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PubMed1980

Structural evidence that complement factor B constitutes a novel class of serine protease.

The 28,000-dalton COOH-terminal cyanogen bromide peptide of complement factor B was isolated disulfide bonded to a second polypeptide of Mr = 3,500. The amino acid sequence of the smaller peptide, CB2-3, and 51 of 55 NH2-terminal residues of the larger peptide, CB2-2, were determined on an automated sequenator. CB2-2 exhibited extensive homology in its primary structure to the known serine proteases and included the sequence, Ala-Ala-His-Cys, which is part of the active site of these enzymes. By contrast, CB2-3 demonstrated only limited sequence identity with the NH2 terminus of the serine proteases. Mild acid hydrolysis was employed to further cleave CB2-2 into fragments of Mr = 20,000 and 8,000. On analysis the 8,000-dalton peptide was observed to contain the active site serine sequence, Gly-Asp-Ser-Gly-Gly-Pro. The data, therefore, clearly document that factor B is also a serine protease, although its mechanism of activation differs from this class of proteolytic enzymes.

Amino Acid Sequence↗
PubMed2007

Neovascular age-related macular degeneration and its association with LOC387715 and complement factor H polymorphism.

OBJECTIVE: To compare phenotypes of 2 age-related macular degeneration (AMD) susceptibility genes: LOC387715 and complement factor H (CFH). METHODS: Phenotypes of 755 AMD cases were characterized. The number of LOC387715 (T allele at rs10490924, or A69S) and CFH (T1277C at rs1061170, or Y402H) risk alleles were determined in each case. Individuals were divided into 5 groups by genotype: group 1, LOC-/- CFH-/-; group 2, LOC+/- CFH-/- or LOC+/+ CFH-/-; group 3, LOC-/- CFH+/- or LOC-/- CFH+/+; group 4, LOC+/- CFH+/-, LOC+/+ CFH+/-, or LOC+/- CFH+/+; and group 5, LOC+/+ CFH+/+. RESULTS: Signs of neovascular AMD including grade (P = .002), pigment epithelial detachment (P = .001), and subretinal hemorrhage (P<.001) demonstrated significant association with groups 2, 4, and 5 vs groups 1 and 3. Group 5 had a significantly younger mean age (72.3 years) compared with other groups (P = .002). CONCLUSIONS: The AMD cases possessing the LOC387715 (rs10490924) variant may have a higher risk of neovascular AMD. Individuals with AMD who are homozygous for both variants might be at greater risk for earlier onset of neovascular AMD.

Aged↗
PubMed2005

Does complement factor B have a role in the pathogenesis of atypical HUS?

Atypical haemolytic uraemic syndrome (aHUS) is a disorder of complement dysregulation. Because complement factor B (fB) carries the catalytic site of the alternative pathway convertase we examined it as both a potential candidate gene and modifier in the pathogenesis of aHUS. No factor B gene (BF) mutations were found in 20 patients with aHUS. There was no statistical difference between controls and aHUS patients in either BF allele or haplotype frequency. In conclusion, in this small series of aHUS patients we found no evidence that fB has a major role in the pathogenesis of aHUS.

Case-Control Studies↗
PubMed2005

Complement factors and circulating immune complexes in children with urinary schistosomiasis and asymptomatic malaria.

Serum concentrations of circulating immune complexes (CIC), complement factors (Factor B, C4, C8) and complement activities (CH50 and AH50) were determined in Nigerian school children having urinary schistosomiasis with or without symptomatic malaria by polyethylene glycol precipitation method, single radial immunodiffusion and total haemolytic activities respectively. One hundred and forty-seven children were recruited from St. John's Primary School, Mokola, Ibadan, Nigeria.RP ovale only, mixed infection of P. ovale with P. falciparum or mixed infection of P. malariae with P. falciparum were found in subjects with asymptomatic malaria without urinary schistosomiasis (M-USS) but P. malariae or P. falciparum was found in subjects with co-infection of urinary schistosomiasis and asymptomatic malaria (M + USS). Mean value of C4 concentration was significantly reduced in M - USS subjects or subjects having both USS and asymptomatic malaria (M + USS) compared with non-infected controls. Serum concentration of Factor B(FB) was significantly reduced while AH50 was significantly increased in urinary schisosomiasis subjects without malaria (USS-M) compared with M-USS subjects or the controls. These observations implied that complement system in USS-M subjects is activated predominantly via alternative pathway (APW) while complement system is activated via classical pathway (CPW) in M-USS or M+USS subjects. The switch of complement activation pathway from alternative type in USS-M subjects to classical type in M-USS subjects may explain the lower malaria parasite densities often found in children harbouring Schistosoma haematobium parasites.

Adolescent↗
PubMed1995

Duplication of the MHC-linked Xenopus complement factor B gene.

We have previously reported the molecular cloning of the mammalian major histocompatibility complex (MHC) class III gene, complement factor B (Bf) from Xenopus laevis, and linkage of the gene to the frog MHC. Here, we estimated the copy number of the Xenopus Bf gene by genomic Southern blotting analysis and demonstrated that Xenopus laevis has two copies of the Bf gene. Both genes co-segregated with the MHC-linked HSP70 genes among 19 offspring of an f/r x f/r cross, indicating a close linkage of the two Bf genes to the frog MHC. Both genes are transcribed and contain open reading frames. When compared with the previously determined cDNA sequence (Xenopus Bf A), the predicted amino acid sequence of the second cDNA species (Xenopus Bf B) shows 82% overall identity. Polymerase chain reaction analysis indicated that all of the partially inbred frogs with the f, r, g, and j MHC haplotypes, as well as 12 outbred frogs tested have both Bf genes, suggesting that the duplicated Bf genes are stable genetic traits in Xenopus laevis.

Amino Acid Sequence↗
PubMed1990

Identification and sequence analysis of four complement factor H-related transcripts in mouse liver.

Mouse liver RNA analyzed by Northern blotting with a full-length complement factor H cDNA probe demonstrates the 4.4-kilobase (kb) H mRNA as well as three additional hybridizing species of 3.5, 2.8, and 1.8 kb, respectively. Further characterization of these alternative transcripts was pursued by isolation of additional cDNAs from a liver library using a full-length H probe. Twelve clones homologous to but distinct from H were isolated, analyzed by restriction mapping, and divided into four classes, A, B, C, and D, based on their sequences. Clones from classes A, B, and C all contained nearly identical 5'-untranslated regions and leader sequences that differed from H at more than 50% of their nucleotide positions. The 5'-untranslated and leader sequences of the class D clone were unrelated to the corresponding regions of H or the class A, B, or C clones. The remaining portions of the H-related cDNAs were made up of short consensus repeats, 7 in class A, 4 in class B, 13 in class C, and 5 in class D. To determine the relationship between the H-related transcripts and the cDNA clones, Northern blots of liver RNA were analyzed by hybridization with two probes, one specific for the class D cDNA and the other reacting specifically with the class A, B, and C cDNAs. The class A/B/C probe detected transcripts of 3.5, 2.8, and 1.8 kb in liver RNA, and the class D probe hybridized to a distinct 1.8-kb message. Additionally, a cosmid genomic library was screened with H cDNA, and nine H-related clones were isolated. They spanned a region of approximately 120 kb, defining at least two discrete H-related gene loci. These results identify new members of the super-family of C3b/C4b binding protein genes.

Amino Acid Sequence↗
PubMed1990

Mapping of a retinoic acid-responsive element in the promoter region of the complement factor H gene.

Retinoic acid receptors are members of the steroid/thyroid hormone receptor superfamily. Pursuant to the discovery that dexamethasone increases complement factor H expression, we examined the effects of retinoic acid on this gene. Both H mRNA and protein levels are increased by retinoic acid in L cells. Using the luciferase reporter gene system we have identified a region of the H promoter required for the retinoic acid response. This region contains an imperfect palindrome of the TGACC motif, present in thyroid hormone and estrogen-responsive elements. We demonstrate specific binding of the retinoic acid receptor beta to this sequence of the H gene by DNA-protein gel retardation assay. Therefore, these studies extend the sphere of influence of the retinoids to complement, an intrinsic component of the humoral immune system.

Animals↗
PubMedDate not supplied

Complement factors in adult peripheral nerve: a potential role in energy metabolism.

Complement cascade factors are known to play a critical role in myelin clearance after peripheral nerve injury. Here we show that components of both the classical (C1qa, C1qb, C1qc, C2 and C4) and alternative (C3, B and adipsin) pathways are expressed by uninjured peripheral nerve as well. mRNAs of components of the alternative pathway were predominantly found in the peri/epineurium, although factor C3 and factor B were also detected in the endoneurial compartment of adult nerve. Interestingly, adipsin mRNA was detected only in peri/epineurium, while adipsin protein was present in both peri/epineurium and endoneurium. This suggests that adipsin is transported to the endoneurium via the circulation from the peri/epineurium or outside of the nerve. Factor 5 and factor 9, necessary for the formation of the membrane-attack complex, were not detected in any part of the healthy peripheral nerve, which together with the observed presence of negative regulators of complement activation, is likely to prevent damage to the healthy nerve caused by complement activation. By analogy with the known role of complement factors in fat, we propose that local expression of these factors plays a role in the regulation of fatty acid homeostasis in the nerve and, thereby, in energy metabolism cross-talk between different compartments of the peripheral nerve.

Adult↗
PubMed1994

Genomic analysis of the F subtypes of human complement factor B.

Factor B of human complement is encoded within the Major Histocompatibility Complex (MHC) and is polymorphic, with up to 30 alleles defined by electrophoretic mobility. One of the most common alleles, BF*F, is subdivided into the FA and FB subtypes, which differ at the gene level by non-synonymous base substitutions in the seventh codon. We have found at this position a new restriction site polymorphism, as a Bsl I site absent from the FB allele. Using this restriction polymorphism, we have developed a method for BF F subtype determination, based on amplification by polymerase chain reaction of the 5' end of the BF gene, and digestion with Bsl I. This new method has been applied to a panel of 29 selected BF F individuals. A single strand DNA conformation analysis of the same region of the gene allowed us to confirm the above DNA-based BF F subtyping. During this study, two BF*F1 alleles showed discrepancies between protein and DNA typing, which were confirmed by our sequencing data. These were identical, in the 5' region, to BF*S and BF*FB genes, respectively. In a comparison with two protein subtyping methods, identical results were found for only one third of the selected samples. The conflicting results may arise, in part, from previously undescribed molecular heterogeneity within BF F subtypes, or from the presence of a null allele. Our new method allows BF*F subtyping to be used with confidence in the definition of disease-associated MHC haplotypes.

Alleles↗
PubMed1999

Cloning and characterization of the non-catalytic heavy chain of mouse complement factor I gene: structure comparison with the human homologue.

The gene sequence encoding the non-catalytic heavy chain of mouse complement factor I (mCFI) was cloned and its exon-intron organization and domain structure characterized. The genomic organization of mCFI differs in several aspects from its human homologue (hCFI). The intron sizes are remarkably different. Exons 2 and 4 in mCFI are larger than their counterparts in hCFI by 9 bp and 6 bp respectively. Whereas the diversity (D) region of hCFI is encoded by two exons (exon 7 or hD2 and exon 8 or hD4), this region in mCFI is encoded by three exons; exon 6A or mD1 (located at the 3'-end of the LDLr A2 domain), exon 7 or mD2 and exon 8, an extended exon (56 bp) composed of mD3, fused upstream of mD4. In contrast, hCFI lacks D1 and D3 subregions and exon 8 in hCFI consists of only hD4, 36 bp in length. Thus the heavy chain of mCFI is organized into 10 exons compared to 9 exons in hCFI.

Amino Acid Sequence↗
PubMed1990

Bb fragment of bovine complement factor B: stimulation of the oxidative burst in bovine monocytes.

In a previous study, we reported that fragment Bb of bovine complement factor B activated bovine monocytes, as demonstrated by the uptake of 3H-deoxyglucose. In the present study, the effects of Bb on the production of superoxide anion and hydrogen peroxide by bovine monocytes was investigated. The production of superoxide was measured by the superoxide dismutase inhibitable reduction of cytochrome c. The change in absorbance was determined by a spectrophotometer at a wavelength of 550 nm. Hydrogen peroxide production was measured by the horse-radish peroxidase-dependent oxidation of phenol red. The resulting color change was measured by a spectrophotometer at a wavelength of 620 nm. Fragment Bb (20 micrograms/mL) induced the generation of 0.96 +/- 0.2 (mean +/- SEM) nanomoles of superoxide/2.5 x 10(5) monocytes at 5 min. The production of superoxide peaked at 15 min (1.24 +/- 0.3 nanomoles). The production of hydrogen peroxide was also rapid: 0.195 +/- 0.05 nanomoles/2.5 x 10(5) monocytes at 5 min with a peak at 15 min (0.250 +/- 0.04 nanomoles). These observations show that fragment Bb, which has serine protease activity, induces bovine monocytes to generate reactive oxygen intermediates such as superoxide and hydrogen peroxide.

Animals↗
PubMed2005

Serum complement factor I decreases Staphylococcus aureus phagocytosis.

Complement-mediated opsonization of Staphylococcus aureus is a critical host defense in animal models. Specifically, C3b and CD35 play important roles in effective opsonophagocytosis of S. aureus. We have shown that complement control protein factor I mediates cleavage of the complement opsonin C3b bound to the S. aureus surface. In this study, we examined the physiologic relevance of this observation by determining whether factor I-mediated cleavage of S. aureus-bound C3b decreased phagocytosis of S. aureus by neutrophils. Compared with controls, anti-factor I antibody inhibited C3b-cleavage on the S. aureus surface by >83% (as measured by iC3b generation) and increased phagocytosis of S. aureus by >100%. Treatment of C3b-coated S. aureus with factor I increased generation of iC3b (75%), decreased the total amount of C3-fragments bound to the S. aureus surface (58%), and decreased the number of bacteria phagocytosed (40%). Testing specifically for C3-fragments shed from the S. aureus surface, we found that factor I increased shedding (43%). Notably, these factor I-mediated effects were of the same magnitude regardless of whether factor H, a known cofactor for factor I, was present. These findings indicate that S. aureus benefits from, and possibly manipulates, the normally host-protective activity of factor I cleavage of C3b, which results in bacterial escape from complement-mediated opsonophagocytosis. Because escaping opsonophagocytosis-mediated destruction is a necessary mechanism for bacterial survival resulting in human disease, preventing cleavage of C3b on the S. aureus surface, and thereby enhancing opsonophagocytosis, is a promising potential target for therapeutic intervention.

Antibodies, Blocking↗
PubMed2006

Complement factor H variant Y402H is a major risk determinant for geographic atrophy and choroidal neovascularization in smokers and nonsmokers.

PURPOSE: The complement factor H (CFH) gene polymorphism Y402H (1277T-->C) has been associated with susceptibility to age-related macular degeneration (AMD). The purpose of this study was to confirm this association in a U.K. population, to determine whether the association holds for both geographic atrophy (GA) and choroidal neovascularization (CNV), and to investigate interactions with smoking. METHODS: A case-control study was undertaken in 443 cases of AMD, with 262 spouses as control subjects. All subjects completed a health and lifestyle questionnaire, had an ophthalmic assessment with fundus photography, and were genotyped. RESULTS: The frequencies of the C allele and CC genotype were significantly higher in cases than in controls. In comparison to the TT genotype, the odds ratios for AMD associated with the CT and CC genotypes were 3.1 (CI 2.0-4.6) and 6.3 (CI 3.8-10.4), respectively. The results were similar in subgroup analyses confined to cases with GA or CNV. The findings were also similar for subgroup analyses restricted to subjects who had never smoked, moderate smokers, or heavier smokers (>20 pack years of smoking). Heavier smokers with the CC genotype may be particularly at risk. The frequency of the CC genotype did not differ significantly between cases with and without a family history of AMD. There was no evidence that genotype had any influence on age at onset of disease. CONCLUSIONS: The CFH Y402H variant is strongly associated with both GA and CNV in the U.K. population. This association is similar in smokers and nonsmokers. Heavier smokers with the CC genotype may be at particular risk.

Aged↗
PubMed2006

Analysis of the Y402H variant of the complement factor H gene in age-related macular degeneration.

PURPOSE: Recent studies in U.S. populations have indicated that the Y402H variant of the complement factor H (CFH) gene contains a major risk susceptibility allele for age-related macular degeneration (AMD). This study was conducted to ascertain whether this is also true in a non-U.S. population and also whether the at-risk allele is associated with the clinical phenotype of disease and the age at diagnosis. METHODS: Two hundred thirty-six unrelated individuals with AMD and 144 unrelated but ethnically matched control subjects were recruited and examined. All subjects completed a standard questionnaire, were given a fundus examination, and provided a blood sample for DNA extraction. Alleles of Y402H in the CFH gene were determined by use of a MALDI-TOF-based approach followed by statistical analysis. RESULTS: Individuals with AMD who had at least one copy of the C allele of Y402H had an increased risk of disease (odds ratio [OR] 2.98; 95% confidence interval [CI] 1.81-4.93) compared with cases with the T allele. On subgroup analysis, this risk was found to be most significant in individuals with neovascular disease (OR 4.34; 95% CI 1.94, 9.71). In addition, individuals with neovascular disease who were homozygous CC presented with a significant 7.0-year earlier age at diagnosis relative to those individuals who were homozygous TT. The population-attributable risk for the C allele ranged between 47% to 69%, depending on the AMD disease subtype. CONCLUSIONS: The C allele of Y402H represents a significant risk factor in individuals with AMD, and this effect is most pronounced in individuals with neovascular disease.

Aged↗
PubMed1987

The homology of complement factor C8 gamma chain and alpha-1-microglobulin.

The sequence of the complement factor C8 gamma chain shares a remarkable degree of similarity with that of alpha-1-microglobulin, a member of the alpha-2u-globulin superfamily. This superfamily comprises a diverse group of distantly related animal proteins possessing characteristic structural features and similar functions. Comparison of the C8 gamma chain with these proteins supports its homology to them and suggests a possible functional role.

Alpha-Globulins↗
PubMed1992

Complement factor 9 deficiency in serum of human neonates.

The serum concentration of complement factor C9 (C9) was 260 +/- 47 micrograms/ml (+/- SE) in 14 mothers and less than 42 micrograms/ml in each of their 14 neonates. During incubation for 60 min, 11 of 14 maternal sera and 3 of 14 neonatal sera reduced the survival of Escherichia coli O7w:K1:NM to less than 20% of the original inoculum (P less than .03). Eleven neonatal sera did not kill the bacteria. Supplemental C9 (60 micrograms/ml) enhanced the bactericidal capacity of 10 neonatal sera. 125I-labeled C9 was deposited onto E. coli by neonatal sera, but less efficiently than by pooled adult sera. Supplemental IgG enhanced 125I-labeled C9 deposition and potentiated the bactericidal activity of exogenous C9. Therefore, neonatal sera contained diminished concentrations of C9 and killed E. coli inefficiently. In neonatal sera, supplemental C9 was deposited onto E. coli and enhanced bactericidal activity. These effects of C9 were potentiated by supplemental IgG.

Adult↗
PubMed2006

No association between complement factor H gene polymorphism and exudative age-related macular degeneration in Japanese.

Age-related macular degeneration (ARMD) is the leading cause of blindness in the elderly population not only Western but also Asian industrial countries. In Caucasian, a polymorphism of the complement factor H gene (CFH), the C allele of rs1061170 (Y402H), was established as the first strong genetic factor for excursively exudative type of ARMD. In this study, we performed an extensive sequencing of the 22 exons in the CFH gene by recruiting 146 exudative ARMD patients and 105 normal controls of Japanese origin and identified 61 polymorphisms. We found that the frequency of the C allele of rs1061170 (Y402H) is much lower (0.04) in Japanese controls than in Caucasians (0.45). No case disease susceptibility to exudative ARMD was noted for rs1061170 (Y402H) (chi (2) = 3.19, P (corr) = 0.423), or other 12 single nucleotide polymorphisms (SNPs) whose frequency is greater than 0.05. When haplotypes were inferred for 13 SNPs (these 12 SNPs with a frequency greater than 0.05 and rs1061170), three haplotypes whose pattern was similar to those in Caucasians were identified but with substantial difference in frequency. Again we failed to identify genetic association between Japanese exudative ARMD and any of the haplotypes including the J1 haplotype which was shown to be susceptible to ARMD in Caucasians (chi (2 )=( )3.92, P (corr) = 0.157). CFH does not appear to be a primary hereditary contributor to ARMD in Japanese. The absence of CFH contribution to ARMD in Japanese may correlate with the findings in ethnic differences of ARMD phenotypes.

Age Factors↗