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PubMedDate not supplied

Induction of complement factor B activity in human fibroblasts by IL-6/IFN-beta 2 and IFN-gamma.

Human skin fibroblasts synthesize and secrete complement Factor B, a component of the complement alternative pathway, when stimulated by mediators of inflammation such as lipopolysaccharide and various cytokines. Recombinant IL-6/IFN-beta 2 (E. coli) stimulates Factor B synthesis in fibroblasts but the effect is strongly potentiated by the addition of IFN-gamma. When both cytokines are added, the skin fibroblasts secrete significant amounts of biologically active Factor B detectable in a hemolysis test. This cooperative effect of IL-6, which is made by most tissue cells and monocytes and of IFN-gamma which is made by T-lymphocytes may play a role in local inflammatory processes. IL-6 and IFN-gamma also cooperate in the induction of (2'-5') A synthetase, a mediator of IFN action.

2',5'-Oligoadenylate Synthetase↗
PubMed1985

Sepsis score and complement factor B for monitoring severely septic surgical patients and for predicting their survival.

Sepsis score and complement factor B (FB) have been measured in 66 severely septic surgical patients in the intensive care unit, with the aim of monitoring their clinical course and predicting their outcome. Sepsis score correlated well with clinical course. 82% of patients with initial sepsis score less than 20 progressively improved and survived. Only 6% of patients with sepsis score greater than or equal to 20 survived. FB plasma level was significantly higher (p less than 0.01) in patients who subsequently survived. Two indices were identified which could predict patient outcome several days in advance with 100% accuracy: (1) the index of survival from sepsis defined as the combination of sepsis score less than 20 and FB greater than or equal to 45 mg/dl, and (2) the index of death from sepsis defined as sepsis score greater than or equal to 20 and FB less than 40 mg/dl.

Adolescent↗
PubMed2006

Complement factor H increases risk for atrophic age-related macular degeneration.

OBJECTIVE: To determine if the complement factor H gene (CFH) determines risk for development of geographic atrophy (GA). DESIGN: Retrospective case-control study. PARTICIPANTS AND CONTROLS: The independent case-control data set contained 647 age-related macular degeneration (AMD) cases (grades 3, 4, or 5) and 163 controls (grades 1 or 2). METHODS: To determine if CFH had any effect on determining risk for development of GA in an independent case-control data set of 647 AMD cases and 163 controls, the rs1061170 single-nucleotide polymorphism was tested for association, separating grades and analyzing them independently against the controls. Odds ratios were calculated using standard logistic regression models. MAIN OUTCOME MEASURES: The outcome variable was AMD affection status, and genotypes were coded according to a log-additive model. RESULTS: There were 407 grade 5, 107 grade 4, 133 grade 3, 35 grade 2, and 128 grade 1 individuals. There was significant association with AMD when comparing grades 3, 4, and 5 versus the controls. The highest odds ratio was obtained when analyzing the grade-4 cases versus the grade-1 controls (OR = 3.217, P<0.0001). CONCLUSIONS: Our results indicate that CFH increases the risk of developing GA (grade 4) as well as neovascular (grade 5) and milder (grade 3) disease. Although neovascular disease is responsible for the majority of severe vision loss with AMD, GA is also a significant cause of vision loss, and without effective treatment. Therefore, an attempt to clarify its pathogenesis is of the utmost importance.

Aged↗
PubMed2002

Complement factor 3 mediates particulate matter-induced airway hyperresponsiveness.

Epidemiologic studies have suggested that exposure to airborne particulate matter (PM) can exacerbate allergic airway responses; however, the mechanism(s) are not well understood. We and others have recently shown that development of airway hyperresponsiveness (AHR) may be a complement-mediated process. In the present study, we examined the role of complement factor 3 (C3) in the development of PM-induced AHR and airway inflammation by comparing responses between C3-deficient (C3(-/-)) and wild-type mice. Mice were exposed to 0.5 mg of ambient particulate collected in urban Baltimore. Forty-eight hours later, airway responsiveness to intravenous acetylcholine was assessed and bronchoalveolar lavage was conducted. PM exposure of wild-type mice resulted in significant increases in AHR, whereas it did not significantly increase airway reactivity in C3(-/-) mice. Interestingly, PM induced similar inflammatory responses in both wild-type and C3(-/-) mice. Immunohistochemical staining demonstrated marked C3 deposition in the airway epithelium and connective tissue of wild-type mice after PM exposure. These results suggest that exposure to PM may induce AHR through activation of complement factor 3 in the airways.

Air Pollution↗
PubMed1992

Complement factor 2 deficiency: a clinical and serological family study.

Inherited complement deficiencies are associated with a variety of connective tissue diseases. A family with inherited deficiency of complement factor 2 (C2) is described in which two family members with homozygous C2 deficiency developed cutaneous vasculitis and sicca syndrome. The other family members had heterozygous C2 deficiency and each member had the HLA-A25, B18, DR2 (w15) haplotype. The mother had seropositive rheumatoid arthritis. Further studies showed the presence of cryoglobulins, antibodies against endothelial cells, and anticardiolipin antibodies.

Adult↗
PubMed1977

Acute energy deprivation in man: effect on serum immunoglobulins antibody response, complement factors 3 and 4, acute phase reactants and interferon-producing capacity of blood lymphocytes.

The effects of 10 days of total energy deprivation on serum levels of immunoglobulins, antibodies acute phase reactants and on interferon production were evaluated in fourteen healthy, normal-weight males. A significant depression was noted of the serum levels of complement factor 3, haptoglobin and orosomucoid. The titres of mercaptoethanol-sensitive specific antibodies to flagellin were higher in the subjects inoculated at the end of the starvation period than in controls and those inoculated at the start of the period. The serum levels of IgG, IgM, IgA, IgE, alpha-1-antitrypsin and complement factor 4, and the interferon-producing capacity of blood lymphocytes, were not changed. Thus, 10 days of total energy deprivation depresses the serum levels of several acute phase reactants and re-feeding may enhance antibody production.

Antibodies↗
PubMed1994

Biologically active recombinant human complement factor H: synthesis and secretion by the baculovirus system.

A complete cDNA clone (4.3 kb) encoding human complement factor H (hCFH; 155 kDa) has been cloned into the pVL1393 baculovirus expression vector and transfected into Spodoptera frugiperda Sf9 insect cells. A biologically active (92 +/- 15%) 140-kDa protein was secreted into the medium with a yield of more than 5 mg/liter. This is the first report of synthesis of biologically active recombinant hCFH in a heterologous system.

Animals↗
PubMed1979

Dermatitis herpetiformis: lymphocytes, immunoglobulins and complement factors in peripheral blood.

Peripheral blood lymphocytes from patients with dermatitis herpetiformis and healthy controls were investigated in order to determine the percentages of B-lymphocytes, T-lymphocytes and cells with receptors for the Fc part of human IgG (EA-RFC). Furthermore, the serum concentrations of IgG, IgA, IgM, IgD and IgE and the complement factors C3 and C4 were also measured. An increase in the mean percentages of lymphocytes with membrane-bound IgA and IgD, as well as an increase in the mean percentage of cells with receptors for the Fc part of human IgG (EA-RFC) were found in the patient group as compared with the control group. No differences between patient group and control group were found concerning the mean percentage of B-lymphocytes or T-lymphocytes. The mean serum concentrations of the various immunoglobulins and the complement factors investigated did not differ significantly between the two groups.

Adolescent↗
PubMedDate not supplied

Complement factor H: sequence analysis of 221 kb of human genomic DNA containing the entire fH, fHR-1 and fHR-3 genes.

Complement factor H (fH) is a member of a family of proteins involved in the regulation of complement activation (RCA). These proteins share a common structural motif, the Short Consensus Repeat (SCR), which is structurally conserved among related genes and between phylogenetically divergent species. fH is composed of 20 such SCRs and a variety of biological functions have been localised to specific SCR domains. The majority of individual SCRs identified are encoded by single exons, and processes such as gene conversion, duplication and exon shuffling have been implicated in the evolution and genomic radiation of SCR-encoding genes. We have analysed two GenBank sequence entries relating to two overlapping PAC clones sequenced at the Sanger Centre which contain the entire human fH gene and two adjacent fH-related (fHR) genes, fHR-1 and fHR-3. Here, we report the detailed analysis of the assembled 221 kb of contiguous, ungapped genomic sequence from human chromosome 1q32, in part employing the RUMMAGE-DP automated annotation tool. Genomic duplications involving fH and fHR exons were identified and Alu/L1 repeat dating established that the duplications occurred after the separation of rodent and primate lineages. The analysis indicates that retrotransposition as well as single and multiple exon duplication events are likely to have been involved in SCR radiation and RCA gene evolution, facilitated by conservation of splice-phasing and the single-exon, single-SCR nature of the encoded domains.

5' Untranslated Regions↗
PubMed1978

Lymphocyte subpopulations, serum immunoglobulins and complement factors in patients with atopic dermatitis.

The percentages of lymphocytes carrying different classes of membrane-bound Ig, and lymphocytes forming rosettes with sheep erythrocytes (E-RFC), as well as lymphocytes with receptor for the Fc-part of IgG (EA-RFC) were determined in 19 patients with atopic dermatitis. Lymphocyte suspensions were also stained with a specific rabbit anti-human T-lymphocyte antiserum. Furthermore, the serum concentration of IgG, IgA, IgM and IgE and the complement factors C3 and C4 were measured. A small but significant increase in lymphocytes with membrane-bound IgE and an increase in the serum concentration of IgE and complement factor C4 were observed. A decrease in the percentages of lymphocytes with receptors for sheep erythrocytes (E-RFC) was also found. The percentages of lymphocytes that stained with the anti-T antiserum correlated well with the percentages of lymphocytes forming rosettes with sheep erythrocytes. In one patient we found increased IgE positive lymphocytes, increased IgE serum concentration and a decreased T-cell number.

Adolescent↗
PubMed1993

Changes in blood levels of proteinase inhibitors, pregnancy zone protein, steroid carriers and complement factors induced by oral contraceptives.

Three low-dose oral contraceptives Trinordiol, Gynatrol, and Marvelon, containing ethinylestradiol (EE) in combination with triphasic levonorgestrel (LNg), monophasic levonorgestrel, and monophasic desogestrel (DGS), respectively, were given to 65 healthy women, n = 21-22 in each group. Blood levels of antithrombin III (AT III), alpha 2-macroglobulin (alpha 2M) alpha 1-antitrypsin (alpha 1at), complement factors (factor B, C3, C4), pregnancy zone protein (PZP), corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG) and albumin were measured before treatment and during the first and third treatment cycles. AT III levels decreased and alpha 1at levels increased in all three groups during treatment. alpha 2M increased during cycle 3 in the Trinordiol and Gynatrol groups. CBG, PZP and SHBG levels increased in all 3 groups, the CBG and PZP increase being higher in the Marvelon group than in the Gynatrol group. Increases in SHBG levels were found in the order Marvelon > Trinordiol > Gynatrol. Plasma levels of complement factors B, C3 and C4 remained unchanged. It is concluded that the increase in alpha 1at partly compensates for the fall in AT III, that the rise in PZP presumably enhances fibrinolysis, and that LNg has higher anti-estrogenicity and androgenicity than DSG.

Adolescent↗
PubMed2001

Hemolytic-uremic syndrome and complement factor H deficiency: clinical aspects.

A subgroup of patients with hemolytic-uremic syndrome (HUS) has emerged with complement factor H deficiency. These have come to light because of persistent hypocomplementemia, although the molecular finding by Warwicker et al in one pedigree suggests that not all cases exhibit systemic hypocomplementemia. These patients have an atypical presentation in that they do not consistently have a prodrome of enterocolitis although precipitating factors may include infections of various kinds. Patients usually have severe hypertension early in the course of their illness, tend to relapse, and have a poor prognosis. The age of onset varies from neonates to adults. Plasma exchange and replacement with a plasma product containing factor H seem a reasonable option in the absence of better evidence. Kidney transplantation can meet with recurrence of HUS, but the risk of grafting has yet to be established, and a strategy to overcome graft recurrence is needed. Because of the great rarity of this disorder, a strong case can be made for international registries of atypical HUS cases so that clinical and laboratory investigation is promoted.

Complement Factor H↗
PubMed1986

CNBr cleavage of the light chain of human complement factor I and alignment of the fragments.

The light chain and heavy chain of reduced and alkylated human complement Factor I were purified by high-pressure gel-permeation chromatography. CNBr cleavage of Factor I light chain yielded four major fragments, which were purified by gel filtration. N-Terminal sequence analysis of the CNBr-cleavage fragments allowed identification of 200 of the approx. 240 amino acid residues of the light chain. An alignment is proposed, based on sequence analysis of peptides obtained after cleavage at arginine residues of the light chain and on homology of the sequence determined with that of other serine proteinases. The sequence around the active-site serine residue was established and three potential attachment sites for carbohydrate moieties were identified.

Amino Acid Sequence↗
PubMed1995

HIV glycoprotein 41 and complement factor H interact with each other and share functional as well as antigenic homology.

We have shown that complement factor H (CFH) interacts with HIV-1 at the level of the sequence Env 105-119, contained in the C1 domain of gp120. CFH interaction with HIV was evident only after dissociation of the Env complex induced by exposure to sCD4. We hypothesized that CFH could act as a gp41 analog in the interaction with Env 105-119. A panel of partially overlapping, synthetic peptides reproducing the extracellular portion of gp41 was therefore used to compete the binding of CFH to Env 105-119. Three sets of peptides that competed this interaction were identified. These peptides defined a region of functional homology between the gp41 molecule and CFH (Env 580-600), and two regions of interaction (Env 620-640 and Env 650-670). In addition to this, a monoclonal antibody directed against peptide Env 580-600 and a polyclonal mouse antiserum raised against recombinant gp41 were shown to recognize CFH in Western blots and ELISA, respectively, also defining a region of antigenic homology between gp41 and CFH. These data provide evidence for interaction and molecular mimicry between an HIV structural protein and a negative regulator of the complement pathway. We show here that CFH can interact with both HIV Env proteins, suggesting a possible and efficient mechanism of downregulation of the complement cascade at the surface of infected cells.

Amino Acid Sequence↗
PubMed1998

Rational design of boropeptide thrombin inhibitors: beta, beta-dialkyl-phenethylglycine P2 analogs of DuP 714 with greater selectivity over complement factor I and an improved safety profile.

The potent boropeptide thrombin inhibitor DuP 714 caused side effects in laboratory animals that appear to be related to its ability to inhibit complement factor I, thereby activating the complement cascade. Using X-ray crystal structure information, we have designed compounds that have greater selectivity for thrombin over factor I and that have reduced tendency to produce these side effects.

Animals↗
PubMed1999

Induced fit activation mechanism of the exceptionally specific serine protease, complement factor D.

We have investigated the mechanism by which the complement protease, Factor D, achieves its high specificity for the cleavage of Factor B in complex with C3(H2O). Kinetic experiments showed that Factor B and C3(H2O) associate with a KD of >/=2.5 microM and that Factor D acts on this complex with a second-order rate constant of kcat/KM >/= 2 x 10(6) M-1 s-1, close to the rate of a diffusion-controlled reaction for proteins of this size. In contrast, Factor D, which is a member of the trypsin family of serine proteases, was 10(3)-10(4)-fold less active than trypsin toward both thioester and p-nitroanilide substrates containing an arginine at P1. Furthermore, peptides spanning the Factor B cleavage site were not detectably cleaved by Factor D (kcat/KM </= 0.5 M-1 s-1). These results imply that contacts between Factor D and the C3(H2O)B complex, outside the vicinity of the cleavage site in Factor B, generate >/=9 kcal/mol of binding energy to stabilize the transition state for reaction. In support of this, we demonstrate that chemical modification of Factor D at a single lysine residue that is distant from the active site abolishes the activity of the enzyme toward Factor B while not affecting activity toward small synthetic substrates. We propose that Factor D may exemplify a special case of the induced fit mechanism in which the requirement for conformational activation of the enzyme results in a substantial increase in substrate specificity.

Acetylation↗
PubMed1988

Two populations of complement factor H differ in their ability to bind to cell surfaces.

Using hydrophobic affinity chromatography on phenyl-Sepharose, human complement factor H can be separated into two subpopulations, phi 1 and phi 2. Although phi 1 and phi 2 are known to differ in their aggregation properties under non-physiological low ionic strength conditions, no difference in aggregation state was detected under the conditions used for cell-binding experiments. We have investigated these two subpopulations further to determine whether functional differences exist between them. The subpopulation phi 2 was found to bind specifically and saturably to the surface of Raji cells. The binding of the other subpopulation, phi 1, was low, and essentially non-specific. A monoclonal anti-factor H antibody, BGH-1, was raised which recognizes preferentially the phi 2 subpopulation and inhibits the binding of factor H to cell surfaces.

Antibodies, Monoclonal↗
PubMed1995

The binding of apobec-1 to mammalian apo B RNA is stabilized by the presence of complementation factors which are required for post-transcriptional editing.

C to U RNA editing in mammalian intestinal apolipoprotein B mRNA creates an in-frame translational stop and the synthesis of a truncated protein called apo B48. This site specific cytidine deamination is mediated by an enzyme complex of which the catalytic component (apobec-1) is a 27 kDa zinc-binding protein. apobec-1, expressed in bacteria, will bind to mammalian apo B RNA as well as a number of other AU-rich RNA templates. Apo B RNA-binding activity can be competed by the addition of tRNA, an effect which can be overcome by the addition of complementation factors such as chick enterocyte S-100 extracts. Thus, apobec-1 may be a non-specific RNA binding protein which requires the presence of complementation factors to stabilize and enhance its binding in the setting of the holo-enzyme.

APOBEC-1 Deaminase↗