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PubMed2000

Synthetic peptides which inhibit the interaction between C1q and immunoglobulin and prolong xenograft survival.

BACKGROUND: Acute vascular xenograft rejection (AVXR), also termed delayed xenograft rejection (DXR), occurs when hyperacute rejection (HAR) is prevented by strategies directed at xenoreactive natural antibodies and/or complement activation. We have hypothesized that AVXR/DXR is initiated in part by early components of the complement cascade, notably C1q. We have developed synthetic peptides (termed CBP2 and WY) that interfere with the interaction between C1q and antibody. METHODS: CBP2 and the WY-conjugates were used as inhibitors of immunoglobulin aggregate binding to solid phase C1q. Inhibition of complement activation by the peptides of the classical system was determined using lysis assays with sensitized sheep red blood cells or porcine aortic endothelial cells as targets and of the alternate complement pathway using guinea pig red blood cells as targets. Two transplant models were used to study the effects of administering peptides to recipients: rat heart transplant to presensitized mouse, and guinea heart transplant to PVG C6-deficient rats. RESULTS: CBP2 and WY-conjugates inhibited immunoglobulin aggregate binding to C1q. The peptides also inhibited human complement-mediated lysis of sensitized sheep red blood cells and porcine aortic endothelial cells in a dose-dependent manner and the WY-conjugates prevented activation of the alternate complement pathway as shown by inhibition of guinea pig red blood cells lysis with human serum. In addition, the use of the peptides and conjugates resulted in significant prolongation of xenograft survival. CONCLUSIONS: The CBP2 and WY peptides exhibit the functional activity of inhibition of complement activation. These peptides also prolong xenograft survival and thus provide reagents for the study of the importance of C1q and other complement components in transplant rejection mechanisms.

Animals↗
PubMed1986

Production and characterization of a murine monoclonal IgM antibody to human C1q receptor (C1qR).

A hybridoma cell line that produces a monoclonal antibody (MAb) to cell surface C1q receptor (C1qR) has been produced by fusion of the P3 X 63-Ag8.653 mouse myeloma cell line with the spleen cells of a CD-1 mouse that had been hyperimmunized with viable Raji cell suspensions (5 X 10(7) cells/inoculum). This MAb, designated II1/D1, is an IgM antibody with lambda-light chain specificity. Radiolabeled or unlabeled, highly purified II1/D1 was used to determine that: this antibody competes for C1q binding sites on C1qR-bearing cells; the molecule recognized by this MAb is the C1qR; and cells that are known to bind C1q also bind II1/D1 in a specific manner. Western blot analysis of solubilized Raji, or U937 cell membranes, showed that the 125I-MAb detected a major protein band of approximately 85,000 m.w. in its unreduced state, indicating that the C1qR is similar, if not identical, in both types of cells. Analyses of 125I-II1/D1 binding experiments revealed that the antibody bound to Raji cells or U937 cells in a specific manner. Uptake of the antibody was saturable, with equilibrium virtually attained within 35 min. Scatchard analysis of the binding data using the intact MAb suggests that the affinity constant KD is 2.9 X 10(-10) M, and at apparent saturation, 24.6 ng of the antibody were bound per 2 X 10(6) cells, giving an estimated 7.8 X 10(3) antibody molecules bound per cell. That the II1/D1 antibody is specifically directed to the C1q was further evidenced by an ELISA in which the ability of C1qR-bearing cells to bind the MAb was abrogated by c-C1q in a specific and dose-dependent manner. These results indicate that the II1/D1 is a specific antibody directed against the C1q and can be a useful tool in studying the biologic interaction of human C1q with its receptors on a variety of cells.

Animals↗
PubMed1989

Substitution of asparagine324 with aspartic acid in the Fc portion of mouse antibodies reduces their capacity for C1q binding.

The sequence of the heavy chain C region of mouse mutant IgG2a antibodies with reduced capacity for C1q binding but with retained ability for Fc receptor-mediated functions was determined by cDNA cloning and by mRNA sequencing. The specific mutation was found to be the substitution of asparagine324 with aspartic acid. Asparagine324 represents a new residue relating to the C1q-binding sites previously described.

Amino Acid Sequence↗
PubMed1981

A simple two-step procedure for the purification of plasma C1q from different animal species.

Plasma C1q from human, rat, rabbit, dog and sheep were isolated by a 2-step affinity chromatography procedure. In the first step the method exploits the affinity of C1q for heparin and in the second the interaction between C1q and IgG. The precipitation of C1q by the SO4(2-) groups in agarose gels was used as a means to rapidly monitor the elution of C1q. This interaction was found to be non-species specific and therefore obviates the need for immunochemical and/or haemolytic assays. The isolation procedure is rapid, simple and is not confined to one species. Pure functionally active C1q was obtained from all species in yields of approximately 85-95%.

Animals↗
PubMed2000

Spontaneous improvement in a case of C1q nephropathy.

A 17-year-old girl showed mild proteinuria accompanied by hematuria and mild hypocomplementemia. A light microscopic study of the first renal biopsy specimen showed diffuse mild to moderate mesangial proliferation and thickening of the glomerular basement membrane (GBM). An immunofluorescence study showed dominant positive staining (3+) of IgG and C1q in the glomerular mesangium and capillary loop. Staining for C3 and fibrinogen was weak or 1+. Staining for IgA and IgM was negative. Electron-dense deposits were present in the mesangial area and also in the subepithelial, subendothelial, and intramembranous space. Urinary findings improved after dipyridamole treatment. The second renal biopsy, which was performed 5 years later, showed histological improvements, and various pictures of washing-out of deposits were also noted in an electron microscopic study. However, dominant positive staining for IgG and C1q was persistent in an immunofluorescence study. The glomerulopathy of this case belongs in the criteria of neither membranoproliferative glomerulonephritis nor lupus nephritis but could be designated as C1q nephropathy. This is the first report of a histological improvement in C1q nephropathy.

Adolescent↗
PubMed1987

C1q solid-phase radioimmunoassay: evidence for detection of antibody directed against the collagen-like region of C1q in sera from patients with systemic lupus erythematosus.

In earlier studies we showed that the C1q-binding IgG in the sera from patients with systemic lupus erythematosus (SLE) tested by C1q solid-phase radioimmunoassay is cofractionated with monomeric IgG on gel filtration and mostly binds to C1q via the F(ab')2 region. In this study, we found that C1q, even when stripped of its immune complex-binding globular regions by pepsin digestion, retained a substantial part of its ability to bind IgG from SLE sera, suggesting that the collagen-like region of C1q is involved in binding to the SLE IgG. Heat-inactivation of C1q also failed to abolish its ability to bind IgG from SLE sera. In contrast, the binding of C1q to heat-aggregated IgG was completely abrogated by these treatments. In addition, the reaction of heat-aggregated IgG with the solid-phase C1q was markedly dependent on ionic strength whereas the binding of IgG from SLE sera with the solid-phase C1q persisted at high concentrations of salt. These findings suggest that the Clq-binding IgG in SLE sera is, at least in part, antibody directed against the collagen-like region of C1q.

Autoantibodies↗
PubMed1997

Neurons express proteins of the classical complement pathway in Alzheimer disease.

Occurrence of the classical pathway complement proteins C1q, C1r, C1s, C2, C3, C4, C5, C6, C7, C8 and C9 was studied in human hippocampus and temporal cortex by immunohistochemistry and Western blotting. In Alzheimer disease (AD) cases, positive staining for all of these proteins was observed in pyramidal neurons and senile plaques. In control cases, weaker pyramidal neuron staining was observed except for C1q and C1s which were not detected. On Western blots of AD hippocampal extracts, bands corresponding to those detected in normal serum were found for each of the complement proteins. Comparable bands were also detected in normal hippocampal extracts with the exception of C1s which was not observed. The intensity of the bands was generally stronger in AD than in normal extracts, but, in the latter, there was considerable variability between cases and between bands in a single case. These data suggest that pyramidal neurons may be a source of the complement components known to be associated with Alzheimer lesions.

Aged↗
PubMed1986

The endothelial surface and responses to injury.

Pulmonary microvascular endothelial cells are known to play an active role in the events that lead to vascular damage in the inflammatory response. The endothelial surface, normally immunologically privileged and very actively antithrombogenic, can respond to certain stimuli, generally injurious, by becoming strongly procoagulant and by expressing Fc and C3b receptors. Like macrophages, activated endothelial cells can provide a common source and substratum for combined hemostatic and complement-linked reactions. Such transformations of endothelial functions may involve alterations in the endothelial glycocalyx and, in addition, may be important for the entrapment and disposal of phagocytosed particulates. What is clear is that it is not simply absence of endothelium that has a bearing on the outcome of inflammatory stimuli but that structural and functional responses of the endothelial surface to injury, resulting in altered expression of hemostatic and immunologic potential, may have an important bearing on the role of the endothelium in the regulation of microvascular permeability.

Animals↗
PubMed1996

Localisation of the C1q binding site within C1q receptor/calreticulin.

C1q receptor (C1qR/collectin receptor) is located on many cell types. Binding of C1q to these cells elicits numerous responses. Protein sequencing has shown that C1qR is almost identical to calreticulin (CaR), an abundant multifunctional protein. Radioiodinated C1qR and CaR bind to C1q with identical characteristics. Three recombinant C1qR/CaR domains (N-, C-terminal domains and central P-domain) were expressed using the Thiofusion system, and used to study the interaction with C1q. Both the N- and P-domains were implicated in C1q binding. A region, termed the S-domain, spanning the N and P intersection was expressed, and showed concentration-dependent binding to C1q, demonstrating that the C1q binding site lies within this region.

Amino Acid Sequence↗
PubMed1997

Distribution of receptors of collagen and globular domains of C1q in human lung fibroblasts.

Fibroblasts are the predominant cell type responsible for the synthesis of collagen and other matrix elements in normal and fibrotic lungs. We have previously reported that human lung fibroblasts are heterogeneous in C1q binding and that subpopulations differing in C1q binding can be isolated and subcultured. We have investigated the distribution of receptors for C1q-collagen domain (cC1q-R) and globular domain (gC1q-R) in adult human lung fibroblasts. Fibroblasts were isolated from cultures of adult human lung explants in medium containing fresh- or heated plasma-derived human sera and separated by FACS-cell sorting into populations binding to C1q with high- (HF) and low- (LF) fluorescence. The cC1q-R was obtained from fibroblast membrane preparations by affinity chromatography through an anti-cC1q-R antibody column and its distribution was determined by Western analysis. The presence of gC1q-R was determined by immunoblots using an anti-gC1q-R antibody raised against a synthetic peptide. The results showed that a 54 kD protein crossreacting with anti-cC1q-R antibody was produced by LF cells, but it was barely detectable in HF cultures. Immunostaining with anti-cC1q-R antibody revealed that most of the cells in LF cultures were positive while the HF cells were negative. A 38 kD protein recognized by anti-gC1q-R antibody was produced by lung fibroblasts; however, no differences were detected in its distribution between LF and HF cultures. SDS-polyacrylamide gel electrophoresis of membrane proteins binding to an affinity column of C1q-globular fragment showed that the HF cultures contain a approximately 51 kD protein, which was a minor component in LF membranes. These data show that cC1q-R is expressed predominantly by a population of human lung fibroblasts, while the 38 kD gC1q-R is produced by all cells. Another 51 kD protein appears to be produced by a separate population of fibroblasts which does not express cC1q-R. Our results indicate that two lung fibroblast subtypes may be distinguished based on production of the 54 kD putative cC1q-R and another 51 kD protein which binds to C1q-globular domain.

Adult↗
PubMed1997

A second serine protease associated with mannan-binding lectin that activates complement.

The complement system comprises a complex array of enzymes and non-enzymatic proteins that is essential for the operation of the innate as well as the adaptive immune defence. The complement system can be activated in three ways: by the classical pathway which is initiated by antibody-antigen complexes, by the alternative pathway initiated by certain structures on microbial surfaces, and by an antibody-independent pathway that is initiated by the binding of mannan-binding lectin (MBL; first described as mannan-binding protein) to carbohydrates. MBL is structurally related to the complement C1 subcomponent, C1q, and seems to activate the complement system through an associated serine protease known as MASP (ref. 4) or p100 (ref. 5), which is similar to C1r and C1s of the classical pathway. MBL binds to specific carbohydrate structures found on the surface of a range of microorganisms, including bacteria, yeasts, parasitic protozoa and viruses, and exhibits antibacterial activity through killing mediated by the terminal, lytic complement components or by promoting phagocytosis. The level of MBL in plasma is genetically determined, and deficiency is associated with frequent infections in childhood, and possibly also in adults (for review, see ref. 6). We have now identified a new MBL-associated serine protease (MASP-2) which shows a striking homology with the previously reported MASP (MASP-1) and the two C1q-associated serine proteases C1r and C1s. Thus complement activation through MBL, like the classical pathway, involves two serine proteases and may antedate the development of the specific immune system of vertebrates.

Amino Acid Sequence↗
PubMed2000

[Apoptosis and C1q: possible explanations for the pathogenesis of systemic lupus erythematosus].

Dysregulation of apoptosis may play a major role in the pathogenesis of systemic lupus erythematosus (SLE). A defective clearance of apoptotic cells or inappropriately high rates of apoptosis may lead to a pathologic accumulation of abnormal cell material with a secondary autoimmune response. Experimental findings in apoptotic keratinocytes and C1q knock-out mice suggest an important role of C1q in the clearance of apoptotic cell material. In addition, there are several links between C1q and SLE: Most the patients with C1q deficiency develop a SLE-like syndrome. SLE itself often causes secondary C1q deficiency and autoantibodies to C1q are detected in almost all patients with active lupus nephritis. These observations suggest a central role of C1q in apoptosis and in the pathogenesis of SLE.

Animals↗
PubMed1986

Conformational changes in C1q upon binding to IgG oligomers.

The interaction between C1q and immune complexes is inhibited by 1-anilino-8-naphthalenesulfonate (ANS) in the concentration range of 2-4 mM. ANS binds to Clq with a 20-fold higher affinity than to IgG [(1986) Mol. Immunol. 23, 39-44] and therefore it is possible to label only C1q with ANS in the presence of IgG. Under such conditions no inhibition is observed. Addition of monomer IgG to a solution of C1q-bound ANS did not significantly alter the fluorescence of the ANS. However when oligomeric IgG was added there was a 2-fold increase in fluorescence over the same IgG concentration range. When C1q was pretreated with diethylpyrocarbonate there was little change in the fluorescence when IgG oligomers were added to C1q:ANS solutions. These results suggest that C1q undergoes conformational changes upon binding to IgG oligomers.

Anilino Naphthalenesulfonates↗
PubMed1989

Further evidence for dilution-dependent dissociation of C1q in human serum.

Dissociation of the C1q subcomponent in native C1 upon dilution was reexamined by using ultracentrifugation in a sucrose gradient and high performance liquid chromatography system with a size exclusion column for separating the dissociated C1q fractions. The antigenic content of C1q in each fraction was detected by ELISA and Western blotting; binding to erythrocyte antibody was also determined. The results confirmed a previous claim that C1q in native C1 dissociated as a function of dilution: up to 14.5% of C1q antigen was in the low molecular weight form (approximate S value: 4-5). Commercial preparations of purified C1q also contained C1q antigen in the low molecular weight form.

Centrifugation, Density Gradient↗