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PubMed1981

Circulating immune complexes in Behçet's syndrome: purification, characterization and cross-reactivity studies.

The C1q-binding assay was performed on 30 sera from patients with Behçet's syndrome and circulating immune complexes were found in 46%. Circulating immune complexes were isolated and purified from the sera of two patients by immunoadsorption on a column of polymethylmetacrylate beads coated with C1q and then labelled with 125I. In double immunodiffusion these purified immune complexes were found to contain IgG, C1q, C1s and C3. Anti-IgG activity was not detectable in the purified immune complexes while specific cross-reactivity was found in a solid-phase radioimmunoassay with the majority of the sera of behçet's syndrome.

Antigen-Antibody Complex↗

PubMed1990

Immunoalkaline phosphatase technique applied to paraffin wax embedded tissues in diagnostic renal pathology.

An indirect immunoalkaline phosphatase (IAP) technique was used to evaluate the glomerular deposition of immunoglobulins, C3, C1q and fibrinogen. In 80 renal biopsy specimens the results obtained using this technique were compared with those obtained by direct immunofluorescence to see if it could be used as a viable alternative. The IAP technique was straightforward to perform, it yielded quick results, and was highly reproducible, provided that a standardised short fixation period of two and a half hours was used. For the detection of immunoglobulin deposits, the IAP results correlated well with those of immunofluorescence. Despite poorer performance in identifying complement components and fibrinogen it could, within certain limits, provide an adequate diagnostic alternative to immunofluorescence. Each technique gave false negative results, those of immunofluorescence being related to its failure to identify mesangial deposition of IgA in two cases where its distribution seemed to be focal, and those of IAP to a failure to detect linear deposition of IgG in all three cases of anti-glomerular basement membrane disease.

Alkaline Phosphatase↗

PubMed1984

Circulating immune complexes in regularly dialyzed patients with chronic renal failure.

The prevalence of circulating immune complexes (CIC) was investigated using the C1q binding assay (C1q BA) and the conglutinin binding assay (Kg BA) in 200 patients undergoing maintenance hemodialysis. Increased C1q binding was found in 45% (87 of 194) of the patients, and the modified Kg BA gave elevated values in 31% (20 of 65). The prevalence of CIC was similar in American and Swiss patients, and in patients undergoing hemodialysis, self-dialysis or peritoneal dialysis. In patients with 'nonimmunological' renal diseases, CIC were detected with similar frequency. No change in CIC was noted during hemodialysis in 6 additional patients tested. The abnormality was not related to age, sex, duration of dialysis, hepatitis B antigenemia, bacterial infections, or transfusions. Anti-DNA antibodies were absent in all subjects tested and the results of the C1q BA were not changed by DNase digestion of eight sera with high C1q binding. Rheumatoid factor activity (RF) was detected in approximately one-fifth of the patients, and there was a direct correlation between positive C1q binding and RF. There was no correlation between CIC and lymphocytotoxic antibodies. This study demonstrated a high prevalence of CIC in dialyzed uremic patients and established its relationship to other immunological abnormalities.

Antibodies, Antinuclear↗

PubMed1984

Antibody-independent C1 activation by E. coli.

Antibody-independent interactions of C1 with several E. coli strains were examined. Purified C1 was directly activated by the semi-rough mutant E. coli J-5, its parental wild-type strain, E. coli 0111:B4, and two clinical isolates, E. coli (P) and E. coli (A), in the absence of C1 inhibitor. E. coli J-5 activated C1 about 10-fold more rapidly and bound approximately threefold more C1 than the other strains. E. coli J-5, but not the other strains, also bound C1s2, provided that the subcomponent was offered to the bacteria in the presence of C1q and calcium; such binding was thus independent of the presence or absence of C1r2. After C1 activation in the absence of C1 inhibitor, activated C1s spontaneously dissociated from E. coli 0111:B4, (P), and (A), but remained associated with E. coli J-5. The regulatory protein C1 inhibitor prevented C1 activation by the weaker activators, E. coli strains 0111:B4, (P), and (A), but had no effect on C1 activation by E. coli J-5. Although C1 inhibitor thus failed to modulate C1 activation by E. coli J-5, it did block the enzymatic activity of activated C1 bound to this strain. Analyses of the molecular processes involved revealed differences with other systems. In the presence of C1 inhibitor, the C1s subunit of C1 activated by E. coli J-5 underwent further cleavage with the release into the supernatant of C1s fragments and complexes of C1 inhibitor with light chain fragments. Such fragments were not disulfide-linked to the remainder of the C1s molecule. The bulk of the heavy chain remained adherent to the surface of E. coli J-5. This finding documents the presence of a binding site for activated C1s on the surface of E. coli J-5 and localizes this site to the heavy chain. These studies thus indicate that several E. coli strains are direct C1 activators. Furthermore, E. coli J-5 provides another example of a direct C1 activator having binding sites not only for C1q but also for dimeric C1s. The studies also show that there are multiple properties of particles which determine the ability to activate C1, the rate of activation, the possibility of regulation of the activation process by C1 inhibitor, and the fate of activated C1.

Antibodies, Bacterial↗

PubMed1988

Glomerular annular-tubular immune deposits in adult hemolytic uremic syndrome.

An 82-year-old female developed hemolytic uremic syndrome (HUS) after a prodromal illness of bloody diarrhea. No specific enteric pathogen was isolated. A renal biopsy performed 5 days after the onset of azotemia revealed typical thrombotic microangiopathy. By electron microscopy, massive annular-tubular deposits admixed with fibrillar fibrin were demonstrated in glomerular capillaries. Immunofluorescent staining of the intracapillary material was positive for IgG, IgM, C3, C1q and fibrin-related antigens. No evidence of plasma cell dyscrasia, cryoglobulinemia or systemic lupus erythematosus was found, and the patient recovered renal function uneventfully in 2 months. Organized immune deposits appear to have played a role in the pathogenesis of HUS in this patient.

Aged↗

PubMed1996

Autoantibodies to the collagenous region of C1q occur in three strains of lupus-prone mice.

We have developed an ELISA to measure murine autoantibodies to the collagenous region (CLR) of C1q, using the whole human C1q molecule as the solid-phase ligand, in the presence of 1 M NaCl. The assay was validated by testing positive sera from 20 mice using purified mouse C1q, and from 10 mice using purified human C1q-CLR, as the solid-phase ligands. There were highly significant correlations between results obtained with human C1q (whole molecule) and: (i) mouse C1q (rsp = 0.73, P less than 0.001), and (ii) human Clq-CLR alone (rsp = 0.86, P = 0.001). Antibodies to Clq were measured in 53 MRL/lpr, 17 BXSB and 25 NZB/W lupus-prone mice. Median (range) anti-C1q (CLR) antibody levels in MRL/lpr, BXSB, and NZB/W autoimmune mice aged 3 months were 22 (16-66), 21 (17-39) and 19 (15-27) EU, respectively. The median anti-Clq antibody level in MRL/lpr mice aged 5 months was 76 (35-142) EU, significantly higher than that at 3 months (U = 558, P less than 0.0005). Median anti-C1q antibody level in NZB/W mice at 8 months was 37 (13-74) EU and in BXSB mice at 11 months was 62 (31-231) EU, significantly higher than corresponding values at 3 months (U = 326, and U = 4, P less than 0.001, respectively). This is the first demonstration of anti-C1q (CLR) antibodies in NZB/W and BXSB mice. The pathologic significance and the potential utility of these antibodies for monitoring disease in lupus-prone mice are under evaluation.

Aging↗

PubMed1983

Relative importance of C4 binding protein in the modulation of the classical pathway C3 convertase in patients with systemic lupus erythematosus.

Serum concentrations of C1q, C4, C4 binding protein (C4bp), C3 and C2 haemolytic activity have been measured in 110 samples from 20 patients with systemic lupus erythematosus (SLE). Significant reductions in comparison to normal levels were found in the mean serum concentrations of C4, C3 and C4bp as well as C2 haemolytic activities. For patients serum concentrations of C4 correlated with C2 haemolytic activities (r = 0.91) and C4bp (r = 0.79); the C2 haemolytic levels correlated with the concentration of C4b (r = 0.72). It is concluded that serum concentrations of the complement components C4 and C2, which are the constituents of the classical pathway C3 convertase, are regulated by C4bp in vivo. Further metabolic studies are required to determine the causes of decreased serum concentrations of C4bp in patients with SLE.

Carrier Proteins↗

PubMed1989

Models for C1. Tools or toys? The real biological challenge.

C1 modelling, based on structural and functional data, does not yet bring the different laboratories to a consensus on C1 activation, activity and associated controls. The heart of C1 beats in its subcomponent C1r2, which, from its domain structure and its twinning with subcomponent C1s, represents the challenge for the knowledge of C1. The 8-shaped model proposed for the C1r2-C1s2 association, with a head-to-tail interaction between the C1r catalytic domains, appears as the hub of an active world in the bosom of C1q. More detail is now required on protein-protein interactions inside C1 to refine the available models or to propose alternatives. Precise data on the interactions of C1 proteins with activators, substrates or control proteins are also likely to bring pertinent help in proposing future models for C1.

Binding Sites↗

PubMed1986

Erythema multiforme: a possible pathogenetic role of increased reactive oxygen species.

Recently, it has been suggested that reactive oxygen species (ROS) produced by activated polymorphonuclear leukocytes (PMNs) exert auto-oxidative tissue damage at the site of inflammation. In the present study, a possible role of ROS in the pathogenesis of erythema multiforme (EM) was investigated by determining the capacity of the sera from patients for generating ROS from PMNs. Significantly increased hydroxyl radical production was observed, which is one of the most potent ROS capable of causing tissue damage. This change was not observed when PMNs were incubated with sera from patients with bullous pemphigoid (BP) or inflammatory acne, indicating that this finding was not a common feature of immunologically mediated and/or inflammatory cutaneous disorders. Elevated C1q activities and depositions of immunoreactants in the blood vessels were also noticed in some patients. These findings suggest that ROS generated by PMNs are involved in the formation of cutaneous lesions of EM and that immune complexes (ICs) may provide an important mechanism in PMN activation.

Adult↗

PubMed1995

Chronic discoid lupus erythematosus: an immunopathological and electron microscopic study.

We studied 100 cases of chronic cutaneous discoid lupus erythematosus (DLE) to evaluate the diagnostic sensitivity of immunoreactant deposition and its possible role in basement membrane thickening. Histopathology was diagnostic in 71% of cases. Sixty-two percent (41/66) of lesions with thickened and 50% (17/34) with normal basement membrane had immunoreactant deposition. Ultrastructural study of 6 cases (3 with and 3 without immunoreactant deposition) with thickened basement membrane all showed reduplication of the lamina densa. Thickening of the basement membrane appears to be contributed mainly by reduplication of the lamina densa rather than by immunoreactant deposition. The direct immunofluorescence (DIF) test of lesional skin was positive in 58% of patients and was independent of duration of lesion, age and sex. Light microscopy has greater diagnostic sensitivity in confirming DLE lesions than DIF. Direct salt split skin technique did not increase DIF sensitivity. Scalp lesions showed the highest frequency (83%) of immunoreactant deposition. As C1q was the commonest immunoreactant found in our study, we suggest that it should be routinely used when DIF is employed in the evaluation of DLE. DIF is especially helpful in confirming cicatricial alopecia due to DLE.

Adolescent↗

PubMed1981

Association of retroperitoneal fibrosis and interstitial nephritis.

A patient with renal failure and light-chain proteinuria showed roentgenographic evidence of retroperitoneal fibrosis on further examination. Diffuse hyperglobulinemia, low levels of C3 and C4, and elevated C1q binding were noted. Biopsy specimens of the kidney and retroperitoneal tissue disclosed a dense pleomorphic cellular infiltrate with a preponderance of plasma cells. Renal function improved slowly after ureterolysis and institution of prednisone therapy. The case emphasizes the immunologic features of the early phase of idiopathic retroperitoneal fibrosis.

Aged↗

PubMed2000

Sequential determination of ligands binding to discrete components in heterogeneous mixtures by iterative panning and blocking (IPAB).

Biopanning has been used extensively in conjunction with purified components, but there are also examples in which mixtures of targets have been investigated. This study introduces a methodological innovation, termed iterative panning and blocking (IPAB), to extend the range of specific interactions that can be probed in mixtures. Here this procedure is used to probe a mixture of high molecular mass components of human cord blood with phage-peptide display libraries. The initial panning recovered phage that bore the consensus motif Gly-Pro-Arg-Pro, a known fibrinogen-binding motif. These phage bound specifically to purified fibrinogen. A series of peptides containing the Gly-Pro-Arg-Pro motif efficiently blocked the binding of phage having the same motif, presumably by binding to their common target. A second round of panning was performed against the same target mixture in the presence of this blocking peptide. Phage recovered from this second panning exhibited a motif (Ser-His-Tyr) that was subsequently shown to bind specifically to complement component C1q. A second peptide containing this motif specifically blocked the interaction of the phage with C1q. A third round of panning performed in the presence of both the fibrinogen- and the C1q- blocking peptides yielded phage with a new peptide motif (Asn-Pro-Phe) that also bound specifically to C1q, apparently at a new site. The three motifs isolated through this iterative process were distinct in that each was blocked only by its corresponding peptide. This IPAB strategy can be applied to many high diversity selection procedures that target complex mixtures.

Amino Acid Motifs↗

PubMed1999

Surfactant proteins A and D specifically stimulate directed actin-based responses in alveolar macrophages.

Surfactant protein (SP) A and SP-D are the pulmonary members of the collectin family, structurally related proteins involved in innate immune responses. Here, we have examined the abilities of SP-A, SP-D, mannose-binding protein (MBP), and the complement component C1q to stimulate actin-based cellular functions in rat alveolar macrophages and peripheral blood monocytes. Our goal in this study was to examine the cell specificity of the effects of the collectins to understand further the mechanisms by which SP-A and SP-D stimulate alveolar macrophages. We found that SP-A and SP-D have lung cell-specific effects at physiologically relevant concentrations; they stimulate directional actin polymerization and chemotaxis in alveolar macrophages but not in monocytes. Although C1q and MBP weakly stimulate the rearrangement of actin in both cell types, C1q is chemotactic only for peripheral blood monocytes and MBP does not stimulate chemotaxis of either cell type. Neither C1q nor MBP stimulates actin polymerization in alveolar macrophages. These results support the hypothesis that alveolar macrophages express receptors specific for the pulmonary collectins SP-A and SP-D and provide insight into the potential roles of collectins in the recruitment and maturation of mononuclear phagocytes in the lung.

Actins↗

PubMed2001

Anti-C1q antibodies may help in diagnosing a renal flare in lupus nephritis.

It is still uncertain which, if any, immunologic parameters may help diagnose a renal flare of lupus nephritis. Anti-C1q antibody (Ab) titers have been elevated in patients with lupus with renal involvement, but little information is available on whether the titers are different in quiescent and active phases of lupus nephritis. In this study, we compared anti-C1q Ab titers with other serological test results in 48 patients with biopsy-proven lupus nephritis to assess which parameter could offer the best reliability for differentiating between quiescent and active phases of lupus nephritis. Serum C3 and C4 levels, as well as anti-double-stranded DNA, antiendothelial cell, anti-C1q, and antiphospholipid Ab titers, were evaluated in patients with quiescent renal disease (38 samples) and those with clinical evidence of renal activity (23 samples). Only anti-C1q Ab titers correlated with active renal disease in both univariate (P < 0.0001) and multivariate analysis (P < 0.0001), with a sensitivity of 87% and a specificity of 92%. In six patients, immunologic parameters were measured serially. In all patients, the high anti-C1q Ab titers returned to normal values after treatment-induced remission. The other serological parameters did not show a significant association with renal disease activity. In patients with biopsy-proven lupus nephritis, anti-C1q Ab titers appear to be strongly related to renal disease activity. Their measurement may be useful for confirming the diagnosis of renal flares of lupus nephritis.

Adult↗

PubMed1999

Cutting edge: C1q protects against the development of glomerulonephritis independently of C3 activation.

C1q-deficient (C1qa-/-) mice develop antinuclear Abs and glomerulonephritis (GN) characterized by multiple apoptotic bodies. To explore the contribution of C3 activation to the induction of spontaneous GN, C1qa-/- mice were crossed with factor B- and C2-deficient (H2-Bf/C2-/-) mice. GN was present in 64% of the 45 C1qa/H2-Bf/C2-/- mice compared with 8% of the 65 H2-Bf/C2-/- mice and none of the 24 wild-type controls. IgG was detected in the glomeruli of diseased C1qa/H2-Bf/C2-/- kidneys. However, glomerular staining for C3 was absent. Increased numbers of glomerular apoptotic bodies were detected in undiseased C1qa/H2-Bf/C2-/- kidneys. These findings support the hypothesis that C1q may play a role in the clearance of apoptotic cells without the necessity for C3 activation and demonstrate that the activation of C3 is not essential for the development of GN in this spontaneous model of lupus-like disease.

Animals↗

PubMed1996

Eukaryotic expression of recombinant biglycan. Post-translational processing and the importance of secondary structure for biological activity.

Biglycan is a small chondroitin sulfate proteoglycan found in many tissues and is structurally related to decorin, fibromodulin, and lumican. The biological function of biglycan is poorly understood, although several studies have indicated interaction with other extracellular matrix components. We have initiated studies of structural and functional domains of biglycan by transient eukaryotic expression using the vaccinia virus/T7 bacteriophage expression system. A recombinant vaccinia virus, vBGN4 encoding the mature biglycan core protein as a polyhistidine fusion protein under control of the T7 phage promoter was expressed in HT-1080 cells and UMR106 cells. The structure of the recombinant biglycan secreted by these cells was defined by analyzing molecules labeled in the presence of [35S]sulfate, [3H]glucosamine, and [35S]methionine. Glycoforms of biglycan were separated by imidazole gradient elution, under non-denaturing conditions, and comprised: a large proteoglycan form substituted with two chondroitin sulfate chains of molecular mass approximately 34 kDa (HT-1080 cells) or approximately 40 kDa (UMR106 cells); a small proteoglycan form substituted with two chondroitin sulfate chains with a median molecular mass approximately 28 kDa; and a core protein form secreted devoid of glycosaminoglycan chains. All the glycoforms were substituted with two N-linked oligosaccharides, and the disaccharide composition of the two glycosaminoglycan populations were identical. Approximately 70% of the recombinant biglycan secreted by HT-1080 cells was substituted with chondroitin sulfate chains, whereas about 50% of the biglycan expressed by UMR106 cells was substituted with chondroitin sulfate chains. Infection with vBGN4 in both HT-1080 and UMR106 cells resulted in the production of approximately 10 mg of biglycan/10(9) cells per 24 h. The native recombinant biglycan was shown to bind to collagen type V and the complement protein, C1q. However, when the secondary structure of recombinant biglycan was disrupted by exposure to 4 M guanidine hydrochloride, the affinity for collagen type V was dramatically reduced. These data demonstrate the importance of secondary structure to the function of this small proteoglycan.

Amino Acid Sequence↗

PubMed1983

Evaluation and clinical significance of circulating immune complexes after renal transplantation.

Using C1q binding, Kg binding, and Raji cell radioimmunoassays, the relationship between renal allograft rejection and the circulating immune complexes was examined in 90 patients with renal transplants. The data showed that there was a significant quantitative correlation between C1q-binding and Raji-cell-binding activities (Rs = 0.53, P less than 0.001), and that both activities were closely associated with the occurrence of chronic rejection (chi 2 = 45.9-34.1, P less than 0.001). On the other hand, Kg-binding activities were not correlated with C1q-binding or Raji-cell-binding activity (Rs = 0.07-0.17, P greater than 0.1) and a close association was observed with acute rejection episodes (chi 2 = 11.5, P less than 0.001). The results of sucrose density gradient analysis were in keeping with previous findings in that the individual assays detect immune complexes of different compositions: the Raji cell test was shown to measure not only immune complexes but also monomeric IgG. Immunofluorescent studies of the transplant kidney specimens showed that the majority of patients in a state of chronic rejection had glomerular deposits of immunoglobulins and complement--in contrast to negative findings in patients without rejection episodes. All these data indicate that several tests for immune complexes are more informative than the single test for monitoring rejection, and suggest that the appearance of circulating immune complexes after renal allografting is related to the rejection phenomenon.

Antigen-Antibody Complex↗

PubMed1998

C1q as antigen in humoral autoimmune responses.

The observation of anti-C1q antibodies (C1qAb) in patients with various autoimmune diseases has led to the establishment of a strong correlation between these antibodies and renal involvement in patients with systemic lupus erythematosus (SLE). The measurement of anti C1q antibodies requires detailed insight in the reactivity of C1q with immune complexes and the methods to detect C1q as an antigen by solid phase assays. In this overview we describe the pitfulls of the anti C1qAb assay and its use in the measurement of C1qAb. Further we discuss the relevance of C1qAb in the pathogenesis of SLE and especially in relation to lupus nephritis.

Adult↗