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Anti-C3c antiserum was induced by immunizing rabbits with autologous erythrocytes coated with human C3b/C3bi. By absorption with human plasma this antiserum was rendered specific for C3c epitopes which are not expressed on native C3. This specificity may be analogous to that of immunoconglutinin.
Opsonization of the C3b receptor (CR1) on phagocytic cells with C3b enhances both attachment of targets to the cells and subsequent IgG-dependent ingestion of these targets. To explore mechanisms involved in this increased phagocytosis, we adhered cultured human monocytes to surfaces pre-coated with CR1 ligand or control proteins and quantitated ingestion of sheep E opsonized with IgG alone. Three ligands for CR1 resulted in markedly enhanced phagocytosis of targets when compared individually to a panel of non-ligands, as determined by both the proportion of monocytes ingesting targets (percent phagocytosis) and by the number of targets ingested per 100 monocytes (phagocytic index). The ligands included purified C3b, iC3, and Fab fragments of 1B4, a monoclonal anti-CR1, which resulted in a percent phagocytosis of 56.3 (p less than 0.01), 59.0 (p less than 0.01), and 54.4 (p less than 0.02) and a phagocytic index of 281.2 (p less than 0.01), 281.1 (p less than 0.01), and 247.1 (p less than 0.02), respectively. Control proteins including human serum albumin, hemoglobin, Fab fragments of anti-fibronectin, anti-beta 2 microglobulin, and MOPC 21, and Fc fragments of 1B4 and MOPC 21 produced no significant stimulation of phagocytosis, nor did F(ab')2 fragments of monoclonal anti-CR3, M1/70. CR1-specific augmentation of target ingestion was apparent with monocytes cultured in serum-free medium for 1 to 7 days, but was not seen with freshly elutriated cells. Phagocytosis of unopsonized or IgM-coated targets was minimal. These results suggest that the adherent monocytes are primed by CR1 cross-linking for enhanced FcR-mediated phagocytosis even when the CR1 ligand is not present on the targets. This contrasts with the behavior of CR3, and demonstrated functional divergence between these C3 fragment receptors in the phagocytic process.
We analyzed blood from 450 healthy children and adolescents, ages one to 19 y, as well as term and preterm infants, to define age- and sex-specific reference intervals for numerous blood constituents. Reference intervals were derived by using nonparametric methods to determine the 0.025 and 0.975 fractiles. Ten serum proteins were measured with the Behring LN Nephelometer. Girls over 10 years of age had higher concentrations of ceruloplasmin and alpha 1-antitrypsin than other children had. There was no sex-related difference in reference intervals for the other proteins tested. Reference intervals are presented for immunoglobulins G, A, and M, complement fractions C3c and C4, ceruloplasmin, transferrin, alpha 1-antitrypsin, retinol-binding protein, and prealbumin (transthyretin).
The separation of complement factors C3 and C3b by isotachophoresis in 1% agarose gel followed by immunoprecipitation and quantification is presented. Glycine was used as spacer in a nonequilibrium isotachophoresis (Acevedo, F., J. Chromatogr. 1991, 545, 391-396). Tricine, beta-alanine and Tris were the leading ion, terminating ion and counter ion, respectively. After electrophoresis the gel was incubated in rabbit anti-human complement factor C3c. The amounts of C3 and C3b in the sample were measured by optical densitometry of the Coomassie Brilliant blue-stained immunoprecipitates in the agarose gel. The correlation coefficient obtained for the logarithm of the integrated densitometric measurement vs. the logarithm of the amount of applied C3 was higher than 0.98 in calibration experiments. The extent of complement factor C3 activation is calculated as the ratio between the amount of C3b and the amount of C3b plus C3 and expressed as percent. The progress of complement activation from human blood plasma samples induced by Mg2+ and zymosan are presented as examples.
Auranofin [S-triethylphosphine gold-2,3,4,6 tetra-O-acetyl-l-thio-beta-D-glucopyranoside) SK&F 39162) has been administered at 0.1-0.25 mg/kg/day as the sole remission-inducing drug to 46 children affected with juvenile chronic arthritis (JCA). There were 22 males and 24 females; 12 children were affected with pauciarticular onset JCA, 26 with polyarticular onset JCA and 8 with systemic onset JCA. Three sets of efficacy criteria were evaluated quarterly: eight clinical, (Ritchie Index, number of affected, swollen and limited joints, number of joint with increased temperature, morning stiffness, Steinbrocker functional class, physician's disease evaluation), three hematochemical and one therapeutical. In most patients a panel of immunological parameters was routinely performed inclusive of peripheral blood lymphocyte subsets, serum immunoglobulins and C3c-C4 complement components. Patients who showed a definite improvement of at least two out of the three orders of efficacy criteria were classified as responders to auranofin. Out of the 35 patients evaluable after at least six months of treatment there were 24 (68%) responders. Nonresponders had a basal higher level of serum IgA and a basal lower level of serum C4. Both responders and nonresponders presented a reduction of the T4/T8 ratio during auranofin treatment, while only in responders did the basal high levels of IgG and C3c show a definite decrease.
Adsorbents from four commercially available devices, Protein A-Sepharose (Immunosorba Protein A-62,5; Excorim KB, Lund Sweden), Tryptophan-PVA (Immusorba TR-350; Asahi Medical Co., Tokyo, Japan), Phenylalanine-PVA (Immusorba PH-350; Asahi Medical Co., Tokyo, Japan), and Dextran sulfate (Liposorber LA-15; Kanegafuchi Chemical Co. Ltd, Osaka, Japan) were tested under optimal in vitro conditions to determine their adsorption capability for several plasma constituents which are usually the target of plasma therapy. The parameters of interest were: double stranded DNA-antibodies (anti-dsDNA), antiglomerular basement membrane antibodies (anti-GBM), anti-acetylcholin receptor antibodies (AChRAb), circulating immune complexes (CIC), rheumatoid factor (RF), IgA, IgG, IgM, IgE, C3c, C4, LDL-cholesterol, total cholesterol, erythropoietin (EPO) and beta 2-microglobulin (beta 2M). The IgG auto antibodies, CIC and RF can be removed by Protein A-Sepharose, Try-PVA and Phe-PVA. IgG is best adsorbed by Protein A-Sepharose, while IgE can be removed efficiently by Try-PVA. Dextran sulfate is without doubt the best adsorbent for LDL-cholesterol. All four adsorbents bind also complement components C3c and C4. No significant adsorption was found for EPO and beta 2M. The four devices exhibit a quite different adsorption profile which can be used as a guide for the optimal selection of an adsorption column in clinical apheresis.
The authors have studied the correlations between IgA, IgG, IgM, C3c, C4, alpha 1-AGP and the total proteins, total globulins, alpha 1, alpha 2-globulins in normal newborn cord blood. The results indicate some significant correlations between C3c and C4, C3c, C4 and alpha 1-AGP, C3c, C4, alpha 1 1/2AGP and alpha 2-globulins, C4 and beta-globulins, C3c and alpha 1-AGP. The most significant finding has been inverse correlation between IgA and alpha 1, alpha 2-globulins, total globulins and total proteins.
AIM: This study aimed to evaluate the immune system function in patients with uveitis of unknown aetiology. METHODS: The clinical material comprised 19 patients with endogenous uveitis. In all cases the following immunological tests were performed: serum immunoglobulins A, G, M, total IgE, circulating immune complexes, complement components C3c and C4-all determined by laser nephelometry; antinuclear antibodies assessed with indirect immunofluorescence method using HEp-2 cell lines; and antineutrophil cytoplasmic antibodies using indirect immunofluorescence test. In 4 cases lupus anticoagulant was measured with APTT and dRVVT assays. RESULTS: Among our 19 examined patients immunological abnormalities were found in 12 cases. Changes in immunoglobulin concentrations were found in 8 cases. In 4 patients abnormalities of the complement system were observed. Antinuclear antibodies with speckled pattern in indirect immunofluorescence were present in 7 cases. CONCLUSION: In a proportion of patients with endogenous uveitis mild immunological abnormalities were present, suggesting an autoimmune background of the disease. Studies of the immunological profile can therefore help in better evaluation of the patients. It remains to be determined whether the observed immunological alterations are of any importance in the pathogenesis of the studied disease.
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.
IgG in dialysate may have an important role in anti-infection mechanisms during continuous ambulatory peritoneal dialysis (CAPD). As Fc fragment oligosaccharidic chains are crucial for IgG effector functions, we have tested the hypothesis that IgG glycation might occur during CAPD and modify IgG properties. Purified normal IgG was incubated with glucose solutions of different concentrations and pH. Separation of glycated IgG was performed by affinity chromatography. Complement activation (C3c deposition) and phagocytosis by polymorphonuclear leucocytes (PMN) were studied in vitro using Staphylococcus aureus Wood (STAW) as antigen. In addition, we compared the percentages of glycated IgG in IgG purified from sera and dialysates of 12 CAPD patients. The percentage of glycated IgG after in vitro incubation of normal IgG with glucose solutions was directly proportional to glucose concentrations, incubation time and pH. Glycated IgG anti-STAW induced a higher C3c deposition than non-glycated IgG anti-STAW (C3c/IgG (mean +/- SD) 0.96 +/- 0.06 vs 0.79 +/- 0.08; P = 0.027). PMN phagocytosis was not affected by IgG glycation. The percentages of glycated IgG in dialysates of CAPD patients were greater than those in corresponding sera (5.38 +/- 2.36% vs 4.56 +/- 2.47%; P = 0.006). It is concluded that IgG glycation may take place in the peritoneal cavity during CAPD and lead to enhanced complement activation. This could explain the high degree of complement activation previously described in dialysate of CAPD patients and might theoretically result in a reduction of complement factors available in dialysate for adequate anti-infection mechanisms.
C4d deposition in the walls of peritubular capillaries is considered the key phenomenon in the histopathological diagnosis of humoral, i.e. antibody-mediated, allograft rejection. We have earlier proposed that deposition of C3c in glomerular capillaries and simultaneous intravascular accumulation of macrophages in allografts with immediate or early humoral rejection indicates a potentially serious condition with very poor prognosis. The clinical outcome of 45 cadaveric grafts with this phenomenon among 1960 renal allografts transplanted at our centre during 1984-1999, and the recipients of the contralateral kidneys, was retrospectively evaluated. Graft failure occurred in 44/45 grafts within 3 weeks, with graft loss in 33/45 (77%) within 4 months and 37/45 (82%) within 1 year. From the contralateral kidneys, 5/33 (15%) were lost within 1 year. In a recent series of early biopsies, we recognised that of 13 cases showing C4d positivity in peritubular capillaries but lacking C3c in glomeruli, 10/13 (77%) were still functioning after 4 months. The mean number of CD68(+) macrophages per glomerular profile, i.e. the glomerular macrophage index, shows a significant difference between C4d(+)C3c(-) and C4d(+)C3c(+) cases (p<0.001). Our results indicate the existence of a clinically important subgroup of early humoral rejection with particular morphological features.
We have evaluated a partially automated Behring laser nephelometer for the measurement of IgG, IgA, IgM and C3c in serum. The system consisted of a manual Behring laser nephelometer, an automatic cuvette carrier and a Hewlett-Packard 9815 A calculator/printer. The system could process 240 preincubated samples per h when the interval between each voltage reading was set at 15 s. Day-to-day precision was near 6%. We obtained the worst precision for the determination of IgG which requires the smallest volume of diluted sample (10 microliters). The Frigen treatment used to clarify turbid sera seems to decrease IgG and increase C3c concentrations. The addition of polyethylene glycol 6000 at a concentrations of 40 micro/L in the reaction mixture did not improve the assay ranges. Comparison studies with radial immunodiffusion for the four proteins and with the IgM - BMC Immunological Turbidity Test using either least-squares or Deming's regressions gave very good correlation figures, except for C3c and for some IgM paraproteins. We could decrease the cost per test by re-using the plastic cuvettes. The utilization of the calculator-printer greatly simplified data handling but the automatic carrier was not considered a real asset without complete automation.
PURPOSE: This study aimed to evaluate the immune system function in patients with idiopathic posterior uveitis. MATERIAL AND METHODS: 50 patients--29 women (58%) and 21 men (42%)--were examined. Intraocular inflammation intensity was scored on standard uveitis grading system prepared by BenEzra et al. In all cases selected parameters of serum immune system activity--immunoglobulins IgA, IgG, IgM, IgE, complement proteins C3c and C4, circulating immune complexes (CIC) and autoantibodies: ANA, ANCA, ACA were detected. All immune system parameters were assessed in active stage of the disease and then 1, 3, 6, 12 months after the beginning of immunosuppressive therapy. RESULTS: Among 50 patients immunological abnormalities were found in 38 cases (76%). Changes in serum immunoglobulin concentrations were present in 28 patients and the most common pathology was the deficiency of serum IgG in 11 subjects. In 34 cases abnormalities of the complement system were present. In 43 subjects serum CIC were detected. ANA in indirect immunofluorescence test were found in 9 patients. Neither ANCA nor ACA were present in serum of this group of patients. CONCLUSIONS: Non specific abnormalities of immune system parameters found in serum of 38 patients with idiopathic posterior uveitis can indicate their role in pathogenesis of this disease. The deficiency of IgG can be related to CIC formation in this group of patients. Probably circulating immune complexes (CIC) are involved in the pathogenesis of endogenous posterior uveitis and they can act as an aggressor or protector against the retinal autoimmune mechanisms.
The highest reported prevalence of celiac disease (gluten-sensitive enteropathy) is found in the West of Ireland. Recent genetic data have suggested that major histocompatibility complex-linked loci may have a dominant genetic effect for disease susceptibility in this population compared with a recessive effect in other groups. To further understand the role of the MHC in celiac disease in the West of Ireland, we analyzed markers for 22 MHC haplotypes from celiac patients and compared them with 18 nontransmitted haplotypes found in the parents of celiac children, and with reported haplotypes from other populations. An extended MHC haplotype including [HLA-B8, DR3, DQw2, Bf*S, C4A*Q0, and C4B*1] accounted for 50% of celiac haplotypes but only 27% of nontransmitted parental haplotypes. Compared with other reported haplotypes in celiacs, patients from the West of Ireland show a higher prevalence of HLA-A1 as a component of this extended haplotype, suggesting that although the core haplotype is similar between Irish patients and others, the celiac population in the West of Ireland differs at other HLA loci. We did not observe any other common haplotypes among our patients unlike the situation in other populations. These differences may underlie the possible dominant effect of HLA-linked loci and the unusually high prevalence of celiac disease in the Irish population. We also found that the serum levels of complement components C3c, C4, and factor B were significantly lower among celiac patients than nonceliacs. The lower serum level of C4 appears to be related to the presence of deletions and null alleles at the C4A and C4B loci in celiacs.
Circulating soluble immune complexes (CIC), immunoglobulin classes (IgG, IgA, and IgM), acute phase proteins (alpha-l-fetoprotein and alpha-1-acid glycoprotein) and complement factors (C4 and C3c) levels were determined in 52 Nigerian patients with urinary schistosomiasis (USS) and 39 healthy subjects by polyethylene glycol precipitation and single radial immunodiffusion methods respectively. A considerably higher proportion of USS patients than the controls had elevated levels of soluble immune complexes. IgM, IgA and C3c levels were significantly higher in USS patients than the controls. However, serum concentration of C4 was significantly reduced in USS patients than the controls while that of IgG was not significantly reduced in these patients. The mean levels of alpha-l-fetoprotein and alpha-l-acid glycoprotein were comparable in the USS subjects and the controls. Correlation analysis showed association between S. haematobium egg numbers with serum concentration of IgM, C3c and CIC. These observations could be the results of increased rate of CIC formation, and inflammatory responses to schistosome antigens. The study concluded that IgM associated-CIC may be responsible for the immunopathology of chronic schistosomiasis.
Special problems are associated with analysis of human plasma proteins by standard "high-resolution" two-dimensional gel electrophoresis methods in which isoelectric focusing is followed by electrophoresis in sodium dodecyl sulfate/polyacrylamide gels (SDS-PAGE). Individual plasma proteins are often separated into overlapping groups of multiple spots, and identification of individual spots is further confounded by genetic variation. Analytical recovery of components of high molecular mass is also low or variable. These problems may be reduced or overcome by use of a "low-resolution" method consisting of electrophoresis of native proteins at pH 8.6 in an agarose gel followed by SDS-PAGE without added reducing agent. About 60 proteins can be resolved, most as single spots. About 25 of these proteins have been "mapped," and tentatively identified. We have examined 119 plasma samples taken from six donors who were undergoing filtration leukapheresis and 10 donors who were undergoing centrifugation leukapheresis or plateletpheresis. In all cases, passage of blood through a nylon filter induced a significant increase in a doublet of spots tentatively identified as complement component C3c. This was detected in the effluent from the filter throughout the first 30 min of filtration, and to a lesser extent in the venous blood. These spots were not induced by the centrifugation procedures. One filtration donor also showed increased acute-phase proteins 24 h after the procedure.
131 patients with essential hypertension (EH) and 30 patients with secondary hypertension (SH) of renal genesis were examined, all of them Russian inhabitants of Moscow, aged 20-56. In patients with EH increased rate of HLA-B13 and B22 antigens was determined. The highest rate of HLA-B13 antigen in this group was registered in patients without IHD, while patients with IHD had the highest rate of HLA-B22 antigen compared to controls. Patients with SH demonstrated no significant difference in HLA antigens distribution from that in controls. Besides, patients with EH had significantly increased serum concentration of circulating immune complexes (CIC), of IgA and beta 2-microglobulins as well as of three complement components (C3c, C4 and B factor). Similar changes were observed in patients with SH, excluding CIC and C3c, concentration of which did not differ from that in the control group. No strict dependence between the level of immunity humoral factors and presence of HLA-B13 and -B22 antigens was observed. The data gained suggest possible association of HLA system with EH development.
Immunological characterization of semen and male fertility are discussed. The pH of seminal plasma is very similar in groups of fertile and infertile men. Nonspecific immunological factors such as lysozyme, C3c, alpha-1 antitrypsin and beta-2 microglobulin were significantly higher in 14% of infertile men. Seminal antibodies agglutinating spermatozoa are frequently observed in IgG and IgA isotypes. High levels of seminal anti-phospholipid antibodies in seminal plasma could influence epitopes on the endometrium, oocyte or early embryo in patients with repeated unexplained spontaneous miscarriages.