗
C3 degradation products (C3d) in normal pregnancy.
Plasma C3 degradation products (C3d) were measured in 65 normal pregnancies and compared with those of non-pregnant women. No significant difference was detected between the two groups, although a difference had been previously reported. Plasma C3d estimations give an indication of complement activation and may be used as an indicator of disease activity in patients with systemic lupus erythematosus (SLE), irrespective of pregnancy.
Complement C3↗
Expression of specific binding sites on Candida with functional and antigenic characteristics of human complement receptors.
Receptors for C3 degradation fragments (CR1, CR2, and CR3) are present on many human cells including phagocytes and lymphoid cells and may be critical in the attachment of invading microorganisms. In these studies Candida were found to mimic the human CR by binding erythrocytes coated with specific human C3 fragments. Yeast forms of Candida species were adhered to glass slides and were allowed to germinate. Sheep erythrocytes (E) were coated with IgM (EA) and human complement components to prepare EA, EAC14, EAC3b, EAC3bi, and EAC3d. These test cells were then examined for adherence to the organism. Antibodies to human CR1, CR2, and CR3 were used to evaluate their potential for blocking adherence of the test erythrocytes to Candida. Fluorescein-labeled antibodies to human complement receptors were also used to characterize the binding sites. EAC3bi and EAC3d, but not E, EA, or EAC14, bound extensively to the germ tubes and pseudohyphae of Candida albicans and C. stellatoidea. EAC3b bound infrequently. Other Candida species, generally considered less pathogenic, bound significantly fewer specific test erythrocytes than C. albicans. Monoclonal antibodies to human CR1 and CR3 (3D9, 1B4, C511, 2B6, anti-B2, Mo1, and anti-Mac-1), in general, did not block adherence of test erythrocytes. Blocking of adherence of EAC3bi and EAC3d test erythrocytes coated with small quantities of C3 fragments occurred with high concentrations of monoclonal (anti-CR2) HB-5 and polyclonal (anti-CR2) anti-GP 140. Immunofluorescence studies demonstrated binding of Mo-1 to the germinated forms of the organism, whereas binding of the other antibodies was not seen. These studies suggest a surface constituent on the organism similar to CR on human cells. Additional studies are necessary to further define the molecular nature of the binding site. The ability of organisms to mimic human CR may be more generalized than previously known and may serve as a mechanism for modification of the inflammatory and immune response.
Antibodies, Monoclonal↗
Membrane receptors for IgG and complement (C4, C3b and C3d) on human eosinophils and neutrophils and their relation to eosinophilia.
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Animals↗
Development and clinical application of electroimmunoassays for the direct quantification of the complement C3 split products C3c and C3d.
The present report describes the development of electroimmunoassays for the direct quantification of C3d and C3c, split products of the third complement factor (C3). Both methods were developed as rocket immunoelectrophoreses, using two antibody preparations with specificities against the C and D epitopes on C3. A stable calibrator preparation for C3c and C3d was produced by autolytic cleavage of C3. Investigations of patients with anaphylactic reactions or chronic immunological disorders showed that quantification of C3c and C3d in plasma by these methods reflected the degree and rate of complement activation. C3d determination was found to be the most sensitive and reliable indicator of C activation, both during acute and chronic activation since C3c is eliminated considerably faster from the circulation than C3d (estimated half lives of 2 h and 4 h, respectively). Treatment of rheumatoid arthritis patients with prednisolone caused a prompt decrease of plasma C3d values, indicating that the clinical effect may be due to inhibition of complement activation.
Antibody Specificity↗