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PubMed2004

Identification of a novel C1q family member in color crucian carp (Carassius auratus) ovary.

Potential roles of C1q/tumor necrosis factor (TNF) superfamily proteins have been observed in vertebrate oogenesis and oocyte maturation, but no ovary-specific member has been identified so far. In this study, we have cloned and identified a novel member of C1q family with a C1q domain in the C-terminal from fully grown oocyte cDNA library of color crucian carp and demonstrated that the gene might be specifically expressed in ovary and therefore designated as Carassius auratus ovary-specific C1q-like factor, CaOC1q-like factor. It encodes a 213 amino acid protein with a 17 amino acid signal peptide. There is only one protein band of about 24.5 kDa in the extracts from phase I to phase IV oocytes, but two positive protein bands are detected in the extracts of mature eggs and fertilized eggs. Furthermore, the mobility shift of the smaller target protein band cannot be eliminated by phosphatase treatment, but the larger protein band increases its mobility on the gel after phosphatase treatment, suggesting that the larger protein might be a phosphorylated form. Immunofluorescence localization indicates that the CaOC1q-like proteins localize in cytoplasm, cytoplasm membrane and egg envelope of the oocytes at cortical granule stage and vitellogenesis stage, whereas they were compressed to cytoplasm margin in ovulated mature eggs and discharged into perivitelline space between cytoplasm membrane and egg envelope after egg fertilization. Further studies on distribution and translocation mechanism of the CaOC1q-like factor will be benefit to elucidate the unique function in oogenesis, oocyte maturation and egg fertilization.

Amino Acid Sequence↗
PubMed1989

Antibody to a cryptic, solid phase C1Q antigen in membranoproliferative nephritis.

IgG containing material detected in membranoproliferative nephritis (MPGN) serum with a solid phase (sp) Clq ELISA has been presumed to be immune complexes. However, in serum from 13 MPGN patients containing large amounts of spClq-binding material, sucrose density ultracentrifugation and sieve chromatography showed spClq-binding protein to sediment at 7S or cofractionate with IgG. One serum (stored for 12 years) contained, in addition, spClq-binding material sedimenting at more than 19S. Isolated MPGN IgG was shown to bind to spClq. SpClq-binding material could be totally removed from MPGN serum by absorption with BSA-anti-BSA immune precipitates, and by acid elution of the precipitates IgG binding to spClq could be recovered. F(ab')2, isolated from pepsin digested MPGN IgG, continued to bind spClq. Binding of MPGN IgG or F(ab')2 to spClq was not inhibited by 2 M NaCl. Incubation of MPGN serum with 125I Clq followed by sucrose density ultracentrifugation resulted in a peak of radioactivity at 11S, the sedimentation rate of Clq, giving evidence that material binding fluid phase Clq is not present. SpClq-binding IgG was detected in 54% of 68 MPGN patients. These results indicate that the 7S spClq-binding IgG represents antibody to a cryptic antigen revealed only when Clq fixes to a solid surface.

Antigen-Antibody Complex↗
PubMed2004

Pediatric IgA nephropathy: clinical features at presentation and outcome for African-Americans and Caucasians.

AIM: To determine the disease severity at onset and outcome for African-American and Caucasian pediatric patients with IgA nephropathy diagnosed at the Le Bonheur Children's Medical Center since 1990. DESIGN/METHODS: The study population included all patients diagnosed with IgA nephropathy at the Le Bonheur Children's Medical Center from January 1990 through February 2004. All were below age 18 at biopsy. Clinical features assessed at diagnosis were age, gender, presence of hypertension, history of macroscopic hematuria, degree of proteinuria, severity of renal histology and pattern for immunofluorescent reactants. STATISTICS: Student's t-test was used to compare age at biopsy and length of follow-up between the 2 groups. Fisher's exact test was used to compare features at presentation and patterns of immunofluorescence. Kidney survival was predicted by the Kaplan-Meier method. RESULTS: Forty-seven patients (17 African-American, 29 Caucasian) were studied. Clinical features at diagnosis and pattern for all immunofluorescent reactants did not differ significantly between the 2 groups. Mesangial deposition of C1q occurred in 4/17 African-Americans as compared to 1/27 Caucasians (p = 0.06). Four patients (2 African-Americans, 2 Caucasians) progressed to end-stage renal disease. Predicted kidney survival was 96% (94% in African-Americans and 97% in Caucasians) at 1 year and 91% (94% in African-Americans and 89% in Caucasians) at 5 years from diagnosis. Mean time from diagnosis to end-stage renal disease or last follow-up was 3.3 years (3.8 for African-Americans, 3.0 for Caucasians). Macroscopic hematuria occurred prior to diagnosis for 90% of the Caucasian as compared to 61% of the African-American patients (p = 0.03). Urinalysis was normal at last follow-up visit for 24% of African-American patients and 32% of Caucasian patients. CONCLUSION: In a relatively small sample from a single center, except for the difference in macroscopic hematuria, clinical features at diagnosis and outcome of IgA nephropathy appear similar for African-American and Caucasian pediatric patients.

Black or African American↗
PubMed2004

Exploitation of host cell cytoskeleton and signalling during Listeria monocytogenes entry into mammalian cells.

Deciphering how Listeria monocytogenes exploits the host cell machinery to invade mammalian cells during infection is a key issue for the understanding how this food-borne pathogen causes a pleiotropic disease ranging from gastro-enteritis to meningitis and abortions. Using multidisciplinary approaches, essentially combining bacterial genetics and cell biology, we have identified two bacterial proteins critical for entry into target cells, InlA and InlB. Their cellular ligands have been also identified: InlA interacts with the adhesion molecule E-cadherin, while InlB interacts with the receptor for the globular head of the complement factor C1q (gC1q-R), with the hepatocyte growth factor receptor (c-Met) and with glycosaminoglycans (including heparan sulphate). The dynamic interaction between these cellular receptors and the actin cytoskeleton is currently under investigation. Several intracellular molecules have been recognized as key effectors for Listeria entry into target cells, including catenins (implicated in the connection of E-cadherin to actin) and the actin depolymerising factor/cofilin (involved in the rearrangement of the cytoskeleton in the InlB-dependent internalisation pathway). At the organism level, species specificity has been discovered concerning the interaction between InlA and E-cadherin, leading to the generation of transgenic mice expressing the human E-cadherin, in which the critical role of InlA in the crossing of the intestinal barrier has been clearly determined. Listeria appears as an instrumental model for addressing critical questions concerning both the complex process of bacterial pathogenesis and also fundamental molecular processes, such as phagocytosis.

Actins↗
PubMed1986

Statistical analysis of a liquid phase radioimmunoassay for immune complex determination.

A computer program is presented which enables iterative determination of the weighted standard curve and the quality control parameters calculation for the liquid phase radioimmunoassay which employs binding of labelled C1q as a measure of the presence of immunological complexes in serum samples. 22 independently performed laboratory tests were evaluated with respect to the presence of relationship between the dose (standardized human IgG aggregates) and response (fraction of radiolabelled C1q bound). On 14 occasions the plotted curve was sigmoidal in shape, the rest of the curves did not reach lower or upper asymptote. When the logistic transformation of this data was used the dose-response curve was linear and could be plotted with the use of the least square method. This allows calculation of the two other parameters of the sigmoidal curve (slope and midpoint). The slope of the weighted regression line, intercept point with the axis of ordinates and correlation coefficient were determined by means of the least square method for weighted linear regression with repetitions. When the iterative procedure was completed, content of immunological complexes in sera was calculated. The program is written in Fortran for the ODRA 1300 computer series. The printout consist of three parts. First part contains the original data, parameters and information about the form of input data. The second part of the printout consist of the results, obtained from non-weighted and weighted regression lines and the plotted regression line. The third part of the printout contains the final results of immune complexes determination.

Antigen-Antibody Complex↗
PubMed2005

C1q nephropathy: features at presentation and outcome.

The study population comprised all 20 patients followed since 1990 through December 2004 at the Le Bonheur Children's Medical Center with diagnosis of C1q nephropathy (55% boys; 60% African Americans). All were aged under 18 years at biopsy (mean 11.2 years, 65% aged 11 or over); the youngest presented at age 10 months and progressed to end-stage renal disease at 14 months. None had clinical or laboratory features of systemic lupus erythematosis or membranoproliferative glomerulonephritis. Clinical features assessed at diagnosis were age, gender, blood pressure, history of macroscopic hematuria, urinary protein to creatinine ratio, serum creatinine, estimated glomerular filtration rate, renal histology, and pattern for immunofluorescent reactants. At the time of biopsy 40% had nephrotic syndrome and 30% nephrotic range proteinuria without nephrotic syndrome. Three patients with nephrotic syndrome also had chronic renal insufficiency at diagnosis. The most common histological feature was focal segmental glomerulosclerosis in 40%, but 30% had minimal change lesion. Four patients, all with nephrotic syndrome at diagnosis, progressed to end-stage renal disease. Of the 12 patients not presenting with nephrotic syndrome, none had chronic renal insufficiency at last follow-up. Kidney survival was 94% and 78% at 1 and 5 years, respectively, in all patients and 88% and 49% in those presenting with nephrotic syndrome.

Adolescent↗
PubMed2000

Characterization and molecular cloning of rat C1qRp, a receptor on NK cells.

Here we report the generation of monoclonal antibodies (mAb) LOV3 and LOV8 to a 110-130-kDa membrane glycoprotein expressed by rat NK cells. This NK surface molecule was identified by eucaryotic expression cloning as the structural orthologue of the phagocytosis-stimulating receptor for complement factor C1q and mannose-binding lectin on human macrophages, C1qRp. Rat C1qRp is a monomeric type I integral membrane protein consisting of 643 amino acids with an N-terminal lectin-like domain, five epidermal growth factor-like domains, a transmembrane domain and a 45-residue cytoplasmic domain. It is encoded by a single gene on rat chromosome 3q41-q42 and is 67% and 87.5% identical at the amino acid level to human and mouse C1qRp, respectively. Rat C1qRp is expressed by resting and by activated NK cells, on subpopulations of NKR-P1(+) T cells (NK/T cells), dendritic cells, macrophages and granulocytes, but not by B cells or NKR-P1(-) T cells. Expression of this innate immune receptor is therefore not restricted to hematopoietic cells of the myeloid lineage, but is also expressed on subsets of cells of lymphoid origin. The mAb did not affect the cytotoxic function of NK cells, and C1qRp on NK cells may have functions not related to NK killing.

Amino Acid Sequence↗
PubMedDate not supplied

Circulating immune complexes in HBsAg-positive and HBsAg-negative chronic liver diseases.

Circulating immune complexes (CIC) were investigated by the fluid-phase C1q-binding test in serum samples from 131 subjects with various clinical types of HBsAg-positive and HBsAg-negative chronic hepatitis diagnosed on both clinical and laboratory criteria, including liver biopsy; serum samples from 28 asymptomatic HBsAg carriers and 75 healthy controls were also examined. The results of these findings were correlated with the liver damage and the clinical course of the disease. CIC were detected in all categories of chronic hepatitis with a significant prevalence only in patients with liver cirrhosis. No correlation was found between the levels of CIC, the presence of circulating HBsAg, and active inflammation or necrosis in any of the different types of chronic hepatitis. In contrast, a highly significant correlation was found between the prevalence of CIC and a more severe prognosis in patients with CAH and liver cirrhosis. The findings suggest that the presence of CIC is not specific for a given type of chronic liver disease and that they do not play any role in the pathogenesis of liver damage. The correlation observed between the presence of CIC and an unfavourable course of chronic liver disease suggests that CIC may modify the host's immune defence mechanisms.

Antigen-Antibody Complex↗
PubMed1982

Evaluation of assays to detect immune complexes as an immunodiagnostic aid in patients with melanoma.

Sera from 211 melanoma patients were tested before and after surgery for the presence of immune complexes (i.c.) by the 125I-C1q radioimmunoassay (C1q RIA) and a nephelometric monoclonal rheumatoid factor assay (mRhF). The patients were grouped according to stage of disease and therapy. Before surgery stage III patients had a higher incidence of i.c. (26.9%) than stage II (17.5%) and stage I (6.1%) patients. The incidence of i.c. in the latter patients did not differ from that of normal controls. Stage I patients treated with BCG therapy had a higher incidence of i.c. before and after surgery to remove melanoma compared with untreated patients. The incidence of i.c. in stage I and II patients was higher in sera taken after surgical removal of tumour compared to that in sera taken before surgery. Sequential studies revealed that i.c. often appeared then disappeared prior to clinical detection of recurrences. These results suggested that antigen excess was a frequent cause for failure to detect i.c. A prospective evaluation of the usefulness of assays for i.c. to monitor disease activity in melanoma patients was conducted. In some individual patients detection of i.c. was a prelude to recurrence from melanoma but the high false negative rate and the presence of elevated i.c. levels unrelated to recurrent tumour suggested that these assays wound be of limited diagnostic value in the management of melanoma.

Adult↗
PubMed1984

Clinical significance of circulating immune complexes in 'lone' cryptogenic fibrosing alveolitis and those with associated connective tissue disorders.

The clinical, radiographic and physiological features, and progression rates of forty unselected patients with cryptogenic fibrosing alveolitis (CFA) have been studied in relation to serum immune complexes measured by a C1q binding technique. Twenty (50%) had levels greater than normal. Those with associated connective tissue disorders (twenty-four) had a higher frequency of raised C1q binding than those with 'lone' CFA (sixteen) (63% compared to 31%). As observed previously in this group, those with associated disorders also had higher titres of immune complexes. Twelve of thirteen with polyarthritis had immune complexes and a considerably shorter duration of disease compared with those without joint symptoms (P less than 0.01). Several other observations suggest that immune complexes are especially associated with earlier disease. These include a trend towards a younger age and a lesser radiographic profusion score; a shorter duration of symptoms in relation to titres of immune complexes amongst those with raised values (P less than 0.05) and a higher transfer factor coefficient (Kco) (P less than 0.02). The relationship between Kco and the presence of immune complexes was still observed when those with 'lone' CFA were analysed separately. Other clinical features including sex, severity of dyspnoea and lung volumes did not distinguish those with and without complexes, either for the whole group of patients or when those with and without associated connective tissue disorders were analysed separately. Analysis of eighteen patients followed to death showed no correlation between length of survival from first symptoms and immune complexes, neither was there any clear association with corticosteroid responsiveness and immune complexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigen-Antibody Complex↗
PubMed1990

A new C1q solid-phase assay for the detection of IgM immune complexes: application to the follow-up of kidney graft recipients with recurrent cytomegalovirus infection.

A C1q solid-phase enzyme assay for detecting circulating immune complexes (CIC) containing immunoglobulins M was developed. IgM immune complexes (IgM-CIC) bind to purified C1q-coated microplates. The amount of bound IgM-CIC is determined by adding anti-mu-alkaline phosphatase conjugate. This assay proved IgM-CIC specific; it does not detect IgG-CIC nor free anti-CMV IgM. Furthermore Rheumatoid Factor (RF) does not interfere with this test. Then, 119 renal allograft recipients were followed-up for the presence of seric IgM-CIC. Among them, 86 patients developed a recurrent Cytomegalovirus (CMV) infection and 33 did not. In the non-infected population, IgM-CIC were detected in only 15.2% of the patients. In contrast, patients with recurrent CMV infection showed a significantly higher frequency of detectable IgM-CIC (62.8%) (p less than 0.01). These IgM-CIC were detected: (a) during the first two or three weeks after graft; (b) in the course of the second month post graft. This second peak of IgM-CIC was never observed in subjects non-infected with CMV. IgM-CIC occurred before or at the same time as the detectable anti-CMV IgM and virus excretion in urines. Presence of IgM-CIC was not influenced by graft rejection episodes. Such a marker might help in discriminating immune response to viral infection from immune graft rejection.

Antibodies, Viral↗
PubMed1985

[Circulating immune complexes in breast cancer].

The occurrence of circulating immune complexes (CIC) was investigated in serum samples from 139 patients with breast cancer, using the 125I-C1q binding test. In the 85 cases of regional forms, the level of Clq binding activity did not appear to be correlated with the clinical TN stage, nor with the local treatment of the tumor. Conversely it was clearly elevated in the 13 cases of inflammatory breast tumors, and the decrease of CIC at the post-chemotherapy, but pre-surgical stage may involve the inflammatory signs in this augmentation of CIC. Frequency of occurrence and levels of CIC were slightly increased in the 41 metastatic breast cancer patients when compared to the cases of local breast carcinoma. In the disseminated forms, increase, no change, or decrease of CIC levels showed a poor correlation to progression, stabilisation, or improvement of the disease. CIC seems to be of slight prognostic value in breast cancer with local forms, but regarding progression of the disease, metastatic breast cancer patients with elevated CIC did not prove to be unfavorable group. So far, CIC did not appear to be a tumor marker or an evident prognostic factor of clinical relevance in breast cancer. Assays for antigen-specific CIC might be of greater clinical significance, in breast cancer, than the antigen non specific assays available at present.

Acute Disease↗
PubMed1989

Effect of immunosuppressive therapy on humoral immune response in multiple sclerosis.

The purpose of this study was to evaluate the effect of various therapeutic regimens on: 1) intrathecal IgG synthesis on the basis of IgG Index value, 2) oligoclonal IgG spectrum visualized by SDS-PAGE of unconcentrated CSF, 3) CSF antibody specific activity against MBP estimated by solid phase RIA and expressed in cpm/micrograms IgG, and 4) immune complex (CIC) level in the CSF estimated by C1q binding solid phase RIA. CSF antibody against Gal-C and ganglioside was also estimated. Patients with clinically definite MS were selected according to 4 therapeutic regimens: group 1, subjected to Mega-dose prednisone therapy (4000 mg over 54 days), group 2, subjected to moderate dose prednisone therapy, group 3 subjected to Mega-dose Solu-Medrol therapy (7500 mg over 10 days), and group 4, subjected to intravenous Cyclophosphamide therapy (4000 mg over 10 days). This last group was characterized by chronic progressive course of disease. Intrathecal IgG production was significantly reduced in all 4 groups as a result of therapy. More pronounced reduction was obtained in Mega-dose prednisone (p below 0.001) and CY (p below 0.001) treated group. Therapeutic regimens did not influence the IgG oligoclonal pattern. The moderate dose prednisone therapy and Mega-dose Solu-Medrol therapy on CSF IgG anti-MBP antibody specific activity were less effective than the Mega-dose prednisone medication. CY therapy did not influence anti-MBP antibody specific activity in MS group characterized by chronic progressive course of disease. The influence of therapeutic regimens on elevated CIC level in the CSF was insignificant. In our study CSF the anti-galactocerebroside antibody appeared to be of IgM class.

Antibody Formation↗
PubMed1983

Reactivity of low molecular weight material in cellular immune complex assays.

A major difference in molecular size of material reactive in the C1q binding assay and two cellular assays (Raji and L1210) for immune complexes, is reported. Elevated C1q binding of pathological sera was associated with material in the range 7-19S, as determined by Sepharose 6B chromatography of sera from patients with chronic inflammatory and neoplastic lung diseases. By contrast, reactivity of identical sera in the Raji and L1210 assays was linked predominantly with material of molecular size 7S. Dissociation of immune complexes on storage and/or in consequence of the chromatographic procedure was effectively discounted. Furthermore, differential binding of 7S IgG fractions tested at a standard concentration indicated that reactivity in either test was not attributable to non-specific binding of IgG. In a previous study, saturation of FcR (on L1210 and Raji) and C3R (on Raji only) by heat-aggregated IgG failed to distinguish whether binding directly involved these receptors or other cell surface components. In the present investigation, no firm correlations emerged between reactivity in the two tests and possible candidate antibodies reactive with cell surface components such as anti-lymphocyte and anti-nuclear antibodies. It is therefore suggested that low molecular weight binding may be attributable to more than one factor including 7S IgG (immune complex dissociated, or otherwise), autoantibodies, IgG-C3 complexes and possibly very small immune complexes (Ag1, Ab1). The assumption that Raji and L1210 and possibly other cellular assays detect only high molecular weight immune complexes is questionable and the need for further characterization of other reactive material is emphasized.

Antibodies, Antinuclear↗
PubMed2006

Anti-dsDNA antibody subtypes and anti-C1q antibodies: toward a more reliable diagnosis and monitoring of systemic lupus erythematosus and lupus nephritis.

The putative distinct diagnostic and pathogenic potential of aDNA-Ab subtypes, differing in their affinity or epitope specificity, was subject of several studies with controversial results. Comparing five assays, characterized by different reaction conditions and nature/source of dsDNA, we investigated the abovementioned problem in a retrospective study on 100 systemic lupus erythematosus (SLE) patients and 100 controls (other CTD, autoimmune hepatopathies). As demonstrated, only assay 3 (Farrzyme, TBS, UK) and 5 (Farr-RIA, Trinity Biotech, Ireland) are really suitable to detect primarily high avidity aDNA-Ab. Both were significantly linked to lupus nephritis (specificity 84%) and highly specific for SLE (95 and 96%). Thereby, assay 3 was found to be the first solid phase ELISA probably suitable to replace the Farr-RIA. Classical ELISAs (assay 1, Orgentec, Germany, and 2, Bindazyme, TBS, UK), detecting aDNA-Ab more or less independent from their avidity, or tests with only intermediate specificity for high avidity Ab (assay 4, ELIAdn, Sweden Diagnostics, Germany), were less specific for SLE (83, 79, 91%, respectively) and not associated with renal involvement (specificity 54-57%). At least in the patients studied here, obvious antigen-related differences could not be observed. With slight differences, all assays were suitable to monitor disease activity and therapy in SLE, agreeing with the ECLAM score in about 70-80% of cases. For lupus nephritis, aC1q-Ab are as specific as high avidity aDNA-Ab and capable to close a diagnostic gap in some cases. Thus, to enhance the specificity (up to 98%) and to consider the distinct diagnostic/pathogenic potential of aDNA-Ab subtypes in SLE, under routine clinical laboratory conditions it should be recommended to combine a sensitive screening test with a more specific second assay.

Adult↗
PubMed1987

Associations between clinical disease, circulating antibodies and C1q-binding immune complexes in human onchocerciasis.

Onchocerciasis is a disease where often there are high levels of serum antibodies and high parasitic loads. The role of immune complexes in the development of the disease is investigated here by studying non-specific and Onchocerca volvulus specific immune complex levels, as well as the antibody concentrations, in the sera of 372 people living in either Southern (199) or Northern (173) Sudan; sera from Sudanese individuals (31) and Caucasians (21) living outside the onchocerciasis endemic area were also tested. The levels of non-specific immune complexes (NS-IC) in these sera were measured by a solid phase radio-immunoassay and those of O. volvulus-specific immune complexes (OV-IC) by an assay measuring antibody-excess complexes using C1q-coated plates. The concentrations of O. volvulus IgG antibodies were measured by ELISA. Immune complex and antibody levels of the serum donors were compared with regard to their clinical status due to onchocerciasis. These clinical changes were classified according to onchocercal lesions related to either the active destruction of microfilariae (acute changes), or the long term tissue alterations (chronic changes). Data was analysed using the Odds Ratio method. A negative association between microfilarial load and immune complex level was found, with the higher levels of OV-IC present in patients with the lower levels of dermal microfilariae (i.e., less than 10 mf/mg). Significant associations between immune complex levels and the severity of onchocercal disease were also found. Levels of OV-IC specific immune complexes were higher in infected individuals carrying dermal onchocercal lesions than in those without such clinical changes; there was no apparent relationship between these levels and the presence of ocular lesions. OV-IC levels varied considerably within each age group and from age to age. A weak positive association was detected between microfilarial load and parasite-specific IgG antibody concentration in the sera. On average younger individuals (less than 25 years) had the higher antibody levels with a gradual reduction in mean concentrations with age. The significance of these serological findings in terms of the pathogenesis of onchocerciasis is discussed.

Age Factors↗
PubMed1991

C1 subcomponent complexes and C2 cleavage in active systemic lupus erythematosus.

We studied the activation and C1 inactivator-dependent dissociation of the first component of complement, the C1q(C1r-C1s)2 complex, in relation to recruitment of the classical activation pathway in the circulation of 24 patients with systemic lupus erythematosus (SLE). The patients were divided into three groups on a clinical basis, and were investigated during flares of disease activity. Group I had mild symptoms, group II major extrarenal manifestations, and group III manifest renal disease. High serum concentrations of trimer complexes containing C1 inactivator, activated C1r and zymogen C1s(C1 IA-C1r-C1s) were found in the majority of the patients. Some patients with high C1 IA-C1r-C1s concentrations showed no evidence of classical pathway activation, indicating that C1 activation was controlled by the action of C1 IA at the C1r level. By contrast, formation in serum of tetramer complexes in which C1 IA was firmly bound to both C1r and C1s (C1 IA-C1r-C1s-C1 IA) was associated with C2 and C3 cleavage in EDTA plasma, and with manifest hypocomplementemia. Low C1 IA-C1r-C1s-C1 IA values were observed in conjunction with substantial C2 cleavage in a few patients. Thus, C1 IA-C1r-C1s-C1 IA may not always be a sensitive indicator of classical pathway activation. Efficient recruitment of the classical pathway was related to disease severity, with some overlap between the clinical groups. In conclusion, C1 dissociation with formation of C1 IA-containing complexes was consistently found in patients with active SLE. The results suggested that C1 IA-dependent control of C1 activation was of biological significance in the disease.

Adolescent↗
PubMed2004

Histidine-rich glycoprotein binds to cell-surface heparan sulfate via its N-terminal domain following Zn2+ chelation.

Histidine-rich glycoprotein (HRG) is an alpha2-glycoprotein found in mammalian plasma at high concentrations (approximately 150 microg/ml) and is distinguished by its high content of histidine and proline. Structurally, HRG is a modular protein consisting of an N-terminal cystatin-like domain (N1N2), a central histidine-rich region (HRR) flanked by proline-rich sequences, and a C-terminal domain. HRG binds to cell surfaces and numerous ligands such as plasminogen, fibrinogen, thrombospondin, C1q, heparin, and IgG, suggesting that it may act as an adaptor protein either by targeting ligands to cell surfaces or by cross-linking soluble ligands. Despite the suggested functional importance of HRG, the cell-binding characteristics of the molecule are poorly defined. In this study, HRG was shown to bind to most cell lines in a Zn(2+)-dependent manner, but failed to interact with the Chinese hamster ovary cell line pgsA-745, which lacks cell-surface glycosaminoglycans (GAGs). Subsequent treatment of GAG-positive Chinese hamster ovary cells with mammalian heparanase or bacterial heparinase III, but not chondroitinase ABC, abolished HRG binding. Furthermore, blocking studies with various GAG species indicated that only heparin was a potent inhibitor of HRG binding. These data suggest that heparan sulfate is the predominate cell-surface ligand for HRG and that mammalian heparanase is a potential regulator of HRG binding. Using recombinant forms of full-length HRG and the N-terminal N1N2 domain, it was shown that the N1N2 domain bound specifically to immobilized heparin and cell-surface heparan sulfate. In contrast, synthetic peptides corresponding to the Zn(2+)-binding HRR of HRG did not interact with cells. Furthermore, the binding of full-length HRG, but not the N1N2 domain, was greatly potentiated by physiological concentrations of Zn2+. Based on these data, we propose that the N1N2 domain binds to cell-surface heparan sulfate and that the interaction of Zn2+ with the HRR can indirectly enhance cell-surface binding.

Animals↗