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PubMed1984

Identification of the Raji cell membrane-derived C1q inhibitor as a receptor for human C1q. Purification and immunochemical characterization.

We have shown previously that an activity which is capable of precipitating purified C1q and inhibiting some of the C1q-dependent biologic reactions could be solubilized from the membranes of both normal human peripheral B lymphocytes and a B cell-derived lymphoblastoid cell line (Raji), both of which are known to possess receptors for human C1q. In this report we present evidence that this membrane-associated C1q inhibitor is a chondroitinase-insensitive macromolecule and is the receptor for human C1q. The receptor was solubilized from membranes of Raji cells with Nonidet P-40 and purified to homogeneity using C1q-Sepharose 4B affinity chromatography. Equilibrium density gradient centrifugation analysis revealed that the complex could be resolved into a protein-rich, low density fraction and a carbohydrate-rich, high density fraction. The large hydrodynamic size, coupled with the high buoyant density, suggests that a proteoglycan is a constituent of the complex and indicates that the receptor might be a macromolecular complex of a proteoglycan portion noncovalently linked to a 60-70 kD glycoprotein. The glycoprotein moiety, in turn, consists of two or more identical (70,000 mol wt) polypeptide chains held together by disulfide bonds and constitutes the C1q receptor (C1qR). Sucrose density ultracentrifugation analysis showed that the isolated receptor sediments with an apparent rate of 4.2 S. Immunochemical analyses demonstrated that a typical preparation of the C1qR complex consists of approximately 23% uronic acid and approximately 21% galactosamine with a galactosamine-to-glucosamine ratio of 3.2. Binding of C1q to the receptor was found to be optimal at low ionic strength and neutral or near-neutral pH (7-7.4). The isolated receptor was found to inhibit C1q hemolytic function, abrogate C1q-dependent rosette formation, and block the C1q-dependent, cell-mediated cytotoxicity, all of which are activities mediated by the receptor.

Amino Acids↗
PubMed1984

[Circulating immune complexes: optimization and characteristics of the C1q(I125) fixation test].

The present paper describes the optimisation of a liquid phase [125I] C1q binding assay for the detection of circulating immune complexes. Blood must be collected without any anticoagulant. The serum can be stored or transported as usual without damage. A 90 min incubation is needed to reach the equilibrium of the reaction; polyethylene glycol (2,5% final concentration) is added to precipitate the [125I] C1q-CIC complex. By its simplicity and reproducibility, this test can be currently employed, especially in the case of treatment by plasmapheresis.

Antigen-Antibody Complex↗
PubMed1994

The effects of histidine residue modification on the immune precipitating ability of rabbit IgG.

Treatment of anti-ovalbumin rabbit IgG with diethylpyrocarbonate (DEPC) at concentrations up to 100 microM led to a progressive decrease in the rates of formation of insoluble immune complexes, without affecting the final extent of immune complex formation. DEPC concentrations approximately 10-fold higher were needed to give comparable decreases in the rates of immune complex formation by F(ab')2. Treatment of DEPC-treated IgG with hydroxylamine led to substantial restoration of the rates of formation of insoluble immune complexes. Carbethoxylation of two histidine residues per IgG molecule had little effect on rates of formation of insoluble immune complexes, but these rates were markedly decreased in samples of IgG with four to five histidines per molecule modified. There were parallel decreases in the protein A-binding activity and in the rates of formation of insoluble immune complexes in IgG treated with increasing concentrations of DEPC. The presence of complement protein C1q restored the rates of formation of insoluble immune complexes of DEPC-treated IgG.

Animals↗
PubMed2000

Binding of Tamm-Horsfall protein to complement 1q measured by ELISA and resonant mirror biosensor techniques under various ionic-strength conditions.

The purpose of the present study was to quantify the binding affinity between Tamm-Horsfall protein (THP) and complement 1q (C1q) using ELISA and a resonant mirror biosensor. In ELISA, immobilized THP was incubated with soluble C1q under both low and physiological ionic-strength conditions. Tamm-Horsfall protein bound C1q with an equilibrium dissociation constant (KD) of 1.9 +/- 0.6 nmol/L in low ionic-strength Tris buffers (20 mmol/L NaCl, pH 7.5) and with a lower affinity (KD of 13.4 +/- 4.7 nmol/L) in physiological-strength Tris buffers (154 mmol/L NaCl, pH 7.5). A resonant mirror biosensor, which monitors binding events in real-time, was used to quantify the KD of this reaction, as well as to estimate the kinetic parameters. In these studies, THP and C1q bound with an association rate constant, kass, of 1.25 x 105 L/mol per s and a dissociation rate constant, kdiss, of 0.002-0.005/s. The calculated KD for the THP/C1q binding in low ionic-strength buffers was higher (averages of 10-15 nmol/L) than that obtained by the ELISA, while physiological ionic-strength buffers still reduced the affinity of this binding by an order of magnitude. In conclusion, THP consistently bound C1q with high affinity using several techniques. At least a portion of this interaction involved electrostatic events, as demonstrated by the influence of ionic strength on the binding affinity.

Adjuvants, Immunologic↗
PubMed1998

Antisulfatide polyneuropathy: antibody-mediated complement attack on peripheral myelin.

Increased titers of circulating antisulfatide antibodies are consistently associated with a variety of chronic axonal and demyelinating polyneuropathy syndromes. Previous studies have shown that the pattern of antisulfatide binding to neural tissues correlates with the type of neuropathy. This suggests a possible role for antisulfatide antibodies in inducing peripheral nerve dysfunction, although their exact contribution to the pathogenesis of neuropathy is still unknown. We examined sural nerve biopsy specimens from two patients with sensorimotor and small fiber sensory neuropathy associated with high titers of IgM monoclonal antibodies to sulfatide. Electrophysiological and pathological findings were consistent with predominant demyelination in the patient with sensorimotor involvement, whereas evidence of demyelination was obtained only by teased fiber examination in the other patient. The ultrastructural study disclosed in both cases the presence of myelinated fibers with widely spaced myelin, due to a separation of leaflets of the intraperiod lines. Immunocytochemistry, performed on frozen sections, demonstrated the presence of IgM and complement product C3d bound to myelin sheaths of almost all fibers. Few fibers were immunoreactive for complement components C1q and C5. In addition, the terminal complement complex neoantigen C5b-C9, not associated with S protein, was detected on some myelinated fibers. The results suggest that, at the least in some forms of demyelinating neuropathy associated with antisulfatide antibodies, pathological changes are complement mediated. Our data further confirm previous clinical and experimental observations that complement activation initiates separation of myelin intraperiod lines.

Aged↗
PubMed2003

Activation of complement in the central nervous system: roles in neurodegeneration and neuroprotection.

The complement system is an essential effector of the humoral and cellular immunity involved in cytolysis and immune/inflammatory responses. Complement participates in host defense against pathogens by triggering the formation of the membrane attack complex. Complement opsonins (C1q, C3b, and iC3b) interact with surface complement receptors to promote phagocytosis, whereas complement anaphylatoxins C3a and C5a initiate local inflammatory responses that ultimately contribute to the protection and healing of the host. However, activation of complement to an inappropriate extent has been proposed to promote tissue injury. There is now compelling evidence that complement activation in the brain is a double-edged sword in that it can exert beneficial or detrimental effects depending on the pathophysiological context. This review focuses on the roles of the complement system in the pathogenesis of acute brain injury (cerebral ischemia and trauma) and chronic neurodegeneration (Alzheimer's disease). Because many effects of the complement appear to promote neuronal survival and tissue remodeling, directing activation of the complement system in the brain may provide a better therapeutic rationale than inhibiting it.

Alzheimer Disease↗
PubMed1995

Participation of the blood platelet in immune reactions due to platelet-complement interaction.

OBJECTIVE: Review of different aspects of the primary interaction of complement with blood platelets in immunological reactions and the effect on platelet activation in healthy people and patients. DATA SOURCES AND SELECTION CRITERIA: Relevant original papers and review articles mainly of the English-written literature. RESULTS: Besides their major role in hemostasis and wound healing, blood platelets are involved in immunological reactions. They are not only able to interact with IgG through Fc receptors (FcR), they also react with complement components. This review summarizes interactions of complement with mainly human platelets. Such interactions may occur through complement receptors of the plasma membrane (e.g. C1q receptor, complement receptors 2 and 4), but also in a receptor-independent way including activation of the platelet by the membrane attack complex of complement C5b-9. In addition, activation of complement at the surface of the platelets may be induced after binding of anti-platelet antibodies to membrane glycoproteins (e.g. GpIIb/IIIa, GpIb/IX) or after binding of platelet-nonspecific immune complexes via FcR. Complement activation in turn may be regulated by various means including specific plasma or membrane proteins [e.g. decay-accelerating factor (DAF), membrane cofactor protein (MCP), membrane inhibitor of reactive lysis (MIRL), C8-binding protein (C8bp, homologous restriction factor hrf)]. As a further way of self-protection against complement attack, platelets may actively release C5b-9, deposited at the surface as C5b-9-enriched membrane vesicles. CONCLUSIONS: Two lines of interaction of platelet with complement can be distinguished. On the one hand, platelets are equipped with membrane proteins which protect them from complement attack against themselves. On the other hand, membrane receptors for activated complement components as well as for IgG are expressed on the surface, which enable the platelet to intervene in immunological reactions. This property varies between platelets of different species and needs further investigation also in view of the platelet as an intersection between immunology and hemostasis.

Antigen-Antibody Complex↗
PubMed1999

Functional definition of a B cell epitope, KGEQGEPGA, on C1q the Fc-binding subunit of the first component of complement.

A synthetic peptide representing the C1q epitope KGEQGEPGA has been shown to suppress or delay the onset of CII-induced arthritis when applied intravenously (i.v.) prior to an intradermal (i.d.) challenge, in a mouse model; the phenomenon being associated with the development of immunoglobulin (Ig)M antibodies specific for the KGEQGEPGA epitope. Here we show that this amino acid sequence provides an immunodominant B cell epitope that is recognised by autoantibodies present in the sera of patients with chronic inflammatory diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis, two diseases associated with an immune response to C1q. The peptide's ability to produce peptide specific IgM when applied i.v. in both normal and athymic mice but not in mice exhibiting the x-linked B-cell associated Bruton's tyrosine kinase defect permits classification of the KGEQGEPGA peptide as a T-cell independent antigen type-2 (TI-2). IgM monoclonal antibodies raised against the peptide are able to functionally block activation of the complement cascade by C1q, via a mechanism that inhibits the C4 consumption. Antibodies to this immunodominant epitope may therefore modulate inflammatory processes by interfering with the activation of the classical pathway of the complement.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1983

Circulating immune complexes in toxoplasmosis: detection and clinical correlates.

The 125I-C1q binding test was employed to detect circulating immune complexes in serum of 27 subjects with acute toxoplasmosis. The subjects had no known underlying disease. Elevated C1q binding activity (C1q-BA) was found in the serum of each of three adults with the systemic febrile form of toxoplasmosis, seven of 19 patients with the lymphadenopathic form, and one of four infants with congenital infection. The patients with the systemic form of illness had significantly greater mean C1q-BA than did those with the lymphadenopathic form (P less than 0.001). In six episodes of symptomatic toxoplasmosis associated with elevated C1q-BA, follow-up sera were obtained after resolution of all signs and symptoms. Each of these sera showed normalization of C1q-BA. We conclude that immune complex like material is frequently present in the serum of patients with toxoplasmosis and parallels disease activity.

Adolescent↗
PubMed1991

C1q nephropathy: a pediatric clinicopathologic study.

We report on 15 children with proteinuria, at the nephrotic level in the majority of cases, who had no histologic glomerular alterations (eight cases), or focal and segmental glomerular scarring with (three cases) or without (four cases) mesangial proliferation. In all cases, immunofluorescence (IF) microscopy showed prominent mesangial C1q deposits with variable amounts of immunoglobulins. Ultrastructurally, most had conspicuous mesangial electron-dense deposits. Cases with no glomerular histologic alterations were histologically indistinguishable from minimal change disease (MCD), yet they uniformly had an unsatisfactory response to oral prednisone. Thus, the presence of immune deposits with a prominent C1q contribution identifies a group of cases that respond poorly to steroids and that, if light microscopy is considered in isolation, might otherwise be designated MCD.

Adolescent↗
PubMed1995

A porin from Klebsiella pneumoniae: sequence homology, three-dimensional model, and complement binding.

A recombinant plasmid containing ompK36, the gene coding for the Klebsiella pneumoniae outer membrane protein OmpK36, was constructed by transposon mutagenesis and subcloning. Clones were identified in a cosmid library in Escherichia coli on the basis of their reaction with antiserum against the OmpK36 protein and by the presence in gel electrophoretic analysis of a band in E. coli outer membranes migrating with a mobility corresponding to 36 kDa. The ompK36-encoded protein exhibited characteristic properties of porins, such as heat modifiability and resistance to trypsin. The sequence of the gene revealed that OmpK36 is a close relative of the enterobacterial porin family, with a high degree of homology with E. coli OmpC, PhoE, and OmpF. On the basis of the structures of OmpF and PhoE porins, determined previously by X-ray analysis, it appears likely that the three-dimensional structure of OmpK36 also contains the motif of a 16-stranded beta-barrel, with long loops on one end and short turns on the other. Like the OmpC porin from E. coli, OmpK36 contains a long insertion in loop 4. The results of a binding study of complement component C1q to OmpK36 and the analysis of the OmpK36 model suggest that C1q binding sites are covered by the lipopolysaccharide core in the native porin.

Amino Acid Sequence↗
PubMed1982

[Circulating immune complexes, detection in human glomerulonephritis by the PEG-EDTA technique (author's transl)].

In a prospective study, we screened sera samples of 128 patients with glomerulonephritis (GN) for the presence of circulating immune-complexes (CIC) fixing C1q by precipitation of native C1q with 2% polyethylene glycol (PEG) in the presence of 10 mM EDTA. The amount of precipitated C1q, as measured by Mancini, is less than 27% (m +/- 2 SD) of the original value in control sera. We found 35/128 (27%) positives samples, distributed as follows: 4/17 (24%) in acute GN, 10/15 (67%) in SLE, 2/16 (13%) in membraneous GN, 13/24 (54%) in membranoproliferative GN, 3/16 (19%) in segmental focal hyalinosis, 2/10 (20%) in minimal lesions nephrotic syndrome, and 1/30 (3%) in mesangial IgA GN. We then correlated these results with clinical, serological and pathological data. Whatever the type of GN, the presence of CIC fixing C1q correlated significantly, well with : the presence of chronic renal failure (serum creatinine greater than or equal to 2 mg/dl) (X2 = 5.48, p less than 0.02), the presence of hypocomplementemia (X2 = 12.30, p less than 0.001), the presence of low serum C3 (X2 = 8.25, p less than 0.01), the activation of C3 through normal pathway (low serum C4 and/or C1q) (X2 - 18.12, p less than 0.001) and the presence of glomerular deposits of C3 (X2 = 8.52, p less than 0.01), of C4 (X2 = 7.10, p less than 0.01), and of C1q (X2 = 4.11, p less than 0.05). The technique is simple, does not require labeled C1q, and allows the further study of antigen or antibody determinants of the complexes. Its sensitivity is near that of the 125 I-C1q binding assay technique. Such routine screening is a major immunopathologic step in the investigation of human GN.

Adult↗
PubMed1993

Rapid isolation and biochemical characterization of rat C1 and C1q.

Using a human IgG-Sepharose column to which rabbit anti-human IgG was bound (rabbit anti-human/human IgG-Sepharose), human and rat C1 or C1q were isolated from serum in a single step, and the C1q further purified to homogeneity by FPLC. This procedure allowed the rapid isolation of haemolytically active C1 or C1q, with a yield equal to or greater than published methods. The availability of human and rat C1q allowed comparison of the two molecules, revealing differences in their mobility on SDS-PAGE as well as on agarose gel electrophoresis. Amino terminal sequence analysis demonstrated greater than 78% residue identity between rat C1q A, B and C chains and the published human and mouse sequences. Similar amino acid compositions suggest that the homology extends throughout the molecules. In addition to the major A:B and C:C dimer bands, rat, unlike human C1q, contained minor dimer species. These may reflect heterogeneity in glycosylation and or lysine and proline hydroxylation.

Amino Acid Sequence↗
PubMed1997

The systemic lupus erythematosus (SLE) disease autoantigen-calreticulin can inhibit C1q association with immune complexes.

Following its release from cells during infection and inflammation, calreticulin (CRT) can act as an autoantigen in diseases such as SLE. Why CRT is a target of protective immunity and whether it may interfere with innate immunity once released from cells during inflammation is unclear. In the present study, we found that CRT was detected more frequently in SLE sera and in higher amounts than found in control sera. Approximately 40% of SLE sera tested contained autoantibodies against CRT as detected by ELISA and immunoblotting. CRT was found to be predominantly in the sera of SLE patients associated with immune complexes and C1q, and only bound to the surfaces of neutrophils in the presence of low levels of calcium and magnesium. In order to further investigate the C1q-CRT interaction, recombinant CRT and its discrete domains (N-, P-, and C-domains) were produced in Escherichia coli. CRT binds to globular head region of C1q primarily via its N- and P-domains. The N-domain was shown to be the most autoantigenic region of CRT, as the anti-CRT autoantibodies from most patients reacted against this region. CRT also altered C1q-mediated immune functions. The P-domain of CRT bound to C1q and reduced the binding of immune complexes in SLE sera to immobilized C1q. Full length CRT and its N- and P-domains were able to reduce the C1q-dependent binding of immune complexes to neutrophils and solid-phase bound C1q. We conclude that CRT, once released from leucocytes during inflammation, may not only induce an antigenic reaction, but also interfere with C1q-mediated inflammatory processes.

Adult↗
PubMed1992

Western blot analysis of human IgG reactive with the collagenous portion of C1q: evidence of distinct binding specificities.

An enzyme-linked immunosorbent assay (ELISA) with purified collagenous C1q fragments in the solid phase was used for detection of C1q-specific immunoglobulins in the sera of twelve patients with systemic lupus erythematosus (SLE) or the SLE-like disease hypocomplementemic urticarial vasculitis syndrome (HUVS). By clinical criteria, four patients had SLE, and three HUVS. Five patients had overlap syndromes. All patients demonstrated high concentrations of C1q-specific IgG and markedly low concentrations of circulating C1q. Detection of C1q-specific IgG in SLE sera was facilitated by employment of saturating concentrations of collagenous C1q fragments in the solid-phase ELISA. When added to SLE serum, immune complex-fixed C1q inhibited binding of IgG to the C1q fragments, whereas addition of C1q alone had limited inhibitory effects. Under similar conditions, using approximately equimolar amounts of C1q relative to solid-phase C1q fragments, no ELISA inhibition was obtained after addition of C1q or immune complex-fixed C1q to a HUVS serum. Even in large excess, purified C1q did not inhibit binding of HUVS-IgG to solid-phase C1q fragments. Thus, possible interactions between HUVS-IgG and native Clq are probably of low affinity. By Western blot analysis, IgG reactive with the B and C chains of C1q was found in the eight patients with evidence of HUVS, five of whom also showed IgG binding to C'-C' and A'-B' dimers of collagenous C1q fragments. Sera from SLE patients were negative by Western blot analysis. It seems likely that C1q-specific IgG in SLE primarily recognizes assembled C1q molecules or collagenous C1q fragments expressing conformational epitopes of bound C1q. Interestingly, patients with evidence of HUVS fairly consistently had zymogen (C1r-C1s)2 complexes in their serum, while patients with SLE showed high concentrations of complexes containing Cl inhibitor, C1r and C1s. Different binding specificities of C1q-reactive IgG could be of importance with regard to pathogenetic mechanisms in SLE and HUVS. There was no correlation between findings of C1q-specific IgG and a variety of autoantibodies associated with SLE and SLE-like disease.

Adolescent↗
PubMed2001

Ultraviolet-radiation-induced keratinocyte apoptosis in C1q-deficient mice.

Exposure to ultraviolet B radiation is an important trigger of both systemic and cutaneous disease flares in individuals with systemic lupus erythematosus. More than 90% of individuals with homozygous C1q deficiency develop a systemic-lupus-erythematosus-like illness, which is typically associated with a severe photosensitive rash. Apoptotic, human keratinocytes have been shown in vitro to bind C1q, in the absence of antibody. These observations, together with the hypothesis that a major source of the autoantigens driving the immune response in systemic lupus erythematosus comes from apoptotic cells, led us to investigate the effects of murine C1q deficiency on ultraviolet-radiation-induced keratinocyte apoptosis in vivo. In this work, we demonstrated C1q binding to apoptotic murine keratinocytes in vitro and showed for the first time that C1q is also present on sunburn cells in vivo. In addition to C1q, we detected C3 deposition on sunburn cells in both wild-type and C1q-deficient mice, suggesting activation of the alternative pathway. Following acute ultraviolet exposure in vivo, no difference in the rate of clearance of sunburn cells was found in C1q-deficient mice from three different genetic backgrounds, compared with strain-matched wild-type controls. Furthermore, chronic ultraviolet exposure did not result in the production of autoantibodies or the development of glomerulonephritis. Our findings suggest that C1q does not play a critical role in the physiologic clearance of apoptotic murine keratinocytes in vivo.

Acute Disease↗
PubMed2004

[Significance of serum anti-Clq Ab in evaluation of lupus nephritis activity and its curative effects of pharmacotherapy on lupus nephritis].

OBJECTIVE: To investigate the significance of serum anti-C1q Ab of evaluation of lupus nephritis activity and its curative effects of cyclophophamide therapy on lupus nephritis (LN). METHODS: The level of serum anti-C1q antibody of 75 patients with LN was examined by enzyme-linked immunosorbent assay (ELISA) of the 75 patients the incipient cases had never received corticosteroid and immunosuppressant and the recurrent cases had stopped the immunosuppressant treatment for more than 3 months and were treated, if so, with prednisone with the dosage </= 10 mg/d. Thirty-one patients underwent renal biopsy. The patients underwent treatment of cyclophophamide. The relationships between serum anti-C1q Ab level and lupus nephritis activity, renal pathohistology, as well as laboratory parameters were analyzed, followed by further regular follow-up to investigate its influence to the curative effect. RESULTS: Fifty-five of the 75 patients (73.3%) were anti-C1q Ab positive with the level of (92 U/ml +/- 41 U/ml). The mean time of conversion of urinary protein into negative was 9 months in the positive C1q positive group and 6 months in the C1q negative group. One year after, 25% of those with positive C1q antibody failed to convert into urinary protein negative, and 90% of those with negative C1q antibody converted into urinary protein negative. One year after, 32% of those whose serum C1q antibody remained positive 1 month after the treatment failed to convert into urinary protein negative, and 91% of those whose serum C1q antibody remained positive 1 month after the treatment converted into urinary protein negative. The serum anti-C1q Ab level was positively correlated with the lupus nephritis clinical active index, proteinuria, and titer of anti-dsDNA, and was negatively correlated with the levels of serum C3 and C4. Renal biopsies showed a positive correlation between the serum anti-C1q Ab level and the activity index of renal pathohistology. Multivariate analysis showed that the serum anti-C1q Ab level after treatment were associated with the curative effect and prognosis of LN. CONCLUSION: Serum anti-C1q Ab is not only a good index of lupus nephritis activity, but also reflects renal involvement and curative effect. That serial measurement of serum anti-C1q Ab may provide better clinical strategies for the therapy.

Adult↗
PubMed1982

Dissociation of C1 and concentration dependence of its activation kinetics.

The activation of the zymogen C1s to the enzyme C1s in the human C1 complex [C1q(c1rC1s)2] was studied as a function of the concentrations of (C1rC1s)2 and C1q which were saturated with oligomers of rabbit IgG. A large concentration dependence of the sigmoidal kinetics was observed in the 2-180 nM concentration range. This was explained by association-dissociation equilibria between the antibody-saturated C1q and various forms of the (C1rC1s)2 complex (unactivated to activated). The establishment of these equilibria (binding constant 2 x 10(7) M-1) was assumed to be fast as compared to the rates of the activation steps (rate constants 10(-3) and 10(-2) sec-1 at 30 degrees C). The fast re-equilibration of the C1 complex explains the finding that small amounts of antibody-saturated C1q catalysed the activation of large amounts of C1s. The interpretation of the kinetic results was supported by a direct demonstration of the dissociation of C1 into C1q and (C1rC1s)2 by analytical and density gradient centrifugation. No difference was found between the rates of activation and the dissociation properties of reconstituted C1 and C1 isolated from serum.

Centrifugation, Density Gradient↗