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PubMed1984

Studies on prothrombin complex concentrates contact factors, complement components and proteinase inhibitors.

The behaviour of contact factors, complement components and antiproteases during the preparation of prothrombin complex concentrates by adsorption of the clotting components on DEAE-Sephadex has been studied. The pro-enzymes: factors XII, XI and prekallikrein were removed by pre-elution in function of the salt concentration. In contrast, high molecular weight kininogen was considerably enriched in PCC preparations. C4 of the complement system displayed an analogous behaviour. C1s reached a 4-5 fold plasma concentration but C3 only 30% of the normal plasma level. The prothrombin complex concentrate contained no antithrombin III nor alpha 2M nor alpha 2 antiplasmin but a three fold plasma concentration of C1-inactivator and a 15 fold increase of inter-alpha-trypsin inhibitor. NAPTT (Non Activated Partial Thromboplastin Time) ratios did not seem to be in accordance with either the presence or the absence of contact enzymes. Moreover 0.20 M NaCl appeared as the minimal pre-elution molarity necessary to ensure a NAPTT ratio above thrombogenic values. Molecular alteration of high molecular weight kininogen and C4 was observed and its significance discussed. Complex formation between C1-inactivator and proteases was shown to be another sign of undesirable proteolytic events.

Blood Coagulation Factors↗
PubMed1984

Complete primary structure for the zymogen of human complement factor B.

The entire amino acid sequence of complement factor B has been established combining both protein and DNA sequencing strategies. The zymogen consists of 739 amino acids, has four asparagine-linked carbohydrate sites, and has independently disulfide-bonded NH2- and COOH-terminal regions. The catalytic subunit, Bb, is a unique serine protease containing 259 amino acids that are not integral to any of the classical serine proteases. It is proposed that this region of the Bb fragment functions as a cofactor-binding domain for C3b. The Ba fragment was found to contain three regions of internal sequence homology which were unrelated to the "kringle" regions of prothrombin and plasminogen and which suggest an independent evolution for the B genome. Sequence alignment of the active site of B to the serine proteases was made using the three-dimensional structures of chymotrypsin and trypsin as molecular models. Three stretches within the hypothetical model for B contrast markedly with all known serine proteases in both amino acid sequences and predicted configuration. It is suggested that these "altered" regions contribute at least in part to the formation of the catalytic region of the C3 convertase.

Amino Acid Sequence↗
PubMed2004

Complement factors c3a, c4a, and c5a in chronic obstructive pulmonary disease and asthma.

Studies of animal models have shown that the activation of the complement system could have a role in chronic obstructive pulmonary disease (COPD) and asthma by promoting inflammation and enhancing airway hyperresponsiveness. We sought to determine whether the levels of complement factors C3a, C4a, and C5a are elevated at the site of inflammation in patients with COPD and patients with asthma. We analyzed the induced sputum of seven patients with COPD, ten patients with asthma, and twelve healthy nonsmokers. The concentrations of anaphylatoxins in the induced sputum were measured by cytometric bead array. We found significantly increased C5a/C5a desArg concentrations in supernatants of the induced sputum of patients with COPD (P = 0.007) and those with asthma (P = 0.002) compared with the control group. In patients with COPD the C5a/C5a desArg concentrations were significantly negatively correlated with lung diffusion coefficient (r = -0.71, P = 0.035). There was no significant difference in C3a/C3a desArg or C4a/C4a desArg measurements between the three groups of subjects. These in vivo results propose the involvement of complement factor C5a in the pathogenesis of COPD and asthma.

Aged↗
PubMed1996

Efficient destruction of human immunodeficiency virus in human serum by inhibiting the protective action of complement factor H and decay accelerating factor (DAF, CD55).

Activation of the human complement system leads to complement deposition on human immunodeficiency virus (HIV) and HIV-infected cells without causing efficient complement-mediated lysis. Even in the presence of HIV-specific antibodies, only a few particles are destroyed, demonstrating that HIV is intrinsically resistant to human complement. Here we report that, in addition to decay accelerating factor (DAF) being partially responsible, human complement factor H (CFH), a humoral negative regulator of complement activation, is most critical for this resistance. In the presence of HIV-specific antibodies, sera devoid of CFH (total genetic deficiency or normal human serum depleted of CFH by affinity chromatography) lysed free virus and HIV-infected but not uninfected cells. In the presence of CFH, lysis of HIV was only obtained when binding of CFH to gp41 was inhibited by a monoclonal antibody against a main CFH-binding site in gp41. Since CFH is an abundant protein in serum, and high local concentration of CFH can be obtained at the surface of HIV as the result of specific interactions of CFH with the HIV envelope, it is proposed that the resistance of HIV and HIV-infected cells against complement-mediated lysis in vivo is dependent on DAF and CFH and can be overcome by suppressing this protection. Neutralization of HIV may be achieved by antibodies against DAF and, more importantly, antibodies against CFH-binding sites on HIV envelope proteins.

Acquired Immunodeficiency Syndrome↗
PubMed1985

Isolation of human complement factors C3, C5 and H.

An improved method for simultaneous purification of complement factors C3, C5 and H from human plasma has been developed. Using an initial batch separation technique with QAE-Sephadex, followed by chromatography on SP-Sephadex and gel filtration in Sephadex G-200, 600 mg of highly pure C3 can be prepared from 1600 ml of plasma. Simultaneously about 70 mg of highly pure factor H and 30 mg of C5 are obtained by chromatography of post SP-Sephadex material on DEAE-Sephacel. A small amount of C3 in the C5 pool is removed by anti-C3-Sepharose. By maleylation or citraconylation of reduced and alkylated C3, the constitutive polypeptide chains are modified in a way that made them separable by ion exchange chromatography.

Chromatography, Gel↗
PubMed1998

M protein of the group A Streptococcus binds to the seventh short consensus repeat of human complement factor H.

Streptococcus pyogenes evades complement by binding the complement-regulatory protein factor H (fH) via the central conserved C-repeat region of M protein. However, the corresponding binding region within fH has not previously been precisely localized. fH is composed of 20 conserved modules called short consensus repeats (SCRs), each of which contains approximately 60 amino acids. A series of fH truncated and deletion mutants were prepared, and their interaction with M6 protein was examined. The M protein binding site was initially localized to SCRs 6 to 15 as demonstrated by ligand dot blotting, chemical cross-linking, and enzyme-linked immunosorbent assay. SCR 7 was then shown to contain the M protein binding site, as a construct consisting of the first seven SCRs bound M protein but a construct containing the first six SCRs did not bind. In addition, deletion of SCR 7 from full-length fH abolished binding to M protein. SCR 7 is known to contain a heparin binding domain, and binding of fH to M6 protein was almost totally inhibited in the presence of 400 U of heparin per ml. These results localize the M6 protein binding site of fH to SCR 7 and indicate that it is in close proximity to the heparin binding site.

Animals↗
PubMed2002

Diversity of complement factor B/C2 in the common carp (Cyprinus carpio): three isotypes of B/C2-A expressed in different tissues.

Complement factor B and C2 are two critical proteases for complement activation. Some bony fish have been reported to possess duplicated genes for B/C2, but there is no direct evidence regarding possible functional divergence. Here, we report the isolation of the second and third isotypes of carp B/C2-A, a close relative of other bony fish B reported to date, and designated B/C2-A2 and B/C2-A3. B/C2-A1 (previously reported B/C2-A) and B/C2-A2 share 78% amino acid identity and are synthesized mainly in hepatopancreas. On the other hand, B/C2-A3 showed less (approximately 60%) sequence identity with the other two isotypes. It was expressed mainly in kidney and spleen, and was up-regulated after injection of carp with scleroglucan or sodium alginate, known immunostimulants for fish. Phylogenetic analysis suggests that B/C2-A3 diverged before separation of carp and zebrafish. B/C2-A3 represent a novel B/C2-lineage functioning as an acute phase reactant in cyprinid fish.

Amino Acid Sequence↗
PubMed1977

[Serum-complement factors in the pseudo-LE syndrome (author's transl)].

In contrast to the situation in disseminated lupus erythematodes, in pseudo-LE syndrome the serum-complement factors C'3 and C'4 are elevated and not decreased in the active stage of the disease. Although both diseases are defined and easily distinguished by the demonstration of the specific pathognomonic autoantibodies, at least in the active stage, they can also be distinguished by determining these two complement factors. The finding also demonstrates a different pathogenesis of the two diseases. The serum concentration of C'3 activator is elevated both in LE and pseudo-LE. In the former, determining C'4 is a more sensitive test than that of C'3.

Autoantibodies↗
PubMed1995

Deficiency of complement factor C5 reduces early mortality but does not prevent organ damage in an animal model of multiple organ dysfunction syndrome.

OBJECTIVE: To evaluate the role of complement factor C5 in a model of zymosan-induced multiple organ dysfunction syndrome. DESIGN: Experimental animal study. SETTING: Central animal laboratory of a university hospital. SUBJECTS: Twenty-five C5-deficient B2D10/Old and 25 C5-sufficient B2D10/New mice. INTERVENTIONS: On day 0, all mice received an intraperitoneal injection with zymosan suspended in paraffin in a dose of 1 mg/g body weight. MEASUREMENTS AND MAIN RESULTS: Between days 0 and 12, biological parameters (temperature, body weight, and clinical condition) were measured daily and mortality was monitored. Clinical condition was assessed as a symptom score by blindly grading the degree of lethargy, conjunctivitis, diarrhea, and ruffled fur of each mouse on a 2-point scale (maximum score of 4). On day 12, all surviving mice were killed and relative organ weights of lungs, liver, spleen, and kidneys were calculated. Relative organ weight was defined as (organ weight/body weight) x 100%. Zymosan administration induced a typical triphasic illness. Deterioration of the clinical condition, as indicated by the symptom score, and the decrease in temperature and body weight in the acute phase were all significantly less severe in C5-deficient mice (p < .005). In the late phase, no differences could be noticed in the courses of these biological parameters. Overall mortality was 2 (8%) of 25 in C5-deficient mice and 8 (32%) of 25 in C5-sufficient mice (p = .049), a difference that was mainly due to a difference in the acute phase. Organ damage, assessed as the relative organ weights, did not show any statistical differences for any organ between both strains. CONCLUSIONS: Complement factor C5 appears to play an important role in the acute hyperdynamic septic response in this model. However, deficiency of C5 could not prevent organ damage in the late multiple organ dysfunction syndrome phase. This finding suggests that other factors must be more important in the development of the inflammatory response leading to multiple organ dysfunction syndrome.

Aging↗
PubMed2005

Complement factors C1q and C3b in brains with Creutzfeldt-Jakob disease.

Neuronal loss in Creutzfeldt-Jakob disease (CJD) is due to apoptosis and autophagy, however the apoptotic cell death may be related to the influence of cytokines. The role of complement system in induction of this process was recently postulated. In our study we examined the immunoreactivity for "early activation" complement factors C1q and C3b in the brains of the patients with CJD. We showed the positive immunoreactivity for C1q and C3b in neurons mainly in areas of spongiform change, in Purkinje cells, molecular layer and granular layer of cerebellum, and in prion protein positive plaques. The evident positive reactivity of two complement factors may suggest the role of complement system in neurodegeneration in CJD.

Astrocytes↗
PubMed2001

Mutagenesis of apobec-1 complementation factor reveals distinct domains that modulate RNA binding, protein-protein interaction with apobec-1, and complementation of C to U RNA-editing activity.

C to U editing of apolipoprotein B (apoB) RNA requires a multicomponent holoenzyme complex in which minimal constituents include apobec-1 and apobec-1 complementation factor (ACF). We have examined the predicted functional domains in ACF in binding apoB RNA, interaction with apobec-1, and complementation of RNA editing. We demonstrate that apoB RNA binding and apobec-1-interacting domains are defined by two partially overlapping regions containing the NH(2)-terminal RNA recognition motifs of ACF. Both apoB RNA binding and apobec-1 interaction are required for editing complementation activity. ACF is a nuclear protein that upon cotransfection with apobec-1 results in nuclear colocalization and redistribution of apobec-1 from the cytoplasm. ACF constructs with deletions or mutations in the putative nuclear localization signal (NLS) still localize in the nucleus of transfected cells but do not colocalize with apobec-1, the latter remaining predominantly cytoplasmic. These observations suggest that the putative NLS motif in ACF is not responsible for its nucleo-cytoplasmic trafficking. By contrast, protein-protein interaction is important for the nuclear import of apobec-1. Taken together, these data suggest that functional complementation of C to U RNA editing by apobec-1 involves the NH(2)-terminal 380 residues of ACF.

APOBEC-1 Deaminase↗
PubMed2002

Complement factor B gene regulation: synergistic effects of TNF-alpha and IFN-gamma in macrophages.

Complement factor B (Bf) plays an important role in activating the alternative complement pathway. The inflammatory cytokines, in particular TNF-alpha and IFN-gamma, are critical in the regulation of Bf gene expression in macrophages. In this study, we investigated the mechanisms of Bf gene regulation by TNF-alpha and IFN-gamma in murine macrophages. Northern analysis revealed that Bf mRNA expression was synergistically up-regulated by TNF-alpha and IFN-gamma in MH-S cells. Truncations of the 5' Bf promoter identified a region between -556 and -282 bp that mediated TNF-alpha responsiveness as well as the synergistic effect of TNF-alpha and IFN-gamma on Bf expression. Site-directed mutagenesis of a NF-kappaB-binding element in this region (-433 to -423 bp) abrogated TNF-alpha responsiveness and decreased the synergistic effect of TNF-alpha and IFN-gamma on Bf expression. EMSAs revealed nuclear protein binding to this NF-kappaB cis-binding element on TNF-alpha stimulation. Supershift analysis revealed that both p50 and p65 proteins contribute to induction of Bf by TNF-alpha. An I-kappaB dominant negative mutant blocked Bf induction by TNF-alpha and reduced the synergistic induction by TNF-alpha and IFN-gamma. In addition, the proteasome inhibitor MG132, which blocks NF-kappaB induction, blocked TNF-alpha-induced Bf promoter activity and the synergistic induction of Bf promoter activity by TNF-alpha and IFN-gamma. LPS was found to induce Bf promoter activity through the same NF-kappaB cis-binding site. These findings suggest that a NF-kappaB cis-binding site between -433 and -423 bp is required for TNF-alpha responsiveness and for TNF-alpha- and IFN-gamma-stimulated synergistic responsiveness of the Bf gene.

5' Untranslated Regions↗
PubMed1984

Chemical characterization of cyanogen bromide fragments from the beta-chain of human complement factor C3.

The isolated beta-chain of human complement factor C3 (C3 beta) was fragmented by cyanogen bromide. Nine fragments were defined by gel filtration and high-pressure liquid chromatography, and characterized with respect to their Mr, amino acid composition and N-terminal amino acid sequence. Approx. 30% of the primary structure of C3 beta was determined. Alignment of the 3 N-terminal fragments allowed determination of 61 of the amino terminal residues of C3 beta. This region demonstrated 40% homology with the sequence in the N-terminal segment of the alpha-chain of the cobra venom factor.

Amino Acid Sequence↗
PubMed1989

Mapping of the human complement factor I gene to 4q25.

A detailed genetic and physical map of human complement factor I (IF) using somatic cell hybrids, in situ hybridization, and genetic linkage is reported. The gene has been localized to band 4q25. The order GC-INP10-ADH3-EGF-IF-IL2-MNS is proposed for genes on 4q on the basis of genetic and physical mapping techniques. A BclI polymorphism found with the IF probe demonstrated a maternal origin for a de novo deletion of chromosome 4 that was used in physically mapping the gene. The genetic and physical distances around band 4q24 suggest that 1 cM is approximately 1.2 million bp of DNA. This work provides a useful addition to the map of 4q.

Chromosome Mapping↗
PubMed2001

Complement factor I deficiency associated with recurrent meningitis coinciding with menstruation.

BACKGROUND: Complement (C) factor I deficiency is a rare immunodeficiency state frequently associated with recurrent pyogenic infections in early infancy. This deficiency causes a permanent uncontrolled activation of the alternative pathway resulting in massive consumption of C3. PATIENT: A 23-year-old woman with monthly recurrent meningitis episodes, mostly in the perimenstrual period, since August 1999. Previously, at age 16 years, she had meningococcal sepsis, also coinciding with menstruation. OBJECTIVES: To study the patient and her family to elucidate the molecular defects in the pedigree and to evaluate her clinical evolution. RESULTS: We describe clinical, immunological, and treatment follow-up during this period. First, we characterized the existence of a total complement factor I deficiency defined by undetectable levels by enzyme immunosorbent assay. This total deficiency was also found in her sister. Her parents and brother had approximately half of the normal levels. In addition, the patient had very low levels of C3; factor B; and an important reduction of factor H, properdin, C5, C7, and C8 complement components. Additional studies in the patient's sera evidenced high levels of immune complexes containing C1q and immunoglobulin (Ig) G, as well as C3b/factor H, C3b/properdin, C3b/IgG, and properdin/IgG complexes. Treatment with prophylactic antibiotics, antiestrogen medication, plasma infusions, or intravenous immunoglobulin has been unsuccessful in avoiding consecutive meningitis episodes. CONCLUSION: For the first time to our knowledge, these data present an unusual relationship between meningitis episodes and menstruation in factor I immunodeficiency.

Adolescent↗
PubMed1997

Identification of human complement factor H as a chemotactic protein for monocytes.

We used chromatographic separation to purify to homogeneity a monomeric monocyte chemotactic protein of 150 kDa contained in mesothelioma pleural effusions. It was identified by N-terminal amino acid sequencing and immunoblotting as complement factor H, an inhibitor of the alternative complement pathway. Specific antibodies against factor H inhibited the monocyte chemotactic activity of the purified protein, which was most active at 10 nM. Factor H is a restrictive factor of alternative complement pathway activation. The new chemotactic function assigned to factor H in recruiting monocytes to the mesothelioma site might contribute to malignant cell phagocytosis via the iC3b/complement receptor type 3 pathway. These functions link the humoral and cellular immune systems.

Amino Acid Sequence↗
PubMed2006

Further support for the common variants in complement factor H (Y402H) and LOC387715 (A69S) genes as major risk factors for the exudative age-related macular degeneration.

In developed countries, age-related macular degeneration (ARMD) is a common cause of blindness in the elderly. It is a clinically complex and genetically heterogeneous disorder. The etiology of the disorder may involve interactions between genetic and environmental factors. Recently it has been reported that a polymorphism in the complement factor H (CFH) and LOC387715 gene may determine the susceptibility of individuals to ARMD. In order to replicate and to determine the frequency of this polymorphism in ARMD patients, we have analyzed two unrelated families having exudative ARMD. Our analysis has identified the same common polymorphism (Y402H) in the CFH gene in one family and the A69S polymorphism in the LOC387715 gene in the second family. These results further support the notion that CFH and LOC387715 genes are the major risk factors for ARMD.

Aged↗
PubMed1993

Human complement factor B: functional properties of a recombinant zymogen of the alternative activation pathway convertase.

The human complement factor B is a centrally important component of the alternative pathway activation of the complement system. Here we report the isolation, characterization and eukaryotic expression of the first full length cDNA transcript for human factor B. In a factor B dependent haemolysis assay, the recombinant human factor B generated by transient COS cell transfection was shown to reconstitute haemolytic activity of factor B depleted human serum. To study the biological activities assigned to factor B, the availability of recombinant polypeptides representing definite portions of the human factor B molecule is desirable.

Animals↗