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A dynamic estimation of the complement system was obtained by immunochemical estimation of C3, C4, C5, C1q, C3b + C3c, C3d, Ba in children with hemolytic-uremic syndrome. The presence of increased breakdown products of C3 (C3b + C3c, C3d) and of factor B (Ba) suggests an activation of the complement system possibly by the alternative pathway. No definite explanation for these complement abnormalities can be given.
The fractional catabolic rate of C1q was increased markedly in primary biliary cirrhosis, and in HBsAg-positive chronic liver disease. In 3 out of 4 patients with HBSAg-negative chronic active liver disease C1q catabolism was normal. The rate of synthesis of the protein was increased in primary biliary cirrhosis, but it was normal in patients with chronic active liver disease. The fractional catabolic rate and synthetic rate of albumin were normal in these subjects. These data provide further evidence for the activation of the classical pathway of complement in primary biliary cirrhosis and HBsAg-positive chronic active liver disease. In HBsAg-negative chronic active liver disease, the presence of C1q binding macromolecules was not associated with increased C1q catabolism.
Sera from patients with progressive systemic sclerosis (PSS) and mixed connective tissue disease (MCTD) were studied for the presence of circulating immune complexes (CICs) by Clq precipitins, cryoglobulins and the Raji cell and Clq radioimmunoassays. The Raji cell assay was the most sensitive, detecting ICs in 82% of patients with MCTD and in 55% with PSS. However, the median value in MCTD was significantly higher than in PSS (79 vs 20 microgram equivalent AHG/ml serum), and in MCTD, unlike PSS, the CIC levels appeared to parallel disease activity. Ribonucleoprotein (RNP) antigen could not be demonstrated in the Raji cell bound complexes.
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Circulating seric immunocomplexes have a variable significance in every case and small amounts can be founded in nornal people. Sometimes immunocomplexes are a defensive mechanism against chronic antigenemia, but in other cases they produce important tissue injury, as in glomerulonephritis. There are many tests for detecting them, but no single test detects all types of complexes because of their heterogeneity. Authors explain the polyehthilene-glycol precipitation test which is compared it to other methods, as binding to C'1q, Fc or C'3b receptors or physical separation tests. Polyethilene-glycol precipitation was performed in several concentrations of albumin-antialbumin complexes. When eight sera were heated to 60 degrees C during 30 minutes the levels of precipitate decreased and they suggest it is due to antigen and antibody dissociation. Inversely, IgG progressive concentrations increased by formation of heat aggregated immunoglobulins. The 10 times repeated freezing and thawing of sera increased the optical density of precipitates from 0.047 to 0.057 and the raising was higher in pathological than in normal sera. Although the repeated thawing must be avoid its' role does not seem be very relevant.
A new method for the detection of circulating immune complexes using radiolabelled conglutinin as a marker for complement-bound complexes precipitated in low concentrations (3.5%) of polyethylene glycol is described. The optimal laboratory conditions for the test have been defined and certain limitations studied. The technique is simple with good reproducibility and high degree of specificity. In a double-blind study of eighty-seven samples of sera from normals, patients with glomerulonephritis, post-renal transplantation, rheumatic diseases, breast tumours, multiple sclerosis and infections the method was compared and correlated to the Clq-binding assay and the Raji cell test. The radioconglutinin-binding assay was most discriminative for cases of glomerulonephritis, renel transplantation, breast carcinoma and multiple sclerosis and least for rheumatoid arthritis.
Evidence that early members of the classic pathway of complement are involved in the interaction of collagen with the blood platelet is presented. C4 is required for platelet aggregation response to low concentrations of fibrous collagen but not for adhesion of collagen to platelets obtained from guinea pigs genetically lacking C4. The aggregation response is restored, however, by preincubation with either C4 or normal plasma. It is suggested that membrane-bound C1s is the receptor site for collagen, inasmuch as preincubation of normal platelets with antiserum to C1q specifically enhances the platelet-collagen interaction, demonstrating a potential competition between C1q and collagen for the platelet binding site. This concept is further supported by the fact that C1s inhibitors also enhance aggregation response to collagen. Under physiologic conditions, the role of complement in the platelet response to collagen should be highly significant.
Single cosinor analyses of several elements in the complement cascade suggest the occurrence of circadian rhythms in this immunochemical system. Some earlier results, obtained with less specific methods and reported as properdin, on reanalysis also reveal circadian and circannual rhythms in the aspects of immunology represented. The topic of the complement cascade as a whole is briefly reviewed in the content of modern knowledge.
Complexes of IgM equine anti-dansyl antibodies and different dansyl substituted carriers were tested for their ability to fix complement (C). Only dansyl92-Ficoll and dansyl12-poly-L-lysine were found to be effective. Dansyl13-bovine serum albumin, dansyl127-keyhole limpet hemocyanin, and reduced and alkylated dansyl10-ribonuclease were all ineffective. Lack of C fixation by the dansyl-ribonuclease was not due to lack of antibody-antigen complex formation, since binding at the concentrations employed for C fixation was established. However, in contrast, polymerized dansyl-ribonuclease (polydisperse, with m.w. = 74,000 to 230,000) was very effective in inducing C fixation. These results suggest that large antigen size is necessary for IgM to bind in a multivalent fashion to provide the correct conformation for C fixation. A similar conclusion had been made in earlier studies on rabbit IgM by Cunniff and Stollar. Since optimal C fixation occurred at lower antigen concentrations than maximal precipitation, it would appear that complexes in which several combining sites within a given IgM molecule may be bound to the same antigenic surface may be the most effective. The observation that the amount of C1q bound to antibody was the same in the presence and absence of antigen suggests that enhanced C fixation by antibody-antigen complexes is due to additional C component interactions such as C1r or C1s.
Circulating immune complexes have been investigated in jirds (Meriones unguiculatus) infected with the filarial nematode Brugia pahangi. Two-month-old male jirds were inoculated with seventy-five B. pahangi infective larvae into the left groin. At 8 months post-infection, sera of individual animals from a group of seventeen infecteds and seventeen age-matched controls were analysed for immune complexes by (1) a solid-phase C1q binding assay (Clq-SP) and (2) precipitation with 3.5% polyethylene glycol followed by binding of 125I-labelled rabbit anti-jird Ig antiserum (PEG). A significant increase in the level of circulating immune complexes was shown in the infected group as compared with the controls for both assays, with a P value = 0.005 for PEG and P = 0.001 for Clq-SP. Using the mean of the control group +/- 2 s.d. as the upper limit of the normal range, 24% of the infected group had elevated immune complex levels by the PEG assay, and 41% were elevated in the C1q-SP assay. A high degree of variability was noted in the levels of immune complexes among individual animals in the infected group by each test. No correlation between immune complex levels and numbers of circulating microfilariae was found in either assay.
The Clq assay for antigen-antibody complexes was performed on 79 blood samples from 43 patients with juvenile rheumatoid arthritis (JRA). The results were compared with assays for the activation products of C3 (C3c,d), for the concentration of C3, for rheumatoid factor, and for antinuclear antibodies. A statistically significant association was found between Clq binding and positive tests for latex fixation and C3c,d in systemic and polyarticular JRA, but positive results of each assay were found independently. These 3 assays were usually negative in pauciarticular JRA. No relationship was found between Clq binding and C3 concentration or antinuclear antibodies.
Activation of the complement system by iodinated contrast medium (ICM) infusion was studied in 25 children with congenital heart disease who received 76% Urographin during angiocardiographic studies. Total hemolytic activity (CH50), C1q, C3, C4 and C3 activator were determined before and 2, 5, 10, 15 and 20 minutes after Urographin infusion. Results showed that CH50 decreased in 16 patients (64%), C3 in 12 patients (48%), C3 activator in 12 patients (48%), C1q in 11 patients (44%) and C4 in 11 patients (44%). No side effect was encountered in all patients. It is therefore concluded that both the classic and alternative complement pathways could be activated by ICM and no causal relationship could be found between the presence of complement activation and the occurrence of adverse reactions to ICM infusion.
Serum amyloid P-component (SAP) is a normal plasma glycoprotein apparently identical with the P-component associated with amyloid deposits. SAP shows extensive amino acid sequence homology with the C-reactive protein, and both have a similar molecular configuration. SAP undergoes calcium-dependent binding to zymosan, agarose, and amyloid fibrils, but its functional properties are not yet known. We report here that SAP agglutinates complement-(C) coated antibody-sensitized erythrocytes by a calcium-dependent reaction. SAP was found to interact predominantly with a modified form of bound C3b. This modification was achieved by prolonged treatment of EAC43 with heated normal human serum or with isolated C3bINA and beta 1H, and reactivity was reduced upon treatment of the cells with trypsin. SAP thus seems to react with fixed C3 in a manner similar to the reaction of C3 with bovine conglutinin, a molecule that also undergoes calcium-dependent binding to zymosan and agarose. These studies identify a new reactivity for SAP and demonstrate an interaction between an amyloid protein and the C system. The close similarity between the calcium-dependent binding specificities of SAP and of bovine conglutinin may assist in characterization of these molecules and in investigation of their function.
Occurrence of immune complexes in malignant pleural effusions has been investigated by the 125I-c1q binding test. 55% of the pleural effusions had C1q binding activity levels higher than those found in transudates used as controls. The levels of C1q binding activity in effusions were significantly higher than those found in the serum of the same cancer patients. High levels of C1q binding activity were found in malignant effusion independently of type or differentiation of the tumors involved. The C1q binding material had properties of immune complexes. The levels of CH50 and C3d, i.e. the degradation product of C3, in malignant effusion were similar to those of transudates. These observations show a high incidence of immune complexes in malignant effusions and a slight activation of complement inadequate for its local consumption. The persistence in major quantity of immune complexes in malignant effusion suggests local formation or decreased clearance.
The sandwich immunofluorescent complement fixation test proved to be as sensitive as the indirect fluorescent antibody test when anti-C1q was used to detect the binding of complement to antigen-antibody complex of four species of trypanosomes in experimentally infected domestic animals.
Seventy nephrectomy specimens from patients with end-stage renal disease, four renal biopsies from patients with focal sclerosing glomerulonephropathy (FSGN) and normal renal function, and 17 control biopsies from normal renal allograft donors (Group I) were studied by immunofluorescence with respect to deposition of immunoglobulins and classic and alternative complement (C) pathway components. The end-stage kidneys were divided into three groups according to etiology: 16 patients with immune-mediated glomerulonephritis (Group II), 22 patients with congenital and/or familial renal disease (Group III), and 32 patients with systemic or primary renal disease in which an immune-mediated injury could not be established (Group IV). The pattern of immunoprotein deposition in glomeruli in Groups II, III, and IV, and in biopsies of patients with FSGN was similar: peripheral lobular, globular and/or granular, focal and segmental; it was limited to dying glomeruli or abnormal glomerular segments. A statistically significant correlation existed between the percent of properdin-containing glomeruli and the percent of glomeruli undergoing hyalinization in Groups II, III and IV (II, r=0.67; III, r=0.92; IV, r=0.78). No deposition was observed in normal or completely fibrotic glomeruli. In vitro heterologous complement fixation was demonstrated in 17/19 end-stage kidneys in a similar distribution. Early classic C components, C1q and C4, were detected in a somewhat higher frequency in Group II (14/16) than Group III (11/22) and Group IV (20/32) (Group II vs. III, P=.02 and II vs. IV, P=.07). C3 and properdin were detected in 77 to 100% of all 3 groups; in 18 patients, C3 and properdin were present without detectable C1q and C4. Immunoglobulins, primarily IgM, and components of the classic and alternative C pathways are regularly present in hyalinizing glomeruli irrespective of the etiology of the renal failure. These observations suggest that an immune process is operative in glomerular obsolescence regardless of the underlying etiology of the renal disease.
Six patients with secondary syphilis and one control subject were observed over a period of up to 8 hr following the administration of either penicillin or erythromycin. Serial clinical observations were made and blood samples obtained for complement and serological analysis. The patients showed Jarisch-Herxheimer reactions (JHR) of varying intensity which were found to be preceded by and to parallel in degree certain changes in complement and syphilitic antibody titres. Falls in total haemolytic complement, in C4, C3, C6 and C7 and a marked drop in C1INH were observed. There was no change in total GBG/GGG or evidence of conversion of GBG to GGG. Associated falls occurred in the titres of the QFTA and the QTPHA antibodies but not of the QVDRL or QTPI antibodies. C3 conversion was found in the two patients that suffered severe reactions. Immune complexes were not detected and it is suggested that complement activation occurred in the extra-vascular body compartment. The significance of these changes in relation to other plasma enzyme systems and to the development of the full clinical picture of the JHR is discussed.
90 patients, whose renal biopsies showed on light microscopy a pattern of MPGN, have been studied by immunofluorescence. 10 cases showed dense intramembranous deposits. Fluoresceinated antisera against IgG, IgA, IgM, C3, fibrinogen, IgD, IgE, C4, C1q, properdin and C3A were employed. Granular depostis of C3 were observed in all cases; IgG, IgM, properdin, C1q and C4 were found in 2/3 cases; IgA, IgE and C3A were rarely found. The localization of these deposits was parietal and often also mesangial. On the basis of glomerular deposition of C3 with or without immunoglobulins (Ig), we separated the cases into three groups: 1) C3 + Ig (59 cases), 2) predominant C3 (19 cases), 3) isolated C3 (12 cases). Most patients with dense deposits disease were classified in the third group. Deposits of C1q and C4 were found only in the first two groups. The localization of C3 deposits showed a more frequent mesangial extension in the second and third groups. Patients in these 3 groups also had different serum complement profiles. No significant differences in the major clinical features could be found in the 3 groups. Variable immunofluorescence patterns, in agreement with other serological parameters, confirm the heterogeneity of pathogenetic mechanisms in patients with MPGN.