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PubMedDate not supplied

Neuroglial-mediated immunoinflammatory responses in Alzheimer's disease: complement activation and therapeutic approaches.

Increasing evidence points to A beta-containing senile plaques as primary etiological agents in Alzheimer's disease (AD). The mechanism by which these deposits cause neurotoxicity is unresolved, but there are compelling data suggesting that the activated glia found associated with senile plaques contribute to the pathology of AD. These cells appear to release a variety of immunoinflammatory molecules, including complement proteins whose activation products colocalize with senile plaques and dystrophic neurites. Previous studies showed that A beta can bind and activate complement protein C1q, providing a plausible explanation for the initiation of the complement cascade in AD. Data presented here further define the nature of A beta-C1q association, revealing key aspects of the C1q domain involved in binding the amyloid peptide. Moreover, we show that it is possible to inhibit A beta-induced complement activation without affecting the normal immunoglobulin-mediated complement pathway. This indicates that it should be feasible to develop drugs to reduce complement damage in AD without compromising this important immune-defense mechanism throughout the body.

Alzheimer Disease↗
PubMed1995

Identification of C1q as the heat-labile serum cofactor required for immune complexes to stimulate endothelial expression of the adhesion molecules E-selectin and intercellular and vascular cell adhesion molecules 1.

To examine the role of complement components as regulators of the expression of endothelial adhesive molecules in response to immune complexes (ICs), we determined whether ICs stimulate both endothelial adhesiveness for leukocytes and expression of E-selectin and intercellular and vascular cell adhesion molecules 1 (ICAM-1 and VCAM-1). We found that ICs [bovine serum albumin (BSA)-anti-BSA] stimulated endothelial cell adhesiveness for added leukocytes in the presence of complement-sufficient normal human serum (NHS) but not in the presence of heat-inactivated serum (HIS) or in tissue culture medium alone. Depletion of complement component C3 or C8 from serum did not prevent enhanced endothelial adhesiveness stimulated by ICs. In contrast, depletion of complement component C1q markedly inhibited IC-stimulated endothelial adhesiveness for leukocytes. When the heat-labile complement component C1q was added to HIS, the capacity of ICs to stimulate endothelial adhesiveness for leukocytes was completely restored. Further evidence for the possible role of C1q in mediating the effect of ICs on endothelial cells was the discovery of the presence of the 100- to 126-kDa C1q-binding protein on the surface of endothelial cells (by cytofluorography) and of message for the 33-kDa C1q receptor in resting endothelial cells (by reverse transcription-PCR). Inhibition of protein synthesis by cycloheximide blocked endothelial adhesiveness for leukocytes stimulated by either interleukin 1 or ICs in the presence of NHS. After stimulation with ICs in the presence of NHS, endothelial cells expressed increased numbers of adhesion molecules (E-selectin, ICAM-1, and VCAM-1). Endothelial expression of adhesion molecules mediated, at least in part, endothelial adhesiveness for leukocytes, since leukocyte adhesion was blocked by monoclonal antibodies directed against E-selectin. These studies show that ICs stimulate endothelial cells to express adhesive proteins for leukocytes in the presence of a heat-labile serum factor. That factor appears to be C1q.

Antigen-Antibody Complex↗
PubMed1980

Interaction between Schistosoma mansoni and the complement system: binding of C1q to schistosomula.

In earlier studies we have found that activation of the classical complement pathway (CCP) by the immature schistosomes involves the presence of IgG. By investigating the first step of this activation we have demonstrated in the present work that binding of C1q to schistosomula can occur by two different routes: 1) directly, by specific C1q receptors, and 2) indirectly through the IgG previously attached to Fc receptors present on the parasite surface. Only this second mechanism appears to be involved in CCP activation by schistosomula. Moreover, certain low m.w. schistosome antigens (less than 20,000), which activate CCP, also directly fixed C1q. In this case, IgG are not required for C activation. The presence of receptors for host protein, essentially in 2- to 3-hr-old schistosomula, i.e., the life stage of Schistosoma mansoni that are first in contact with the host, could be the first mechanism by which the schistosomes evade the immune attack.

Animals↗
PubMedDate not supplied

Complement aberrations in serum from children with otitis due to S. pneumoniae or H. influenzae.

Complement components C1q, C1s, C3, C4, factor B and properdin were measured, together with C1 subcomponent complexes and Cq binding substances in acute and convalescent samples from patients with relapsing and non-relapsing otitis media due to S. pneumoniae and H. influenzae. Analysis of C1 subcomponent complexes together with the finding of low C1q levels gave evidence of a disturbed C1 function in acute OME. Furthermore, complement activation by the classical and by the alternative pathways was demonstrated. Complement aberrations were more pronounced in relapsing otitis than in non-relapsing otitis. C1q binding substances that might possibly cause the complement aberrations found were present in most of the patients.

Acute Disease↗
PubMed2004

Mini-review: A pivotal role for innate immunity in the clearance of apoptotic cells.

Apoptotic cells can be recognized and taken up by both macrophages and dendritic cells. Phagocytosis of apoptotic cells generally leads to active suppression of cytokine production by professional phagocytes. This is different from the response towards cells that die by necrosis, which induce a pro-inflammatory cytokine profile. Uptake of apoptotic cells involves a large number of receptors and opsonins, which bind to cellular ligands exposed during the various stages of apoptotic cell death. Among the opsonins of apoptotic cells, complement factors, including C1q, and complement-activating members of the pentraxin family play an important role. This is indicated by in vitro phagocytosis studies and supported by the susceptibility to systemic autoimmunity of carriers of genetic deficiencies for early complement proteins. The present review summarizes the role of molecules of innate immunity in the handling of apoptotic cells by macrophages and dendritic cells. It is proposed that C1q and other opsonins prevent autoimmunity and maintain self-tolerance by supporting the efficient clearance of apoptotic material, as well as by actively modulating phagocyte function.

Animals↗
PubMed1984

Complement interaction with immune serum globulin and immune globulin intravenous.

Three complement assays, C1q binding activity, C3 activation in normal human serum, and enhancement of alternative pathway activity, have been used to evaluate the in vitro anticomplementary activity of untreated and heat-aggregated (63 degrees C, 10 minutes) immune serum globulin and immune globulin intravenous prepared by partial reduction and alkylation. Unheated immune globulin intravenous marginally activated endogenous C3 in normal serum, had a fivefold lower affinity for 125I C1q but was very similar to immune serum globulin in enhancing complement alternative pathway activity. Heat-aggregated immune globulin intravenous was about twofold less effective than heat-aggregated immune serum globulin in the activation of C3 in normal serum and had approximately a threefold lower affinity for 125I C1q. The ability of immune globulin intravenous to retain specific complement receptor activity suggests that it would also retain in vivo efficacy in complement-mediated amplification of host defense reactions but that it is safe for intravenous use due to a lower capacity to initiate nonspecific complement activation.

Complement Activating Enzymes↗
PubMed2002

Human C1qRp is identical with CD93 and the mNI-11 antigen but does not bind C1q.

It has been suggested that the human C1qRp is a receptor for the complement component C1q; however, there is no direct evidence for an interaction between C1q and C1qRp. In this study, we demonstrate that C1q does not show enhanced binding to C1qRp-transfected cells compared with control cells. Furthermore, a soluble recombinant C1qRp-Fc chimera failed to interact with immobilized C1q. The proposed role of C1qRp in the phagocytic response in vivo is also unsupported in that we demonstrate that this molecule is not expressed by macrophages in a variety of human tissues and the predominant site of expression is on endothelial cells. Studies on the rodent homolog of C1qRp, known as AA4, have suggested that this molecule may function as an intercellular adhesion molecule. Here we show that C1qRp is the Ag recognized by several previously described mAbs, mNI-11 and two anti-CD93 Abs (clones X2 and VIMD2b). Interestingly, mNI-11 (Fab') has been shown to promote monocyte-monocyte and monocyte-endothelial cell adhesive interactions. We produced a recombinant C1qRp-Fc chimera containing the C-type lectin-like domain of C1qRp and found specific binding to vascular endothelial cells in sections of inflamed human tonsil, indicating the presence of a C1qRp ligand at this site. This interaction was Ca(2+) independent and was not blocked by our anti-C1qRp mAb BIIG-4, but was blocked by the proadhesive mAb mNI-11. Collectively, these data indicate that C1qRp is not a receptor for C1q, and they support the emerging role of C1qRp (here renamed CD93) in functions relevant to intercellular adhesion.

Animals↗
PubMed1988

C1q acts synergistically with phorbol dibutyrate to activate CR1-mediated phagocytosis by human mononuclear phagocytes.

The adherence of human monocytes and culture-derived macrophages to surfaces coated with complement subcomponent C1q has been previously shown to enhance Fc receptor (FcR)-mediated phagocytosis by these cells. We examined the effects of C1q on C3b/C4b receptor (CR1)-mediated phagocytosis by mononuclear phagocytes. A small percentage of human monocytes cultured in the presence of serum became competent to ingest sheep erythrocytes bearing IgM and C4b (EAC4b). This phagocytic activity was enhanced when these cultured-derived macrophages were adhered to C1q-coated surfaces. However, when cultured in a defined serum-free medium, these cells did not ingest EAC4b, even in the presence of C1q. To investigate this differential responsiveness, we studied the effects of C1q in conjunction with cell-activating agents on CR1 activation. Treatment of serum-free cultured monocytes with phorbol dibutyrate (PDBu), prior to addition of the targets, induced these cells to ingest EAC4b. In addition, when exposed to C1q, both the percentage of these PDBu mononuclear phagocytes ingesting EAC4b and the number of targets ingested increased threefold over the level achieved by macrophages treated with PDBu alone. The chemoattractant N-formyl-methionyl-leucyl-phenylalanine did not activate CR1-mediated phagocytosis and did not substitute for PDBu in causing synergy with C1q. Freshly isolated monocytes adhered to human serum albumin-coated glass slides in the absence or presence of PDBu did not phagocytose EAC4b. Also C1q did not stimulate monocyte CR1-mediated phagocytosis. However, addition of PDBu to cells adherent to the C1q surface triggered phagocytosis of EAC4b. The concentration of PDBu and the time of addition of PDBu relative to addition of the EAC4b targets were found to be important parameters for the achievement of maximal synergy in both the freshly isolated and cultured cell systems. This enhanced phagocytic activity was also seen with cells adhered to the purified collagen-like, pepsin-resistant, fragment of C1q. Since this region was previously shown to interact with C1q surface receptors, it appears that occupancy of this receptor is triggering events contributing to the enhanced cellular function. These experiments suggest that C1q and PDBu promote ingestion via CR1 by different but synergistic mechanisms. These data also demonstrate that the CR1-mediated enhancement of phagocytosis is not specific for FcR-mediated ingestion, but also applies to phagocytosis via CR1.

Antigen-Antibody Complex↗
PubMed1996

The mouse C1q genes are clustered on chromosome 4 and show conservation of gene organization.

Mouse complement component C1q is a serum glycoprotein which consists of six A chains, six B chains and six C chains. The three polypeptides are 223, 228, and 217 residues long, respectively, and are encoded by three genes. DNA probes for mouse C1q A, B, and C chains were hybridized to Southern blots of DNA obtained from various inbred mouse strains. On the basis of fragment length polymorphisms, two different alleles of each of the genes could be identified. The distribution of these alleles was determined in the BXD and LXPL recombinant inbred strain series. Comparison with previously reported strain distribution patterns shows that the genes encoding mouse C1q map to the same locus on distal chromosome 4. Overlapping clones spanning the entire gene cluster of C1q were isolated from genomic libraries using specific cDNA probes. The three genes C1qA, C1qB, and C1qC are closely arranged on a 19 kilobase stretch of DNA in the 5' to 3' orientation A-C-B. Each gene consists of two exons separated by one intron. Sequence comparison of C1q from three different species have shown that the B chains have the strongest similarity. Southern blot analysis of chromosomal DNA from 14 vertebrate species demonstrated highest similarity between the C1qB genes, followed by C1qC and finally C1qA.

Amino Acid Sequence↗
PubMed1982

[Berger's disease. Study of eleven cases (author's transl)].

Among 39 patients with recurrent hematuria, 11 accomplished criteria of Berger's disease. The frequent association between recurrent hematuria and upper respiratory tract infections as well as constant elevation of serum IgA are emphasized. Their finding as well as the deposition of IgA on the mesangium and C'3 without C1q and C'4 suggest an alternative activation of the complement system which could explain the role of the IgA in the pathogenesis of Berger's disease. The disease can begin as acute glomerulonephritis and occasionally as a nephrotic syndrome, and its' prognosis is generally good in most instances.

Child↗
PubMed1996

Role of C1q in Rhesus haemolytic disease of the newborn.

Present study attempts to find out if maternal anti-D can bind the first complement component C1q and its impact on phagocytosis and severity of Rh haemolytic disease of the newborn (HDN). One hundred Rh immunised women were enrolled, however six having Rh(D) negative infants were excluded. Immunometric assay revealed that of 94 sera, 18 (19.1%) were able to bind C1q but failed to bind C3. Six mothers had anti-C (two bound C1q) and one had anti-E (C1q nonbinding) in addition to anti-D. Various characteristics of anti-D like titre, concentration, IgG subtypes and phagocytic activity showed comparable results (P > 0.3) in C1q binding and nonbinding groups. No significant difference in the severity of Rhesus haemolytic disease of the newborn (Rh HDN), judged by the outcome of pregnancy, cord blood haemoglobin, peak and pre exchange transfusion (ET), indirect serum bilirubin and requirement of ET, was observed in these two groups. Hence this study suggests that though some anti-D sera can bind C1q, there is no further activation of complement pathway and the severity of Rh HDN is not influenced by this phenomenon.

Complement C1q↗
PubMed2004

Reduced beta-amyloid production and increased inflammatory responses in presenilin conditional knock-out mice.

Mutations in presenilins (PS) 1 and 2 are the major cause of familial Alzheimer's disease. Conditional double knock-out mice lacking both presenilins in the postnatal forebrain (PS cDKO mice) exhibit memory and synaptic plasticity impairments followed by progressive neurodegeneration in the cerebral cortex. Here we further investigate the molecular events that may underlie the observed phenotypes and identify additional neuropathological markers in the PS cDKO brain. Enzyme-linked immunosorbent assay analysis showed reduced levels of the toxic beta-amyloid (Abeta) peptides in the cerebral cortex of PS cDKO mice. Interestingly, the reduction in Abeta40 and Abeta42 peptides is similar in PS1 conditional knock-out and PS cDKO mice. We further examined the gene expression profile by oligonucleotide microarrays in the PS cDKO cerebral cortex and found that a high number of genes are differentially expressed, most notably a group of up-regulated inflammatory genes. Quantitative real-time reverse transcription PCR and Western analyses confirmed the elevated levels of glial fibrillary acidic protein, complement component C1q, and cathepsin S, up-regulation of which has been associated with inflammatory responses in various neurodegenerative processes. Immunohistochemical analysis revealed that the increase in complement component C1q is confined to the hippocampal formation, whereas glial fibrillary acidic protein and cathepsin S are up-regulated throughout the entire neocortex and hippocampus. In addition, strong microglial activation occurs in the hippocampus and the deeper cortical layers of PS cDKO mice. These results indicate that the memory impairment and neurodegeneration in PS cDKO mice are not caused by Abeta accumulation and that loss of PS function leads to differential up-regulation of inflammatory markers in the cerebral cortex.

Amyloid beta-Peptides↗
PubMed2004

Anti-C1q autoantibodies deposit in glomeruli but are only pathogenic in combination with glomerular C1q-containing immune complexes.

Anti-C1q autoantibodies are present in sera of patients with several autoimmune diseases, including systemic lupus erythematosus (SLE). Strikingly, in SLE the presence of anti-C1q is associated with the occurrence of nephritis. We have generated mouse anti-mouse C1q mAb's and used murine models to investigate whether anti-C1q autoantibodies actually contribute to renal pathology in glomerular immune complex disease. Administration of anti-C1q mAb JL-1, which recognizes the collagen-like region of C1q, resulted in glomerular deposition of C1q and anti-C1q autoantibodies and mild granulocyte influx, but no overt renal damage. However, combination of JL-1 with a subnephritogenic dose of C1q-fixing anti-glomerular basement membrane (anti-GBM) antibodies enhanced renal damage characterized by persistently increased levels of infiltrating granulocytes, major histological changes, and increased albuminuria. This was not observed when a non-C1q-fixing anti-GBM preparation was used. Experiments with different knockout mice showed that renal damage was dependent not only on glomerular C1q and complement activation but also on Fcgamma receptors. In conclusion, anti-C1q autoantibodies deposit in glomeruli together with C1q but induce overt renal disease only in the context of glomerular immune complex disease. This provides an explanation why anti-C1q antibodies are especially pathogenic in patients with SLE.

Animals↗
PubMed1993

Inhibitor of C1q secretion suppresses the macrophage response to lipid A for nitric oxide but not for TNF production: evidence for a role of C1q in autocrine binding of TNF.

Studies were designed to further define the modulatory role of complement subcomponent C1q in macrophage activation by Lipid A to mediate production of TNF and cytotoxic nitric oxide (NO). Pretreatment of macrophages for 24 h with 2.5 mM 3,4,dehydro-D,L-proline (DHP), an inhibitor of C1q secretion, suppressed their response to Lipid A activation for cytotoxicity of P815 tumor targets which correlated with a corresponding decrease in NO production. In contrast, DHP-pretreated macrophages displayed an increase in the release of TNF in response to Lipid A as compared to untreated controls. Time kinetic studies indicated that DHP-pretreated macrophages produced higher sustained levels of TNF activity during 1 to 24 h culture with Lipid A than did untreated control macrophages. This was confirmed by increased TNF mRNA expression in response to Lipid A by DHP-treated cells. DHP-pretreated macrophages had reduced levels of cell surface C1q as determined by cytofluorometric analysis of the binding of FITC-labeled anti-C1q, F(ab')2. Macrophages were also found to have reduced binding capacity for phycoerythrin-labeled rTNF (PE-TNF) by cytofluorometric analysis following DHP treatment. Exposure of DHP-pretreated macrophage to soluble C1q at 4 degrees C restored their reduced binding of PE-TNF. C1q was confirmed to bind to macrophages at 4 degrees C as detected by FITC anti-C1q, F(ab')2 and such C1q binding promoted a corresponding increased binding of PE-TNF. Macrophages which were plated over immobilized C1q were also markedly enhanced in their binding of PE-TNF probe. Our results indicate that the inhibition of macrophage secretion of C1q by DHP pretreatment, was accompanied by an increased TNF mRNA expression and release with a decrease in NO generation following Lipid A activation. Since TNF binding to DHP-treated macrophages was reconstituted by the binding of exogenous C1q to the cells, it appears that C1q may be involved in the modulation of autocrine binding of TNF for subsequent generation of cytotoxic NO.

Animals↗
PubMed1982

Anti-C1q column: ligand specific purification of immune complexes from human serum or plasma. Analysis of the interaction between C1q and immune complexes.

An efficient and reproducible procedure has been developed for the specific isolation of immune complexes. PEG precipitation of EDTA serum or plasma was an essential preliminary step to separate complex-bound from free C1q. PEG had no discernible effect on the molecular weight size of the extracted complexes. Redissolved complexes were incubated with a Sepharose-4B column coated with anti-human C1q antibodies and following removal of unbound material the bound complexes were sequentially eluted with 0.02 M EDTA, 0.5 M NaCl and 1 M propionic acid. Characteristics of the affinity column were established by the purification of 125I-labelled BSA-anti-BSA complexes and heat-aggregated IgG (HAGG) incubated in normal human serum (NHS). EDTA and NaCl eluted complexes were of similar molecular size and contained antigen, specific antibody, as well as human IgM, IgG, albumin, C3, C3c, C3d and C1q. Acid eluted complexes contained the highest yield of specific antigen and antibody and comprised in addition human C1q and C3d. Activation of complement components after C1q made the bond between C1q and immune complexes resistant to 0.5 M NaCl and interfered with the binding between solid phase anti-C1q and complex bound C1q. Using BSA-anti-BSA complexes and HAGG activated in NHS it was apparent that only a minority of the complexed material was isolated via the C1q ligand and this probably applies to the C1q binding assay. Most complexed material could be isolated using an anti-C3 affinity column.

Antigen-Antibody Complex↗
PubMed1981

Immunofluorescence studies on the subcomponents of the first component of complement (C1): detection of C1q and C1s in different cells of biopsy material and on human as well as on guinea pig peritoneal macrophages.

The first component of complement (C1) is a macromolecule consisting of three distinct subcomponents, C1q, C1r, and C1s. In regard to its production site and its role in phagocytic processes it was of interest to find out whether these different subcomponents could be detected in human biopsy material only as a complex in individual cells or whether C1 subcomponents could be found on different cells. To study this question, monospecific fluorescein-labelled anti-human-C1q IgG and monospecific rhodamine-labelled anti-human C1q IgG were used. Biopsy material from human rectum was stained with fluoresceinated antisera, either by use of one antiserum or by double staining. Using this technique, these observations were made: C1q as well as C1s were detectable in individual cells in the subepithelial area of the gut. Furthermore, C1q and C1s could be found together in the same cell or separately in different cells. These findings were supported by experiments with cultured peritoneal macrophages either from human or from guinea pig. The examination of the cultured cells with the two antisera revealed that individual cells were stained either by anti-C1q or by anti-C1s antibodies. The specificity of the detection of the individual subcomponents was also proven by the peroxidase technique and by using fluoresceinated anti-human C1q F(ab')2. The membrane immunofluorescent staining revealed the presence of C1q on the membrane of the macrophage.

Animals↗