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PubMed1998

Detection of complement C1q receptors on human spermatozoa.

Clq, the first component of the classical complement pathway, is known to play roles in promoting phagocytic events, in addition to its role in activation of complement. Although the molecular events in fertilization leading to the entrance of the spermatozoan into the egg are not well understood, ultrastructural observations suggest that the process is quasi-phagocytic in nature. There is increasing evidence that complement components might play roles in fertilization. Previously, we have shown that C1q promoted the agglutination of capacitated human sperm as well as their adhesion to zona-free hamster eggs. In the present experiments, human spermatozoa were solubilized and, following their phase separation in Triton X-114, subject to 1-D polyacrylamide gel electrophoresis and immunoblotting for the presence of C1q receptors. Both gC1q-R and cC1q-R were detected. In addition, the ability of C1q to promote sperm agglutination was shown to be dependent upon capacitation, suggesting the increased expression of C1q receptors during this process.

Agglutination Tests↗
PubMed2004

Complement C1q regulates LPS-induced cytokine production in bone marrow-derived dendritic cells.

We show here that C1q suppresses IL-12p40 production in LPS-stimulated murine bone marrow-derived dendritic cells (BMDC). Serum IL-12p40 concentration of C1q-deficient mice was higher than that of wild-type mice after intraperitoneal LPS-injection. Because neither globular head of C1q (gC1q) nor collagen-like region of C1q (cC1q) failed to suppress LPS-induced IL-12p40 production, both gC1q and cC1q, and/or some specialized conformation of native C1q may be required for the inhibition. While C1q did not affect mRNA expression of Toll-like receptor 4 (TLR4), MD-2, and myeloid differentiation factor 88 (MyD88), BMDC treated with C1q showed the reduced activity of NF-kappaB and the delayed phosphorylation of p38, c-Jun N-terminal kinase, and extracellular signal-regulated kinase after LPS-stimulation. CpG oligodeoxynucleotide-induced IL-12p40 and TNF-alpha production, another MyD88-dependent TLR-mediated signal, was also suppressed by C1q treatment. Therefore, C1q is likely to suppress MyD88-dependent pathway in TLR-mediated signals. In contrast, C1q failed to suppress colony formation of B cells responding to LPS or LPS-induced CD40 and CD86 expression on BMDC in MyD88-deficient mice, indicating that inhibitory effects of C1q on MyD88-independent pathways may be limited. Taken together, C1q may regulate innate and adaptive immune systems via modification of signals mediated by interactions between invading pathogens and TLR.

Adaptor Proteins, Signal Transducing↗
PubMedDate not supplied

IgG autoantibodies to complement C1q in pediatric-onset systemic lupus erythematosus.

OBJECTIVE: Antibodies to C1q (aC1q) have been found in up to 50% of adult patients with systemic lupus erythematosus (SLE) and have been associated with proliferative glomerulonephritis. We investigated the prevalence and clinical significance of aC1q in pediatric SLE. METHODS: Antibodies to C1q, measured by an ELISA method, were evaluated in 29 patients with childhood-onset SLE, 26 females and 3 males, aged 7.5 to 19.6 years. RESULTS: Seventeen (59%) of the 29 patients were initially positive for aC1q. No correlation was found between either the presence or titer of aC1q and any of the clinical manifestations, including nephritis. However, a significant correlation was observed between aC1q levels and anti-double-stranded DNA antibodies and C3 values. Serial determinations of aC1q in 23 patients showed a progressive decline in the titers with few significant fluctuations. Antibodies to C1q were not a reliable predictor of increased SLE activity, since they increased or became detectable in only 50% of the pre-flare sera. CONCLUSION: Antibodies to C1q were frequently positive in our patients with pediatric SLE and were correlated with laboratory variables of disease activity. However, unlike in adults with SLE, a high correlation between aC1q and glomerulonephritis was not found in these pediatric patients.

Adolescent↗
PubMed2000

Complement C1q is dramatically up-regulated in brain microglia in response to transient global cerebral ischemia.

Recent evidence suggests that the pathophysiology of neurodegenerative and inflammatory neurological diseases has a neuroimmunological component involving complement, an innate humoral immune defense system. The present study demonstrates the effects of experimentally induced global ischemia on the biosynthesis of C1q, the recognition subcomponent of the classical complement activation pathway, in the CNS. Using semiquantitative in situ hybridization, immunohistochemistry, and confocal laser scanning microscopy, a dramatic and widespread increase of C1q biosynthesis in rat brain microglia (but not in astrocytes or neurons) within 24 h after the ischemic insult was observed. A marked increase of C1q functional activity in cerebrospinal fluid taken 1, 24, and 72 h after the ischemic insult was determined by C1q-dependent hemolytic assay. In the light of the well-established role of complement and complement activation products in the initiation and maintenance of inflammation, the ischemia-induced increase of cerebral C1q biosynthesis and of C1q functional activity in the cerebrospinal fluid implies that the proinflammatory activities of locally produced complement are likely to contribute to the pathophysiology of cerebral ischemia. Pharmacological modulation of complement activation in the brain may be a therapeutic target in the treatment of stroke.

Animals↗
PubMed1976

[Detection of circulating immune complexes by the C1q complement fraction deviation test. 1st application in the study of human glomerulopathies].

The C1q deviation test measures the interference of circulating immune complexes in the fixation of radioactive C1q on target cells. The test was carried out in a large sample of cases of glomerular nephropathies, on the serum of patients with hypertension and on control sera. Positive results were frequently obtained with the sera of patients suffering from acute glomerulonephritis and membranous glomerulonephritis. Positive results were rarer in cases of minimal change discase and of membranoproliferative glomerulonephritis. These results suggest that the deviation of C1q in the serum of patients with various types of glomerulone phropathy may be due to circulating complexes but also to other substances. They indicate that efforts should be continued to isolate and biochemically identify the C1q binding substances in pathological sera.

Acute Disease↗
PubMed1986

[Biosynthesis of the complement component C1q in mouse peritoneal macrophage cultures].

Biosynthesis of C1q complement component by resident peritoneal macrophages from (CBA X C57BL/6)F1 mice has been studied in in vitro experiments. Using anti-mouse C1q antibodies immobilized on CNBr Sepharose it has been demonstrated that 14C glycine incorporates both into intracellular C1q and C1q secreted into the medium. The maximum radioactivity of intracellular C1q was observed 48 h after cultivation, with it dropping drastically between hours 72-96. Kinetics of radiolabelled C1q was similar, but 24 hours delayed. Cell viability during 96 h of cultivation remained unchanged. These data can be considered as the indication of feedback regulation of C1q biosynthesis at the cellular level.

Animals↗
PubMed2005

Gastrointestinal ischemia-reperfusion injury is lectin complement pathway dependent without involving C1q.

Complement activation plays an important role in local and remote tissue injury associated with gastrointestinal ischemia-reperfusion (GI/R). The role of the classical and lectin complement pathways in GI/R injury was evaluated using C1q-deficient (C1q KO), MBL-A/C-deficient (MBL-null), complement factor 2- and factor B-deficient (C2/fB KO), and wild-type (WT) mice. Gastrointestinal ischemia (20 min), followed by 3-h reperfusion, induced intestinal and lung injury in C1q KO and WT mice, but not in C2/fB KO mice. Addition of human C2 to C2/fB KO mice significantly restored GI/R injury, demonstrating that GI/R injury is mediated via the lectin and/or classical pathway. Tissue C3 deposition in C1q KO and WT, but not C2/fB KO, mice after GI/R demonstrated that complement was activated in C1q KO mice. GI/R significantly increased serum alanine aminotransferase, gastrointestinal barrier dysfunction, and neutrophil infiltration into the lung and gut in C1q KO and WT, but not C2/fB KO, mice. MBL-null mice displayed little gut injury after GI/R, but lung injury was present. Addition of recombinant human MBL (rhuMBL) to MBL-null mice significantly increased injury compared with MBL-null mice after GI/R and was reversed by anti-MBL mAb treatment. However, MBL-null mice were not protected from secondary lung injury after GI/R. These data demonstrate that C2 and MBL, but not C1q, are necessary for gut injury after GI/R. Lung injury in mice after GI/R is MBL and C1q independent, but C2 dependent, suggesting a potential role for ficolins in this model.

Alanine Transaminase↗
PubMed1992

Isolation, sequence analysis and characterization of cDNA clones coding for the C chain of mouse C1q. Sequence similarity of complement subcomponent C1q, collagen type VIII and type X and precerebellin.

A mouse macrophage lambda gt11 cDNA library was screened using a genomic DNA clone coding for the C-chain gene of human C1q. Approximately 600,000 recombinant phage plaques were hybridized with peroxidase-labeled human C-chain probe and detected by enhanced chemiluminescence. Five positive clones were obtained. The size of the full-length cDNA is 1019 bp. The sequence identity of the nucleotide sequence with human C1q C chain is 79%, the identity of the deduced amino acid sequences is 73%. The mouse C1q C chain exhibits the same structural features as the human C chain, e.g. conservation of the cysteine residues. Like the mouse A chain, the mouse C chain has an RGD sequence that may be recognized by receptors of the integrin family. No RGD sequences have been found in any of the human C1q chains. The size of the C-chain mRNA (1.2 kb) and its tissue distribution (macrophages being the cell type with the highest mRNA concentration) are identical to the mRNA of the mouse A and B chains. Alignment of human and mouse C1q A, B and C chains exhibits two blocks of highly conserved residues within the C-terminal globular regions. Three other proteins, collagen type VIII and type X and precerebellin share this similarity with C1q, indicating the structural and probably functional importance of these regions within the non-collagenous domains of the molecules.

Amino Acid Sequence↗
PubMed1992

Smooth muscle and epithelial cells express specific binding sites for the C1q component of complement.

In injury and inflammation, interactions of complement C1q with C1q receptors may provide attachment sites for cell localization and tissue regeneration. Cultured smooth muscle cells (58%), epithelial cells (26%), and endothelial cells (25%) attach to C1q-coated surfaces, while only 6% of cultured B cells (Raji) attach. Endothelial and Raji cells express C1q receptors, but C1q receptors (C1qR) on smooth muscle cells and epithelial cells have not previously been demonstrated. Evidence is provided that smooth muscle cells express an average of 1.5 x 10(6) C1qR/cell (K alpha = 10(8) M-1) and that epithelial cells express an average of 0.7 x 10(6) C1qR/cell (K alpha = 1.4 x 10(8) M-1). Binding properties of C1qR, and immunoreactivity to anti-C1qR antibodies, are characterized. The antibodies specifically recognize a 67-kDa component of smooth muscle cell lysates and inhibit cell attachment to C1q substrates. We conclude that distribution of C1qR may be ubiquitous; binding properties, size, and antigenicity of various C1qR may be related, but adhesive function may be tissue specific.

Animals↗
PubMed2006

The tissue pentraxin PTX3 limits C1q-mediated complement activation and phagocytosis of apoptotic cells by dendritic cells.

Pentraxins (PTX) and complement belong to the humoral arm of the innate immune system and have essential functions in immune defense to microbes and in scavenging cellular debris. The prototypic long PTX, PTX3, and the first component of the classical complement pathway, C1q, are innate opsonins involved in the disposal of dying cells by phagocytes. Whether the interaction between various innate opsonins impacts on their function is not fully understood. We show here that characterized Toll-like receptor (TLR) ligands elicit the production of C1q and PTX3 by immature dendritic cells (DC). Moreover, these molecules bind to dying cells with similar kinetics, although they recognize different domains on the cell membranes. PTX3 binds in the fluid phase to C1q, decreasing C1q deposition and subsequent complement activation on apoptotic cells. C1q increases the phagocytosis of apoptotic cells by DC and the release of interleukin-12 in the presence of TLR4 ligands and apoptotic cells; PTX3 inhibits both events. Moreover, PTX3 inhibited the cross-presentation of the MELAN-A/melanoma antigen-reactive T cell 1 (MART-1) tumor antigen expressed by dying cells, even in the presence of C1q. These results suggest that interaction of C1q and PTX3 influences the clearance of apoptotic cells by DC. The coordinated induction by primary, proinflammatory signals of C1q and PTX3 and their reciprocal regulation during inflammation influences the clearance of apoptotic cells by antigen-presenting cells and possibly plays a role in immune homeostasis.

Antigen Presentation↗
PubMedDate not supplied

Activation of human microglia by fibrillar prion protein-related peptides is enhanced by amyloid-associated factors SAP and C1q.

Complement activation products C1q and C3d, serum amyloid P component (SAP) and activated glial cells accumulate in amyloid deposits of conformationally changed prion protein (PrP(Sc)) in Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease and scrapie-infected mouse brain. Biological properties, including the potential to activate microglia, relate to prion (PrP) peptide fibrillogenic abilities. We investigated if SAP and C1q influence the fibrillogenic properties of human and mouse PrP peptide and concomitantly their stimulatory effects on human microglia in vitro. PrP-peptide induced microglial IL-6 and TNF-alpha release significantly increased in the presence of SAP and C1q. Also, SAP and C1q enhanced PrP-peptide fibril formation as revealed by electron microscopy and thioflavin S-based quantitative assays. This suggests that SAP and C1q contribute to fibrillar state-dependent cellular effects of PrP. Combined, ultrastructural and thioflavin assays, together with microglial cytokine release measurements, provide a test system to screen potential, fibrillarity impeding therapeutics for prion disease.

Aged↗
PubMed1990

Influence of the hinge region on complement activation, C1q binding, and segmental flexibility in chimeric human immunoglobulins.

We have characterized a series of genetically engineered chimeric human IgG3 and IgG4 anti-dansyl (DNS) antibodies with identical antibody-combining sites but different hinge region amino acid compositions to determine how the hinge region influences Fab fragment segmental flexibility, C1q binding, and complement activation. Our data support the correlation between "upper hinge" length and Fab segmental flexibility; moreover, we confirm that a hinge region is essential for C1q binding and complement activation. However, the hinge length by itself is not sufficient for complement activity in IgG molecules. We have demonstrated that the IgG4 hinge, which imparts restricted segmental flexibility, reduces the ability of IgG3 molecules to activate complement. We also find that the IgG3 hinge region, which imparts greater segmental motion, is not sufficient to create complement activation activity in IgG4 anti-DNS antibodies. Finally, we conclude that (i) segmental motion is correlated with "upper hinge" length, (ii) hinge length and segmental flexibility is not enough to alter complement binding and activation, and (iii) segmental flexibility does not correlate with proficiency to activate the complement cascade.

Amino Acid Sequence↗
PubMed1985

Fibronectin binding to complement subcomponent C1q. Localization of their respective binding sites.

The interaction of purified human plasma fibronectin with the C1q subcomponent of complement was investigated by using a solid-phase radiobinding assay. 125I-fibronectin binding to native C1q, purified collagen domain (C1q-c) or globular domain (C1q-g) was compared. When the purified domains were insolubilized by binding to plastic, the C1q-c exhibited 59% of the binding demonstrated with intact C1q, whereas the C1q-g exhibited 35% of the binding. N-Terminal sequencing of the globular domain showed that a sequence of seven collagen-like amino acids was retained on each chain of the C1q-g fragment. 125I-fibronectin binding to C1q could be inhibited equally well by fluid-phase C1q and C1q-c, but not by fluid-phase C1q-g, implying that the collagen-like region retained on the C1q-g is masked in the fluid phase. In addition, studies were performed to determine which subunit(s) of C1q bind(s) fibronectin. The percentages of fibronectin bound by the A, B, and C chain of C1q were found to be 38, 21 and 41% respectively. Inhibition studies with purified 200-180 kDa, 50 kDa or 29 kDa fragments of fibronectin show that the binding site on fibronectin for C1q is the 50 kDa gelatin-binding domain.

Amino Acid Sequence↗
PubMed1983

Electron microscopy of the complement protein C1q from the bullfrog, Rana catesbeiana.

The complement protein C1q, isolated from bullfrog (Rana catesbeiana) serum, was found by electron microscopy to resemble human C1q; peripheral globular units, probably six in number, are connected by thin strands to a hollow stem-like central structure. The dimensions of frog and human C1q were also found to be very similar. These results are consistent with earlier observations that frog and human C1q are similar, although not identical, in overall size, subunit structure, amino acid composition, and functional properties. Evidently this protein, which binds to antigen-antibody complexes and to C1r and C1s, thereby forming a physical link between the immune and complement systems, has been highly conserved in evolution.

Animals↗
PubMed1978

Specific antibody-dependent binding of complement component C1q to hapten-sensitized lipid vesicles.

The binding of a component of human complement (C1q) to membrane-bound specific anti-nitroxide antibodies was studied as a function of the physical properties (fluid vs. solid) of vesicle lipids. The antibodies were bound to spin-label lipid haptens in the vesicle membrane. The binding of C1q to the sensitized vesicles shows a maximum as a function of specific IgG concentration. The binding of antibodies and of C1q to the vesicle membrane does not depend strongly on the physical state of the membrane lipids. even at low hapten (0.05 mol%) concentrations. These results are of significance for the understanding of the previously reported effect of lipid physical states on complement depletion.

Antibodies↗