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PubMed2001

The human gC1qR/p32 gene, C1qBP. Genomic organization and promoter analysis.

gC1qR is an ubiquitously expressed cell protein that interacts with the globular heads of C1q (gC1q) and many other ligands. In this study, the 7.8-kilobase pair (kb) human gC1qR/p32 (C1qBP) gene was cloned and found to consist of 6 exons and 5 introns. Analysis of a 1.3-kb DNA fragment at the 5'-flanking region of this gene revealed the presence of multiple TATA, CCAAT, and Sp1 binding sites. Luciferase reporter assays performed in different human cell lines demonstrated that the reporter gene was ubiquitously driven by this 1.3-kb fragment. Subsequent 5' and 3' deletion of this fragment confined promoter elements to within 400 base pairs (bp) upstream of the translational start site. Because the removal of the 8-bp consensus TATATATA at -399 to -406 and CCAAT at -410 to -414 did not significantly affect the transcription efficiency of the promoter, GC-rich sequences between this TATA box and the translation start site may be very important for the promoter activity of the C1qBP gene. One of seven GC-rich sequences in this region binds specifically to PANC-1 nuclear extracts, and the transcription factor Sp1 was shown to bind to this GC-rich sequence by the supershift assay. Primer extension analysis mapped three major transcription start regions. The farthest transcription start site is 49 bp upstream of the ATG translation initiation codon and is in close proximity of the specific SP1 binding site.

3' Untranslated Regions↗
PubMed1986

Serum levels of lactoferrin and myeloperoxidase in chronic idiopathic and secondary neutropenia. A preliminary report.

In 20 patients with chronic neutropenia, serum lactoferrin (S-LF) and serum myeloperoxidase (S-MPO) levels were assessed. By immunofluorescence, granulocyte-bound immunoglobulins were detected in 12 patients, whereas circulating immune complexes were found in the blood of 8 patients by the 125-I-C1q-binding test (C1q-BT). In both groups of patients, there was a relative increase of S-LF and a relative or sometimes absolute increase of S-MPO. In the latter group, results of the C1q-BT correlated positively with S-MPO but negatively with neutrophil counts. No correlations between S-LF or S-MPO and the results of the granulocyte immunofluorescence test were found. Our results suggest that S-LF and S-MPO levels may be helpful in the further study of patients with chronic neutropenia, to gain more insight into the pathogenetic mechanisms operative in this disease.

Agranulocytosis↗
PubMed1986

Circulating immune complexes in the sera and ascites of hepatocellular carcinoma or chronic hepatitis patients.

Circulating immune complexes (CIC) in the sera or ascites of hepatocellular carcinoma (HCC), chronic hepatitis patients and normal healthy persons were measured by polyethylene glycol (PEG) and C1q solid-phase microassay (C1q-SPMA). Both the PEG and C1q-SPMA methods showed the serum CIC levels of HCC patients were significantly higher than those of chronic hepatitis patients and of normal persons. The CIC levels of chronic hepatitis patients were also significantly higher than those of normal persons as detected by PEG method but not by C1q-SPMA. The ascites from HCC patients also had CIC. But the amount of CIC in ascites was significantly lower than those of the serum from the same HCC patients. These results suggest that the increase of CIC may play some pathological role in the HCC patients.

Analysis of Variance↗
PubMedDate not supplied

Antibody-dependent enhancement of viral infection: molecular mechanisms and in vivo implications.

Besides the common receptor/coreceptor-dependent mechanism of cellular attachment, some viruses rely on antiviral antibodies for their efficient entry into target cells. This mechanism, known as antibody-dependent enhancement (ADE) of viral infection, depends on the cross-linking of complexes of virus-antibody or virus-activated complement components through interaction with cellular molecules such as Fc receptors or complement receptors, leading to enhanced infection of susceptible cells. Recent studies have suggested that additional mechanisms underlie ADE: involvement of complement component C1q and its receptor (Ebola virus), antibody-mediated modulation of the interaction between viral protein and its coreceptor (human immunodeficiency virus) and suppression of cellular antiviral genes by the replication of viruses entering cells via ADE (Ross River virus). Since ADE is exploited by a variety of viruses and has been associated with disease exacerbation, it may have broad relevance to the pathogenesis of viral infection and antiviral strategies.

Animals↗
PubMed1989

[A method of isolating C1q from human serum and its use in the solid-phase immunoenzyme determination of immune complexes].

C1q was isolated from human serum by dialysis in 0.24 M EDTA, followed by affinity chromatography on immobilized IgG and removal of IgG traces in a column with anti-IgG antibodies. Microplates were coated with C1q in PBS at 10-20 mg/l, nonspecific binding sites were saturated with human serum albumin. The sera were diluted 16-fold in 0.05 M PBS, 0.01 M EDTA, 0.05% Tween. After incubation with diluted samples the plates were treated with horseradish peroxidase--anti-human IgG conjugates. Enzymic activity was measured by adding p-phenylenediamine (0.2 g/l) in acetate buffer, pH 5.9, containing 0.05% H2O2. The sensitivity of the assay ranged between 2.5 and 300 mg/l.

Antigen-Antibody Complex↗
PubMedDate not supplied

[Specificity, sensitivity and reproducibility of 2 methods of determining serum immunocomplexes (solid-phase C1q and polyethylene glycol precipitation)].

In the last years a few tests for the detection of circulating immune complexes (CIC) have been published. Nevertheless the data concerning their sensitivity and reproductibility are often partial. The Authors have here analysed, following this point of view, two methods for the detection of CIC, based on different mechanisms and therefore able to identify different kinds of CIC; the tests are: the PEG precipitation test and the C1q solid phase method. The reproductibility of the two methods is good, even when the samples have been many times thawn or kept at 20 degrees C for a few weeks; C1q test sensibility appears distinctly better than PEG test sensibility. By the two methods, but particularly with the PEG, it is possible to identify fluctuation of the IC levels during the day. The contemporaneous use of these two techniques can give results really useful to clinically monitorize some immune complexes diseases, such as many human glomerulonephrites.

Antigen-Antibody Complex↗
PubMed1984

Fc receptors on granulocytes from patients with rheumatoid arthritis and Felty's syndrome.

Receptors for the Fc part of IgG on polymorphonuclear cells (FcR) of patients with rheumatoid arthritis (RA), Felty's syndrome (FS) and healthy controls (HC) were studied by means of a rosetting technique with rabbit IgG coated ox erythrocytes. When cold isolated polymorphonuclear cells (PMN) were incubated at room temperature the percentage of rosette forming PMN (RF-PMN) from HC was more than twice that measured directly after isolation at 4 degrees C. The same phenomenon was observed for PMN from patients with RA although the RF-PMN increased by only 1/3. In contrast warming of PMN from patients with FS did not influence the RF-PMN. The presence of surface bound immunoglobulins and intracytoplasmic immunoglobulins was measured by immunofluorescence and appeared to be inversely related to the RF-PMN. A good correlation between the results of the C1q binding assay (C1qBA) and the immunofluorescence score was observed but no correlation existed between the C1qBA and the RF-PMN. These results indicate that the number of PMN expressing FcR in patients with RA and FS is decreased presumably because of the phagocytosis of immune complex like material. The decrease in the availability of FcR may influence the functions of the PMN.

Antigen-Antibody Complex↗
PubMed1981

Loss of suppressor T cell function and circulating immune complexes in chronic active liver diseases.

Suppressor T cell function is decreased in patients with chronic active liver diseases (CALD). To account for the alterations, we examined the effect of sera of patients with various liver diseases on concanavalin A (Con A) induced suppressor T cell activity of normal individuals. The suppressor T cell activity was inhibited by heat-inactivated serum pretreatment in 13 of 27 cases of patients with CALD and in five of 11 cases of patients with acute viral hepatitis, whereas only two sera of 18 patients with other liver diseases affected suppressor cell activity. Using a 125I-C1q-binding test, a significant correlation (P less than 0.01) was detected between the degree of inhibition in the development of suppressor T cells and the level of circulating immune complexes in the sera of CALD patients. The blocking effect of patients' sera disappeared when the immune complexes were removed with polyethylene glycol. These data suggest that circulating immune complexes modulate cellular immunity in patients with CALD by influencing the suppressor T cell function.

Adult↗
PubMed1999

Hypocomplementemic urticarial vasculitis or systemic lupus erythematosus?

The 2 patients presented here showed the typical signs of hypocomplementemic urticarial vasculitis syndrome (HUVS). During follow-up, there was an inverse correlation between anti-C1q autoantibody titer and C1q antigen concentration in serum in both patients over a period of 2 years. The first patient had nephritis characterized by immune deposits in glomeruli and around the tubules. The histological findings, C1q deposits, and presence of tubuloreticular inclusions in capillary endothelial cells suggested a disease process identical to systemic lupus erythematosus (SLE). The second patient, after a lag phase of 2 years, fulfilled a fourth American College of Rheumatology criteria for SLE when she developed anti-double-stranded DNA antibodies. HUVS and SLE overlap, and the criteria for identifying HUVS as an entity distinct from SLE are lacking.

Adult↗
PubMed2006

Comparison of biological activity among nonfucosylated therapeutic IgG1 antibodies with three different N-linked Fc oligosaccharides: the high-mannose, hybrid, and complex types.

The structure of asparagine-linked oligosaccharides attached to the antibody constant region (Fc) of human immunoglobulin G1 (IgG1) has been shown to affect the pharmacokinetics and antibody effector functions of antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). However, it is still unclear how differences in the N-linked oligosaccharide structures impact the biological activities of antibodies, especially those lacking core fucose. Here, we succeeded in generating core fucose-lacking human IgG1 antibodies with three different N-linked Fc oligosaccharides, namely, a high-mannose, hybrid, and complex type, using the same producing clone, and compared their activities. Cultivation of an alpha-1,6-fucosyltransferase (FUT8) knockout Chinese hamster ovary cell line in the presence or absence of a glycosidase inhibitor (either swainsonine or kifunensine) yielded antibody production of each of the three types without contamination by the others. Two of three types of nonnaturally occurring atypical oligosaccharide IgG1, except the complex type, reduced the affinity for both human lymphocyte receptor IIIa (FcgammaRIIIa) and the C1q component of the complement, resulting in reduction of ADCC and CDC. The bulky structure of the nonreducing end of N-linked Fc oligosaccharides is considered to contribute the CDC change, whereas the structural change in the reducing end, i.e. the removal of core fucose, causes ADCC enhancement through improved FcgammaRIIIa binding. In the pharmacokinetic profile, although no significant difference of human neonatal Fc receptor (FcRn)-binding affinity was observed among the three types, the complex type showed longer serum half-lives than the other types irrespective of core fucosylation in mice, which also suggests the contribution of the nonreducing end structure. The present study provides basic information on the effects of core fucose-lacking N-linked Fc oligosaccharides on antibody biological activities.

Animals↗
PubMed1984

The role of circulating immune complexes in the aetiology of polymorphic eruption of pregnancy.

Circulating immune complexes were measured in 35 patients with polymorphic eruption of pregnancy employing three different techniques. No significant abnormalities were detected by the C1q solid phase binding assay and polyethylene glycol precipitation of immunoglobulin G. However, using a solid phase polyclonal rheumatoid factor binding assay, which detects small immune complexes, we demonstrated a significant reduction in the level of circulating immune complexes during the acute stage of the eruption. We suggest that the leakage of small immune complexes through dilated upper dermal vessels may play a role in the aetiology of polymorphic eruption of pregnancy.

Antigen-Antibody Complex↗
PubMed1991

Antibodies to dietary antigens in rheumatoid arthritis--possible molecular mimicry mechanism.

Antibodies in serum from some patients with rheumatoid arthritis, recognize bovine albumin present in the milk, as determined by immunoprecipitation analysis from 125I-milk extracts. This antigen was also immunoprecipitated from bovine sera. These and ELISA studies showed that BSA is preferentially recognized over other proteins present in the milk. Panel studies demonstrated that although the average reactivity for BSA was high, only one third of the sera tested displayed a reactivity above the mean. The possibility of a molecular mimicry mechanism in RA between this food antigen and other human antigens was investigated. A sequence alignment analysis showed that the residues 141-157 of bovine albumin significantly differed from the corresponding fragment of human albumin, but were highly homologous with human collagen type I, C1q and vitamin D binding protein. In support of the immunogenicity of this fragment, we found that representative RA sera displayed a specific reactivity for a synthetic peptide containing the BSA residues responsible for the homology. Furthermore, most of the epitopes recognized on BSA by the RA sera seem to be conformationally dependent as heat denaturation or reduction followed by alkylation lead to a diminished recognition.

Amino Acid Sequence↗
PubMed1991

Circulating immune complexes correlate with remission duration in acute myeloid leukemia.

It has been suggested that circulating immune complexes (CIC) favor tumor progression by suppressing the host's immune response to malignant cells via blocking factors to cell-mediated cytotoxicity. We prospectively measured CIC by the C1q binding assay in 100 untreated patients with acute myeloid leukemia (AML) de novo. The median CIC level was 135, the range 0-1000, and the mean +/- standard error (SE) 175 +/- 18 micrograms/ml. Sixty-eight patients, termed abnormal, had C1q binding levels greater than 2SE above the mean of the normal population (61 +/- 15 micrograms/ml). There were no significant differences between the 32 patients with normal CIC and the 68 with abnormally elevated CIC in any pretreatment characteristic: gender, age, white blood cell count (WBC), platelets, leukemia cell mass, LDH, immunoglobulins, or fibrinogen. Abnormal CIC levels did not correlate with FAB morphology, the presence of a clonal chromosomal abnormality (76% of all patients), or with specific cytogenetic subgroups, although nine of 11 patients with acute promyelocytic leukemia and t(15;17) had abnormal CIC. There were no significant differences in complete remission (CR) rates after the first chemotherapy course (45 vs 40% for normal vs abnormal CIC) or after all courses of treatment (55 vs 65%). Survival from diagnosis was not significantly different for the normal and abnormal groups (9.3 vs 5.8 months, p = 0.24), but survival after achieving a CR was markedly longer for those with normal pretreatment CIC (33.8 vs 11.7 months, p = 0.0068). Pretreatment CIC strongly correlated with remission duration for the 59 patients who achieved CR (16.5 months for 17 normal patients vs 6.9 months for 42 abnormal patients, p = 0.0002). This was independent of age, WBC, leukemia cell mass, or FAB morphology. Within the lowest C1q quartile (less than 60 micrograms/ml), 43% of the patients have not relapsed with a minimum follow-up of 18 months compared to only 6-14% for the three higher quartiles. We conclude that host immunity as assessed by CIC levels has little effect on the initial response to therapy but may play a role in maintaining remission in AML.

Adolescent↗
PubMed2006

ATP-binding cassette transporter A7 enhances phagocytosis of apoptotic cells and associated ERK signaling in macrophages.

The mammalian ATP-binding cassette transporters A1 and A7 (ABCA1 and -A7) show sequence similarity to CED-7, a Caenorhabditis elegans gene that mediates the clearance of apoptotic cells. Using RNA interference or gene targeting, we show that knock down of macrophage ABCA7 but not -A1 results in defective engulfment of apoptotic cells. In response to apoptotic cells, ABCA7 moves to the macrophage cell surface and colocalizes with the low-density lipoprotein receptor-related protein 1 (LRP1) in phagocytic cups. The cell surface localization of ABCA7 and LRP1 is defective in ABCA7-deficient cells. C1q is an opsonin of apoptotic cells that acts via phagocyte LRP1 to induce extracellular signal-regulated kinase (ERK) signaling. We show that ERK signaling is required for phagocytosis of apoptotic cells and that ERK phosphorylation in response to apoptotic cells or C1q is defective in ABCA7-deficient cells. These studies reveal a major role of ABCA7 and not -A1 in the clearance of apoptotic cells and therefore suggest that ABCA7 is an authentic orthologue of CED-7.

ATP Binding Cassette Transporter 1↗
PubMed1983

Localised immune complexes and slipped upper femoral epiphysis.

Slipped upper femoral epiphysis remains a disease of unknown aetiology. Recent evidence has bolstered speculation that the immune system may play a role in the aetiology or pathogenesis of slipped epiphysis or of one of its complications, chondrolysis. This study reports the finding of immune complexes in the synovial fluid of all but one hip affected with slipped epiphysis in a consecutive series. In seven patients, immune complexes were detected by both the Raji cell assay and C1q-binding assay; in two, by the C1q-assay only; and in one, by the Raji cell assay only. No patients had immune complexes in the serum. Twenty-one patients with synovitis of the knee or hip caused by a variety of disorders served as the control group. Two of these patients had immune complexes in their synovial fluid. It appears that the immune complexes characterise the synovitis found with slipped upper femoral epiphysis as distinct from most other synovitides.

Adolescent↗
PubMed1982

Circulating immune complexes in rheumatoid arthritis. Selective removal by cryogelation with membrane filtration.

We have developed a system of extracorporeal circulation that removes proteins of the molecular weight of the circulating immune complexes of rheumatoid arthritis by cryogelation with hollow-fiber membrane filtration. A 52-year-old woman with a 36-year history of severe, unremitting, high-titer, seropositive rheumatoid arthritis who had failed to respond to anti-inflammatory, antirheumatic, and cytotoxic drugs was chosen for a trial of this system. A rapid and sustained decrease in circulating immune complexes as measured by C1q binding occurred, accompanied by a much slower improvement in clinical factors of disease activity. Rheumatoid factor changed very little and loss of other serum proteins by the procedure was relatively modest. This new procedure was successful in removing circulating immune complexes in a patient with rheumatoid arthritis, and in inducing a remission in one who has not had such in 36 years, while sparing volume and other plasma proteins.

Antigen-Antibody Complex↗
PubMed1983

Acute effects of steroids on immune complex profile of patients with systemic lupus erythematosus. Correlation of profile with development of target organ involvement.

Eleven patients with active systemic lupus erythematosus, previously untreated, were studied to 1) determine the acute effect of corticosteroids on circulating immune complex (CIC) levels and 2) correlate the initial CIC profile with the development of organ system involvement. Using serial measurements of CIC as detected by assays for cryoglobulins and binding to C1q, Raji cells, and rheumatoid factor, we found that levels of CIC change little during the first month of high dose daily steroid therapy, but they uniformly decrease to near normal by 6 to 12 months. High levels of CIC detected by Raji cell assay early in the course of systemic lupus erythematosus and before steroid therapy appear to be predictive of the development of chronic lupus nephritis (P less than 0.005).

Adult↗
PubMed1993

Amyloid P component and other acute-phase proteins associated with cerebellar A beta-deposits in Alzheimer's disease.

It is established that amyloid P (AP) component and complement proteins are associated with amyloid beta (A beta)-protein deposits in the cerebral cortex of Alzheimer's disease (AD) subjects. Here, we used immunocytochemical methods to examine the association of these acute-phase proteins with the characteristic diffuse plaques of cerebellum in AD. We observed AP and complement C3d, C1q, C5 and C4bp immunoreactivities in most A beta-protein-reactive plaques of the cerebellum. Further, a1-antichymotrypsin immunoreactivity was apparent in at least 60% of all the cerebellar diffuse plaques examined. Cerebellar tissue bearing the A beta-protein deposits also often exhibited marked angiopathy in the pial vessels. We suggest that diffuse plaques of the cerebellum also acquire components of the chronic inflammatory response evident in neocortical plaques.

Acute-Phase Proteins↗