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Genetic polymorphism of the third component of human complement (C3) has been considered as a powerful marker for population genetics. Some studies on the distribution of gene frequencies have been performed among numerous populations all over the world. This review takes stock of population genetic studies reported up to now and points out some remarks on the distribution of the observed allelic frequencies.
In order to clarify the relation between opsonic activity (OA) in newborn infants and their gestational age, we determined OA by Cypiridina luciferin analog-dependent chemiluminescence (MCLA-CL). In addition, complement C3 which plays the major role in OA, was determined by the two-dimensional immunodiffusion method. Although OA and C3 in newborn infants increased in proportion to their gestational age, the levels were significantly lower in full-term infants than in adults. In neonates with IgM levels of more than 30 mg/dL at birth, both OA and C3 levels were significantly higher than in normal neonates, yet these levels were significantly lower than in adults. These findings suggest that low opsonin activity is an important factor in neonatal susceptibility to infection. When OA is measured by chemiluminescence, MCLA-CL is the preferred technique to luminol-dependent chemiluminescence.
In a clinical study granulocyte phagocytosis, serum levels of IgG and IgA and of the acute phase proteins ceruloplasmin, alpha-1-antitrypsin, transferrin, and of the 3rd component of complement (C3) are simultaneously determined in tumor patients and compared with healthy probands of the same age and with patients being under general surgical treatment. There was found a negative correlation between granulocyte phagocytosis and the IgG level and a positive correlation between phagocytosis and the C3 level in each group. Despite of some significant differences between all groups of probands with respect to the measured parameters no new essential information for clinical use could be received, thus the determination of granulocyte phagocytosis remains the only recommended method.
Despite the availability of different classifications for rapidly progressive glomerulonephritis (RPGN), patients with "idiopathic crescentic GN" have not been yet inserted as a precisely defined subgroup, pointing to their probable heterogenicity. Trying to better define their characteristic, we retrospectively analyzed the clinical, histological and immunopathological features of 41 patients diagnostically labelled "idiopathic RPGN" because they had no evidence of systemic disease (including systemic vasculitis), no anti-GBM mediated glomerulonephritis and no clearly defined primary glomerulopathy. Starting by a thorough morphological review, 2 subgroups were defined: group I (25 patients) with variable degrees of intraglomerular necrosis, and group II (16 patients) with no intracapillary necrotizing lesions. Group I showed no or minimal endocapillary proliferation, intense interstitial infiltrates with periglomerular localization, frequent ruptures of Bowman's capsule and mild degree of glomerular and/or interstitial sclerosis. 16 patients in this group (64%) had irregular deposits of complement C3 at immunofluorescence while the remaining 9 (36%) had no immune deposits. Clinically they had no previous history of preceding urinary abnormalities, had a mean of 1.8 g/day proteinuria and a positivity for ANCA in 92% (12/13). In group II there was frequently marked mesangial proliferation, scarce interstitial infiltrates, no ruptures of Bowman's capsule and marked degrees of glomerulosclerosis and interstitial fibrosis. All patients in this group had clearly defined immune deposits of C3 and/or IgG. Clinically 50% of these patients had a history of recurrent microhematuria and/or proteinuria, a mean of 4.5 g/day proteinuria and negativity for ANCA in all 8 patients tested.(ABSTRACT TRUNCATED AT 250 WORDS)
The anti-HAV humoral immune response in the IgM, IgA, and IgG classes was analyzed weekly in 35 patients with clinically overt hepatitis A during the time of their hospitalization and 2-3 years afterward. In parallel, the dynamics of total immunoglobulins and complement C3 component (C3) levels were determined. The results suggest that the appearance of class-specific anti-HAV is compatible with the course of primary humoral immune response, with IgM and IgA anti-HAV, providing immunity in the early and intermediate phases of the infection, and IgG anti-HAV, providing immunity in the later phase. The overall appearance of anti-HAV, total immunoglobulins, and C3, do not support the view that liver injury is mediated by the humoral immune mechanisms. Instead, the hepatocyte damage is probably caused by direct viral cytotoxicity. This hypothesis is supported by a case of hepatitis A in a patient under immunosuppressive treatment.
Outbred immature CD-1 mice were subcutaneously (s.c.) injected once on postnatal day 17 or on postnatal days 17, 18, and 19 with 17beta-estradiol, diethylstilbestrol, tamoxifen, 4-hydroxytamoxifen, methoxychlor, the methoxychlor metabolite HPTE, nonylphenol, o,p'-DDT, endosulfan, or kepone over a wide dose range (0.1 to 1,000,000 microg/kg). On the day following the last injection, uterine weight/body weight ratios were determined and uterine tissues processed for histologic examination. All compounds except endosulfan and kepone increased uterine wet weight compared to vehicle controls; however, the dose response curve and magnitude of response varied depending on the compound. Choosing the maximum wet weight dose for each compound, uterine tissue was evaluated for epithelial cell height, epithelial and stromal cell proliferation, endometrial gland number, and induction of estrogen-inducible proteins lactoferrin and complement C3. All compounds elicited estrogen-responsive changes in these endpoints that were individually more sensitive than uterine weight alone. We conclude that these endpoints enhance the sensitivity of the uterotropic bioassay.
Anticoagulation has been reported to ameliorate antiglomerular basement membrane glomerulonephritis (anti-GBM-GN) while its effect on chronic immune complex glomerulonephritis (IC-GN) as studied in the NZB mouse is unclear. Chronic serum sickness IC-GN was induced in rabbits by injecting bovine serum albumin (BSA) daily. Anti-GBM-GN was induced by i.v. injection of a known amount of heterologous anti-GBM antibody. Heparin was administered beginning at two to six weeks after the first BSA injections or before the administration of anti-GBM antibody, on various schedules from 5000 U every 12 hr to 8000 U every 8 hr. With this dosage the partial thromboplastin time remained greater than 1-1/2 to 2-1/2 times the control at the time of the subsequent heparin injection. Heparinized and nonheparinized groups were matched according to duration of disease, maximum anti-BSA concentrations or anti-GBM antibody dosage--and no significant differences were found in proteinuria; severity of the glomerular histologic lesions; or immunofluorescence patterns of immunoglobulin G (IgG), third component of complement (C3), BSA or fibrinogen-related antigen(s) (FRA). Crescent formation was not prevented. This study shows that heparin in the maximum permissible dosage is ineffective in preventing glomerular FRA deposition or altering the progression of experimental IC-GN or anti-GBM-GN in rabbits.
BACKGROUND: Nephrotoxic glomerulonephritis is induced by the administration of antibody against the glomerular basement membrane (GBM). We demonstrated previously that Fc receptors for immunoglobulin G (IgG) (FcgammaR) play crucial roles in the induction of accelerated nephrotoxic glomerulonephritis by using FcRgamma-deficient (-/-) mice. Since FcRgamma-/- mice lack the cell surface expression of two activating FcgammaRs, FcgammaRI and FcgammaRIII. The present study aims to identify the FcgammaR responsible for the induction of nephrotoxic glomerulonephritis. METHODS: Accelerated anti-GBM glomerulonephritis was induced in FcgammaRI-/-, FcgammaRIII-/-, and FcRgamma-/- mice by preimmunization with rabbit IgG followed by inoculation of rabbit anti-GBM antibody. Histologic analysis and immunostaining of renal sections were performed. RESULTS: FcgammaRI-/- mice as well as wild-type mice showed severe glomerulonephritis with hypernitremia by the administration of anti-GBM antibody. In contrast, FcgammaRIII-/- mice showed much milder renal involvement, similar to FcRgamma-/- mice. Histologically, FcgammaRI-/- mice showed intracapillary proliferation, glomerular thrombosis, and crescent formation, whereas FcgammaRIII-/- mice showed only glomerular hypercellular changes. The depositions of anti-GBM antibodies, autologous antibodies and complement C3 along the GBM were equally observed among all three FcR-/- mouse types by immunostaining. CONCLUSIONS: Accelerated nephrotoxic glomerulonephritis is induced predominantly through FcgammaRIII but not FcgammaRI.
Deposits of complement C3 and/or immunoglobulin were found in the vessel walls and/or at the dermal-epidermal junction in skin lesions of all of 11 patients with psoriatic arthritis and guttate psoriasis. Similar deposits were seen in 6 out of 15 patients with psoriasis vulgaris. Synovial tissue available from 2 patients revealed deposits in the vessel walls.
The results of experiments with Acanthopanax giraldii polysaccharide (AGP) demonstrated that it inhibited the growth of solid Sarcoma 180 and prolonged the survival time significantly. In tumor-bearing mice, AGP enhanced the phagocytosis and chemiluminescence of macrophages. By the immunofluorescent method, binding of the third component of complement (C3) cleavage product to macrophages and proportion of C3 positive cells were increased. In crossed immunoelectrophoresis, human serum C3 was converted by AGP and appeared as the 3rd peak. The height of the 3rd peak was directly proportional to doses of AGP. The residual CH50 units of human serum decreased dose-dependently. These results suggest that the antitumor activity of AGP is related to the enhancement of immune responses.
The clinically normal skin of the lower back of 30 patients with diabetes mellitus was examined, using the direct immunofluorescence technique. No deposit of immunoglobulins or complement (C3) could be demonstrated, while other authors have previously reported lupus-like deposits in diabetes mellitus. As other discrepant studies of skin immunofluorescence have been published, it is suggested that the standards of the various immunopathology laboratories are different. This may explain why the actual value of the lupus band test remains controversial.
A case of severe bullous dermatosis in the newborn son of a mother with herpes gestationis is reported. Bullous lesions appeared in the child about 2 hours after delivery and regressed completely without specific treatment by the end of the first month, leaving numerous epidermal cysts. The immunologic phenomena were both qualitatively and quantitatively comparable to those obtained in the mother, i.e., deposition of complement (C3) and smaller amounts of IgG at the dermo-epidermal junction of the affected skin. A transient increase of the total serum IgE was demonstrated in the mother, while the serum IgE level in the newborn was less than 5 U/ml. The pathogenetic role of IgG autoantibodies in herpes gestationis and, more generally, in autoimmune diseases is discussed.
Immunofluorescence microscopy of endomyocardial biopsy specimens from heart allograft recipients identified immunopathologic changes in three of 17 patients. These changes included immunoglobulin G and complement C3 deposition in tissue structures such as capillary endothelium and basal membranes, cardiomyocyte sarcolemma, and interstitial tissue. Moreover, the immunopathologic changes could be correlated with acute cellular rejection episodes evidenced by endomyocardial biopsy criteria.
While the interaction of complement component C1q with cellular proteins is extensively studied, much less is known about the binding of the structurally related molecule, mannan-binding lectin (MBL) to various cells. Here we show by cytofluorimetry that the interaction of MBL with immunocompetent cells is much more restricted than that of C1q. It is shown that under conditions of physiological ionic strength MBL binds to human monocyte-derived macrophages (Mphi) and monocytoid cell lines, but not to T and B lymphocytes, in contrast to C1q, which interacts with all these cells under the same conditions. As opposed to the binding of C1q, low ionic strength does not improve the interaction of MBL with Mphi. No competition for cellular binding sites was found when MBL and C1q were added simultaneously to the cells. Studying the functional consequences of the interaction, we found that the release of TNF-alpha from Mphi is induced by C1q but not by MBL. Production of complement C3 by Mphi is stimulated by C1q strongly, while the effect of MBL is much weaker. C3 produced upon C1q-mediated triggering is shown to opsonize RBC, resulting in enhanced phagocytosis. These results suggest that cell membrane molecules binding MBL and C1 q are not identical; moreover, biological functions exerted by these proteins are also markedly different.
Sea urchins have an innate immune response that functions in the absence of adaptive capabilities. It is mediated, in part, by components of the complement system, an important subsystem of the innate response in mammals. A homologue of complement C3, SpC3, has been identified in adult Strongylocentrotus purpuratus and is expressed in coelomocytes. In this study, transcript levels from the gene, Sp064, which encodes SpC3, were examined in developing embryos and found to be present in unfertilized eggs and throughout embryogenesis with a peak in transcript levels just prior to and during gastrulation. In addition, continuous exposure of embryos, beginning with the hatched blastula stage, to heat killed Vibrio diazatrophicus, a marine pathogen of sea urchins, significantly increased Sp064 message content in plutei compared to unexposed controls. These results suggest that sea urchin embryos may use a complement-based immune system for defense against pathogens in their aquatic environment.
The variation in the third component of human complement (C3) and orosomucoid (ORM1) serum proteins, and 6-phosphogluconate dehydrogenase (6PGD), adenosine deaminase (ADA), esterase D (ESD), and acid phosphatase (ACP1) red cell enzymes was examined in two samples from autochthonous populations living on either side of the Sierra de Gredos range in Central Spain. These results support only a moderate differentiation between Gredos subpopulations, which is discussed in relation to other Iberian Peninsula groups. Allele frequencies in Gredos show a remarkable heterogeneity as contrasted with other Iberian populations for most of the markers examined; relatively high C3*S, ORM1*F, ADA*1, ESD*2, and ACP1*C gene frequencies are characteristics of Gredos samples. This differentiation was more marked for the Northern Gredos population and could be related to the geographical peculiarities of this region.
Environmental crystalline silica exposure has been associated with formation of autoantibodies and development of systemic autoimmune disease, but the mechanisms leading to these events are unknown. Silica exposure in autoimmune-prone New Zealand mixed (NZM) mice results in a significant exacerbation of systemic autoimmunity as measured by increases in autoantibodies and glomerulonephritis. Previous studies have suggested that silica-induced apoptosis of alveolar macrophages (AM) contributes to the generation of the autoantibodies and disease. Rottlerin has been reported to inhibit apoptosis in many cell types, possibly through direct or indirect effects on PKCdelta. In this study, rottlerin reduced silica-induced apoptosis in bone marrow-derived macrophages as measured by DNA fragmentation. In NZM mice, RNA and protein levels of PKCdelta were significantly elevated in AM 14 wk after silica exposure. Therefore, rottlerin was used to reduce apoptosis of AM and evaluate the progress of silica-exacerbated systemic autoimmune disease. Fourteen weeks after silica exposure, NZM mice had increased levels of anti-histone autoantibodies, high proteinuria, and glomerulonephritis. However, silica-instilled mice that also received weekly instillations of rottlerin had significantly lower levels of proteinuria, anti-histone autoantibodies, complement C3, and IgG deposition within the kidney. Weekly instillations of rottlerin in silica-instilled NZM mice also inhibited the upregulation of PKCdelta in AM. Together, these data demonstrate that in vivo treatment with rottlerin significantly decreased the exacerbation of autoimmunity by silica exposure.
Employing purified extracellular matrix (ECM) proteins, i.e. type I, III, IV and V collagens (CI, CIII, CIV, CV), laminin (LM) and fibronectin (FN), as antigen sources we detected autoantibodies to conformational and/or denatured ECM antigens among 34 of 50 sera obtained from Hashimotos thyroiditis (HT) patients and 6 of 51 control sera obtained from non-autoimmune thyroid disease patients and healthy donors (HT sera vs. control sera p=4 x 10-9). Reactivity to conformational antigens, mostly due to autoantibodies of the IgG isotype, was observed in 30/50 HT sera and in 6/51 control sera (p=3.5 x 10-7) and was not always concomitant with that to linear antigens, found in 23/50 HT and in 6/51 control sera (p=1.6 x 10-4). Ultrastructural analysis of skin biopsies obtained from 18 HT patients without symptomatic cutaneous diseases revealed defects of the stratified squamous epithelium basement membrane in 11/18, alterations of the stroma in 13/18 and both basement membrane and stromal defects in 9/18. Interestingly, 13/13 (p=0.012) and 9/11 (p=0.012) patients with stromal and basement membrane defects respectively, exhibited serum antibodies to at least one ECM antigen involved in the organization of the altered tissue compartment. Lastly, 10/18 skin biopsies presented immunoglobulin (Ig) and/or complement (C3) deposits along the cutaneous basement membrane zone (BMZ) or in the papillary dermis and 9/10 sera from the same patients simultaneously showed antibodies to at least one ECM antigen involved in the organization of these two skin compartments. Besides, 8/11 HT patients with basement membrane defects exhibited Ig or C3 deposits along the BMZ. Our findings suggest that autoantibodies to ECM molecules might contribute to the development of asymptomatic extra-thyroid skin diseases in HT patients.