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PubMed2005

Frequency in Spanish population of familial complement factor 2 type I deficits and associated HLA haplotypes.

We present two familial cases of complement factor 2 (C2) type I deficiency. Probands had experienced severe pyogenic bacteria infections in childhood and had undetectable levels of C2 and very low level of CH50. Both children were homozygous for the deletion of 28 bp in exon 6 of the C2 gene. Human leukocyte antigen (HLA) typing in family 1 had the commonly reported associations, but family 2 demonstrated a new association of the mutated C2 gene to HLA-A*3101, -Cw*0602, -B*1801, and -DRB1*0901. In addition, for the first time, the frequency of the 28-bp deletion of C2 and its HLA haplotypic associations have been analyzed in a sample of the Spanish population containing 790 haplotypes and 105 phenotypes. Cw*0602 is frequently found in Spanish haplotypes linked to the C2 mutated gene instead of the commonly reported -Cw*1203. The presence of heterozygous or homozygous individuals for the C2 deletion with low levels of IgD in both families supports the existence of a putative dominant susceptibility gene for IgD deficiency in haplotype HLA-B18, -S042, and -DR2. The frequency of the C2 28-bp deletion in heterozygosis is 1.4% (gene frequency 0.007) in Spanish healthy controls, similar to that reported in other white populations.

Child↗
PubMed2006

Investigation on the interaction between colloidal gold and human complement factor 4 at different pH by spectral methods.

The interaction between colloidal gold and human complement factor 4 (human C4) at different pH was investigated by spectral methods, including absorption and resonance light-scattering spectrometry. According to the changes of color and absorption spectra of colloidal gold solution in presence of human C4, the interaction between colloidal gold and human C4 was quantitatively investigated using a semi-empirical "flocculation parameter". At the same time, the changes of resonance light-scattering spectra and transmission electron microscopy (TEM) images indicate that the aggregation of colloidal gold happens by electrostatic interaction in presence of human C4 in the pH range 5-6. However, the colloidal gold solution remains stable at pH >6 and pH <5 due to the repulsive electrostatic interaction between colloidal gold and human C4. The flocculation parameter is directly proportional to the concentration of human C4 in the range from 9.7 to 233.0 microgl(-1). In addition, the interactions between the colloidal gold and bovine serum albumin (BSA) as well as human serum albumin (HSA) were also investigated using the same methods. It was found that there was no aggregation of colloidal gold in presence of BSA and HSA in the pH range 5-6. However, when the pH of solution is 4, the aggregation of colloidal gold happens. Because BSA and HSA have different structure, the intensity of aggregation of colloidal gold in presence of BSA is greater than that in presence of HSA at pH 4.

Animals↗
PubMed2005

Strong association of the Y402H variant in complement factor H at 1q32 with susceptibility to age-related macular degeneration.

Using a large sample of cases and controls from a single center, we show that a T-->C substitution in exon 9 (Y402H) of the complement factor H gene is strongly associated with susceptibility to age-related macular degeneration, the most common cause of blindness in the elderly. Frequency of the C allele was 0.61 in cases, versus 0.34 in age-matched controls (P<1x10(-24)). Genotype frequencies also differ markedly between cases and controls (chi2=112.68 [2 degrees of freedom]; P<1x10(-24)). A multiplicative model fits the data well, and we estimate the population frequency of the high-risk C allele to be 0.39 (95% confidence interval 0.36-0.42) and the genotype relative risk to be 2.44 (95% confidence interval 2.08-2.83) for TC heterozygotes and 5.93 (95% confidence interval 4.33-8.02) for CC homozygotes.

Aged↗
PubMed2005

Y402H complement factor H polymorphism associated with exudative age-related macular degeneration in the French population.

PURPOSE: Identification of genetic factors for age-related macular degeneration (AMD) is of crucial importance in this common cause of blindness. A positive association between Y402H polymorphism of the complement factor H (CFH) gene and AMD has been recently reported in North American populations but not yet in European populations. The exudative form of AMD is rapidly progressive and usually associated with a severe prognosis. Our purpose was to investigate this association in a French population specifically affected with exudative AMD, in a case-control study. METHODS: Two series of unrelated exudative AMD patients, sporadic cases (n=60, mean age 74.9+/-5.7) and familial cases (n=81, mean age 74.0+/-9.4) were compared with healthy controls (n=91, mean age 74.6+/-6.3). The coding region of exon 9 of CFH was examined for the Y402H polymorphism by PCR-direct sequencing. RESULTS: The 1,279-C allele frequencies were significantly higher in exudative AMD patients than controls (0.564 compared to 0.302; p<0.0001). Genotypic distribution of the Y402H polymorphism was significantly different between sporadic cases compared to controls (chi2=14.48 with 2 df, p<0.0007) and between familial cases compared to controls (chi2=23.78 with 2 df, p<0.0001). The odds ratio (OR) for exudative AMD was 3.00 CI95% (1.60-5.62) for heterozygotes (CT) and 6.93 CI95% (3.11-15.46) for homozygotes (CC). CONCLUSIONS: These results suggest the contribution of the Y402H polymorphism of the CFH gene to exudative AMD susceptibility also in the French population. This relationship with the CFH may lead to early detection and new strategies for prevention and treatment of AMD.

Aged↗
PubMed1999

Quantitative detection of human complement factor H-related protein in transitional cell carcinoma of the urinary bladder.

OBJECTIVE: The purpose of this study was to assess a new quantitative urinary tumor marker for transitional cell carcinoma of the urinary bladder (TCC), human complement factor H-related protein (hCFHrp, BTA TRAK). METHODS: Urine samples of 298 individuals (76 healthy volunteers, 118 patients with benign urologic disorders, 104 patients with histologically proven bladder cancer) were examined for the presence of hCFHrp. Samples of all patients were obtained prior to therapy. RESULTS: In comparison to healthy volunteers, patients with TCC had significantly higher urinary levels of hCFHrp (117.60 vs. 2.05 U/ml; p < 0.001). HCFHrp levels were positively correlated with tumor grade and stage. Patients with invasive TCC had significantly higher levels of hCFHrp than patients with superficial TCC (p = 0.001). Marker levels in superficial bladder cancer at high risk of tumor progression (pT1G3) were significantly higher as compared to low and intermediate grade superficial cancers. Elevated levels of hCFHrp were also found in patients with benign urologic disorders (median: 72.65 vs. 117.60 U/ml in cancer patients). Using a cutoff of 17.1 U/ml, hCFHrp had a sensitivity of 72.1% and, due to a high rate of false-positive determinations in patients with benign urologic disorders, a total specificity of 50.5%. CONCLUSIONS: HCFHrp (BTA TRAK) is a sensitive test for detection of bladder cancer and for identification of patients at high risk. Due to a high rate of false-positive results in patients with benign urologic diseases, the test should not be used in an unselected population.

Adult↗
PubMed2000

Sensitivity of human complement factor H related protein (BTA stat) test and voided urine cytology in the diagnosis of bladder cancer.

PURPOSE: We compared the sensitivity of the BTA statdagger test, a rapid, noninvasive, qualitative urine test that detects bladder tumor associated antigen (human complement factor H related protein) in urine, to that of voided urine cytology in patients with primary bladder cancer. We also assessed the effect of tumor size, number, histological grade and stage on test sensitivity. MATERIALS AND METHODS: We evaluated 151 patients with newly diagnosed bladder cancer in a prospective multicenter study. A voided urine sample obtained before transurethral bladder tumor resection was divided for culture, cytology and BTA stat testing. RESULTS: Overall sensitivity of the BTA stat test and urine cytology for detecting primary bladder cancer was 81.5% and 30.3%, respectively (p <0.0001). The sensitivity of each test increased as tumor size, number, histological grade and stage increased. CONCLUSIONS: Sensitivity of the BTA stat test was superior to that of voided urine cytology in all tumor categories. This noninvasive, easy to perform, point of care test may have the potential to replace cytology for diagnosing bladder cancer.

Carcinoma, Transitional Cell↗
PubMed1999

Structural basis of profactor D activation: from a highly flexible zymogen to a novel self-inhibited serine protease, complement factor D.

The crystal structure of profactor D, determined at 2.1 A resolution with an Rfree and an R-factor of 25.1 and 20.4%, respectively, displays highly flexible or disordered conformation for five regions: N-22, 71-76, 143-152, 187-193 and 215-223. A comparison with the structure of its mature serine protease, complement factor D, revealed major conformational changes in the similar regions. Comparisons with the zymogen-active enzyme pairs of chymotrypsinogen, trypsinogen and prethrombin-2 showed a similar distribution of the flexible regions. However, profactor D is the most flexible of the four, and its mature enzyme displays inactive, self-inhibited active site conformation. Examination of the surface properties of the N-terminus-binding pocket indicates that Ile16 may play the initial positioning role for the N-terminus, and Leu17 probably also helps in inducing the required conformational changes. This process, perhaps shared by most chymotrypsinogen-like zymogens, is followed by a factor D-unique step, the re-orientation of an external Arg218 to an internal position for salt-bridging with Asp189, leading to the generation of the self-inhibited factor D.

Amino Acid Sequence↗
PubMed1983

Amino acid sequence of the Bb fragment from complement Factor B. Sequence of the major cyanogen bromide-cleavage peptide (CB-II) and completion of the sequence of the Bb fragment.

The amino acid sequence of peptide CB-II, the major product (mol.wt. 30 000) of CNBr cleavage of fragment Bb from human complement Factor B, is given. The sequence was obtained from peptides derived by trypsin cleavage of peptide CB-II and clostripain digestion of fragment Bb. Cleavage of two Asn-Gly bonds in peptide CB-II was also found useful. These results, along with those presented in the preceding paper [Gagnon & Christie (1983) Biochem. J. 209, 51-60], yield the complete sequence of the 505 amino acid residues of fragment Bb. The C-terminal half of the molecule shows strong homology of sequence with serine proteinases. Factor B has a catalytic chain (fragment Bb) with a molecular weight twice that of proteinases previously described, suggesting that it is a novel type of serine proteinase, probably with a different activation mechanism.

Amino Acid Sequence↗
PubMed2006

Structure-function mapping of BbCRASP-1, the key complement factor H and FHL-1 binding protein of Borrelia burgdorferi.

Borrelia burgdorferi, a spirochaete transmitted to human hosts during feeding of infected Ixodes ticks, is the causative agent of Lyme disease, the most frequent vector-borne disease in Eurasia and North America. Sporadically Lyme disease develops into a chronic, multisystemic disorder. Serum-resistant B. burgdorferi strains bind complement factor H (FH) and FH-like protein 1 (FHL-1) on the spirochaete surface. This binding is dependent on the expression of proteins termed complement-regulator acquiring surface proteins (CRASPs). The atomic structure of BbCRASP-1, the key FHL-1/FH-binding protein of B. burgdorferi, has recently been determined. Our analysis indicates that its protein topology apparently evolved to provide a high affinity interaction site for FH/FHL-1 and leads to an atomic-level hypothesis for the functioning of BbCRASP-1. This work demonstrates that pathogens interact with complement regulators in ways that are distinct from the mechanisms used by the host and are thus obvious targets for drug design.

Amino Acid Sequence↗
PubMedDate not supplied

Localization of the properdin factor complement locus Pfc to band A3 on the mouse X chromosome.

The locus for properdin (properdin factor complement, Pfc), a plasma glycoprotein, has been mapped to band A3 of the mouse X chromosome by in situ hybridization to metaphase spreads containing an X;2 Robertsonian translocation. The X-linkage of the locus has also been confirmed by analysis of Mus musculus x Mus spretus interspecific crosses. The XA3 localization for Pfc places it in the chromosomal segment conserved between man and mouse which is known to contain at least six other homologous loci (Cybb, Otc, Syn-1 Maoa, Araf, Timp).

Animals↗
PubMed2000

Detection of complement factor B in the cerebrospinal fluid of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy disease using two-dimensional gel electrophoresis and mass spectrometry.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary condition with onset in mid-adulthood and is associated with mutations in the Notch-3 gene. (Joutel, A., Corepechot, C., Ducros, A., Vahedi, K., Chabriat, H., Mouton, P., Alamowitch, S., Domenda, V., Cecilion, M., Marechal, J., Vayssiere, C., Cruaud, C., Cabanis, E.A., Ruchoux, M.M. , Weissenvach, J., Bach, J.F., Bousser, M.G. and Tournier-Lasserve, E., Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature, 383 (1996) 707-710) Ultrastructural examination of the pathology of the cerebral infarcts reveals deposits in the vascular smooth muscle cells of the small arteries of the brain, but there is no obvious indication how the Notch-3 mutations give rise the observed pathology, nor is there any information on the exact nature of the deposits. We have investigated cerebrospinal fluid (CSF) from three CADASIL cases with known mutations in Notch-3 using two-dimensional gel electrophoresis. CSF from these patients was compared to that of six controls. We detected a single spot in the protein maps of patients which was absent from all the controls. In-gel tryptic digestion of this protein followed by mass spectrometric analysis of the tryptic fragments and a database search identified the spot as human complement factor B. These preliminary findings suggest that the alternative complement pathway may play a role in the pathogenesis of CADASIL.

Adult↗
PubMed1989

Biosynthesis of complement factor H by human umbilical vein endothelial cells. Regulation by T cell growth factor and IFN-gamma.

The present studies were initiated to characterize a 150-kDa molecule with inhibitory activity for C3bBb formation, which is present in human umbilical vein endothelial cells (HUVEC). Therefore, human endothelial culture supernatants (HECS) were analyzed for the presence of human complement factor H by ELISA. It was found that H was present in HECS. An immunoblot analysis of affinity purified H from HECS showed that the size of HUVEC H was identical to that of plasma H. The mean production of H by HUVEC of first passage cultures was 40 ng/10(6) cells/day. The synthesis of HUVEC H was fully inhibitable by the addition of cycloheximide to the cultures, suggesting that H is de novo synthesized. Additional evidence for de novo synthesis was obtained by using biosynthetic labeling with [35S] methionine, immunoprecipitation, and SDS-PAGE. It was demonstrated that, indeed, HUVEC produce and secrete factor H. Two forms of the protein were identified, the 150-kDa form and also a 45-kDa form, both forms have been identified in plasma. The functional activity of HUVEC H is identical to that of plasma H. IFN-gamma induced enhanced synthesis of H by HUVEC, whereas it had no effect on C3 synthesis. Supernatant from stimulated PBMC, T cell growth factor, enhanced synthesis of both H and C3. The present studies indicate that H is produced by HU-VEC and that H may function as an inhibitor of complement activation at the endothelial cell level and, thereby, together with molecules like decay accelerating factor and membrane cofactor protein, may influence resistance of endothelial cells to complement mediated damage.

Binding, Competitive↗
PubMed2000

Complement factor H is a serum-binding protein for adrenomedullin, and the resulting complex modulates the bioactivities of both partners.

Adrenomedullin (AM) is an important regulatory peptide involved in both physiological and pathological states. We have previously demonstrated the existence of a specific AM-binding protein (AMBP-1) in human plasma. In the present study, we developed a nonradioactive ligand blotting assay, which, together with high pressure liquid chromatography/SDS-polyacrylamide gel electrophoresis purification techniques, allowed us to isolate AMBP-1 to homogeneity. The purified protein was identified as human complement factor H. We show that AM/factor H interaction interferes with the established methodology for quantification of circulating AM. Our data suggest that this routine procedure does not take into account the AM bound to its binding protein. In addition, we show that factor H affects AM in vitro functions. It enhances AM-mediated induction of cAMP in fibroblasts, augments the AM-mediated growth of a cancer cell line, and suppresses the bactericidal capability of AM on Escherichia coli. Reciprocally, AM influences the complement regulatory function of factor H by enhancing the cleavage of C3b via factor I. In summary, we report on a potentially new regulatory mechanism of AM biology, the influence of factor H on radioimmunoassay quantification of AM, and the possible involvement of AM as a regulator of the complement cascade.

Adrenomedullin↗
PubMed1975

Complement factors in gingival crevice material from healthy and inflamed gingiva in humans.

The presence and levels of complement factors C3, C4, C5, and C3 proactivator, were determined by electroimmuno assay in gingival cervice material from five individuals with healthy gingiva and from six patients with chronically inflamed gingiva. Higher concentrations of C3 and C4 were found in samples from chronically inflamed gingiva when compared to those healthy gingiva. The amount of C3 in material from healthy as well as from inflamed gingiva was related to that in plasma, when the albumin in plasma and gingival crevice material was used as a reference. The same was found for C4 in samples from healthy gingiva but in those from inflamed gingiva, the values were significantly lower when related to plasma levels. C5 could not be found in material from healthy gingiva but was present in material from inflamed gingiva. C3 proactivator was present in material from inflamed gingiva in the converted form. No C3 proactivator was found in material from healthy gingiva with the methods used. Analysis of C3 in samples from inflamed gingiva, using crossed immunoelectrophoresis, showed that C3 was converted in these samples. The results indicate that the complement system may be activated in gingival crevice material from inflamed gingiva.

Adult↗
PubMed1990

In vitro phosphorylation of human complement factor C3 by protein kinase A and protein kinase C. Effects on the classical and alternative pathways.

Complement factor C3, recently found to contain covalently bound phosphate, was phosphorylated in vitro by cyclic AMP-dependent protein kinase (protein kinase A) and Ca2(+)-activated, phospholipid-dependent protein kinase (protein kinase C). Both protein kinases phosphorylated the same serine residue(s) located in the C3a portion of the alpha-chain. In addition, protein kinase C phosphorylated the beta-chain to a lesser extent. Protein kinase A gave a maximal incorporation of 1 mol of phosphate/mol of C3 while that value with protein kinase C was 1.5 mol of phosphate/mol of C3. The velocity in pmol of [32P]phosphate/(min x unit kinase) was 20 times higher for protein kinase C than for protein kinase A although a 10 times lower ratio of protein kinase to C3 was used in the former case. The apparent Km for C3 was 2.6 microM when protein kinase C was used. The phosphorylated C3 was found to be more resistant to partial degradation by trypsin than unphosphorylated C3. It was also found that phosphorylation of C3 in the C3a portion of the alpha-chain inhibited both the classical and alternative complement activation pathways on an approximately stoichiometric basis.

Amino Acids↗
PubMed2005

Increased potency of a novel complement factor 5a receptor antagonist in a rat model of inflammatory bowel disease.

We have previously shown that complement factor 5a (C5a) plays a role in the pathogenesis of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats by using the selective, orally active C5a antagonist AcF-[OP(d-Cha)WR]. This study tested the efficacy and potency of a new C5a antagonist, hydrocinnamate (HC)-[OP(d-Cha)WR], which has limited intestinal lumenal metabolism, in this model of colitis. Analogs of AcF-[OP(d-Cha)WR] were examined for their susceptibility to alimentary metabolism in the rat using intestinal mucosal washings. One metabolically stable analog, HC-[OP(d-Cha)WR], was then evaluated pharmacokinetically and investigated at a range of doses (0.03-10 mg/kg/day p.o.) in the 8-day rat TNBS-colitis model, against the comparator drug AcF-[OP(d-Cha)WR]. Using various amino acid substitutions, it was determined that the AcF moiety of AcF-[OP(d-Cha)WR] was responsible for the metabolic instability of the compound in intestinal mucosal washings. The analog HC-[OP(d-Cha)WR], equiactive in vitro to AcF-[OP(d-Cha)WR], was resistant to intestinal metabolism, but it displayed similar oral bioavailability to AcF-[OP(d-Cha)WR]. However, in the rat TNBS-colitis model, HC-[OP(d-Cha)WR] was effective at reducing mortality, colon edema, colon macroscopic scores, and increasing food consumption and body weights, at 10- to 30-fold lower oral doses than AcF-[OP(d-Cha)WR]. These studies suggest that resistance to intestinal metabolism by HC-[OP(d-Cha)WR] may result in increased local concentrations of the drug in the colon, thus affording efficacy with markedly lower oral doses than AcF-[OP(d-Cha)WR] against TNBS-colitis. This large increase in potency and high efficacy of this compound makes it a potential candidate for clinical development against intestinal diseases such as inflammatory bowel disease.

Animals↗
PubMed2004

Complement factor H deficiency in acute allograft glomerulopathy and post-transplant hemolytic uremic syndrome.

Acute allograft glomerulopathy (AAG) is a distinct form of allograft rejection characterized by cytotoxic T-cell-mediated injury to the renal glomerular and arteriolar endothelium. Acute allograft glomerulopathy is characterized by mononuclear cell infiltration of glomerular capillary tufts in association with endothelial cell hypertrophy and injury. Intra-glomerular thrombi have been described in AAG, suggesting that overlapping features of AAG and post-transplant thrombotic microangiopathy (TMA) may coexist. We present a case suggesting that complement factor H deficiency, a known hereditary risk factor for TMA, may also favor development of AAG. We discuss the potential implications of factor H deficiency in the pathophysiology of renal allograft microvascular injury, leukocyte infiltration and formation of intraglomerular platelet thrombi. We propose that unopposed complement activation is a risk factor for both immune and nonimmune forms of microvascular injuries in renal allografts.

Acute Disease↗