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PubMed1984

Immune complexes and the complement factors C4 and C3 in cerebrospinal fluid and serum from patients with chronic progressive multiple sclerosis.

Immune complexes (IC) have been found in both serum and cerebrospinal fluid (CSF) in multiple sclerosis (MS). The complement system is known to play a major role as a mediator of inflammation in immune complex disease. Therefore, we have investigated paired samples of serum and CSF from 32 patients with progressive MS for IC, the levels of the complement factors C4 and C3, and presence of their activation products (AP). IC was found in serum from 17 of the 32 MS patients (53%) and in CSF from 9 of 31 MS patients (29%). No correlation was found between the occurrence of IC in serum and in CSF. The levels of C3 in serum and CSF from the MS patients did not differ from the levels in a control group, whereas the levels of C4 in MS-serum were elevated and the C4 levels in MS-CSF reduced. A low level of CSF-C4 correlated significantly to the occurrence of CSF-IC. AP of C4 and C3 in serum were seen in 11 of the 32 patients (34%), appearing significantly more frequently among patients with circulating IC. No C4- or C3AP could be identified in CSF.

Adult↗
PubMed2004

Constitutive expression and alternative splicing of the exons encoding SCRs in Sp152, the sea urchin homologue of complement factor B. Implications on the evolution of the Bf/C2 gene family.

The purple sea urchin, Strongylocentrotus purpuratus, possesses a non-adaptive immune system including elements homologous to C3 and factor B (Bf) of the vertebrate complement system. SpBf is composed of motifs typical of the Bf/C2 protein family. Expression of Sp152 (encodes SpBf) was identified in the phagocyte type of coelomocyte in addition to gut, pharynx and esophagus, which may have been due to the presence of these coelomocytes in and on all tissues of the animal. Sp152 expression in coelomocytes was constitutive and non-inducible based on comparisons between pre- and post-injection with lipopolysaccharide or sterile seawater. The pattern of five short consensus repeats (SCRs) in SpBf has been considered ancestral compared to other deuterostome Bf/C2 proteins that contain either three or four SCRs. Three alternatively spliced messages were identified for Sp152 and designated Sp152Delta1, Sp152Delta4, and Sp152Delta1+Delta4, based on which of the five SCRs were deleted. Sp152Delta4 had an in-frame deletion of SCR4, which would encode a putative SpBfDelta4 protein with four SCRs rather than five. On the other hand, both Sp152Delta1 and Sp152Delta1+Delta4 had a frame-shift that introduced a stop codon six amino acids downstream of the splice site for SCR1, and would encode putative proteins composed only of the leader. Comparisons between the full-length SpBf and its several splice variants with other Bf/C2 proteins suggested that the early evolution of this gene family may have involved a combination of gene duplications and deletions of exons encoding SCRs.

Alternative Splicing↗
PubMed1977

Hageman complement and factor.

Complement components are activated by immunologic and non-immunologic mechanisms through various plasma protein systems such as immunoglobulins, properdin, plasmin, thrombin and Hageman factor. The activation of Hageman factor, followed by complement cleavage leading to liberation of various chemical mediators, can be initiated by exposure of negatively charged tissue components due to trauma and infection.

Blood Coagulation↗
PubMed2001

Isolation, characterization and developmental regulation of the human apobec-1 complementation factor (ACF) gene.

Mammalian apolipoprotein B (apo B) mRNA undergoes site-specific C to U deamination which is mediated by a multicomponent enzyme complex containing a minimal core composed of apobec-1 and a complementation factor, ACF. We have isolated and characterized the human ACF gene and examined its tissue-specific and developmental expression. The ACF gene spans approximately 80 kb and contains 15 exons, three of which are non-coding. Multiple alternative splice acceptor sites were found, generating at least nine different transcripts. Of these, the majority (approximately 75-89%) encode functional protein. In order to examine the role of ACF mRNA expression in the regulation of apo B mRNA editing, we examined a panel of fetal intestinal and hepatic mRNAs as well as RNA from an intestinal cell line. A developmental increase in C to U RNA editing has been previously noted in the human intestine. In both instances, the pattern of alternative splicing and overall abundance of ACF mRNA was relatively constant during development in both liver and small intestine. Taken together, the data demonstrate a complex pattern of differential, tissue-specific splicing of ACF mRNA, but suggest that other mechanisms are responsible for the developmental increase noted in intestinal apo B mRNA editing in humans.

APOBEC-1 Deaminase↗
PubMed2003

A novel nuclear localization signal in the auxiliary domain of apobec-1 complementation factor regulates nucleocytoplasmic import and shuttling.

C to U editing of the nuclear apolipoprotein B (apoB) transcript is mediated by a core enzyme containing a catalytic deaminase, apobec-1, and an RNA binding subunit, apobec-1 complementation factor (ACF). ACF expression is predominantly nuclear, including mutant proteins with deletions of a putative nuclear localization signal. We have now identified a novel 41-residue motif (ANS) in the auxiliary domain of ACF that functions as an authentic nuclear localization signal. ANS-green fluorescence protein and ANS-beta-galactosidase chimeras were both expressed exclusively in the nucleus, whereas wild-type chimeras or an ACF deletion mutant lacking the ANS were cytoplasmic. Nuclear accumulation of ACF is transcription-dependent, temperature-sensitive, and reversible, features reminiscent of a shuttling protein. ACF relocates to the cytoplasm after actinomycin D treatment, an effect blocked by the CRM1 inhibitor leptomycin B. Heterokaryon assays confirmed directly that ACF shuttles in vivo. ACF binds to the protein carrier, transportin 2 in vivo, and colocalizes to the nucleus as determined by confocal microscopy. Co-immunoprecipitation experiments revealed that transportin 2 binds directly to the ANS motif. These data suggest that directed nuclear localization and compartmentalization of the core complex of the apoB RNA editing enzyme is regulated through a dominant targeting sequence (ANS) contained within ACF.

Active Transport, Cell Nucleus↗
PubMed1981

Circulating immune complexes, complement factors C3, C4, C1-inhibitor, alpha-1-antitrypsin and immunoglobulins in asthmatic patients.

Sera from 159 adult asthmatic outpatients (extrinsic, n = 82, intrinsic, n = 65 and acetylosalicylic acid (ASA)-sensitive, n = 12) and from 100 controls were tested for total levels of IgG, IgM, IgA, IgE, complement factors C3, C4, C1-inhibitor, alpha 1-antitrypsin and circulating immune complexes. The following results were observed: (1) a marked increase of IgE in extrinsic asthma; (2) a slight increase of IgM, and (3) an equal increase of complement C4 levels in all three asthma groups; (4) normal mean values of C3 levels with a significantly larger standard deviation of the mean in all three asthma groups; (5) an equally slight decrease of protease inhibitors, such as C1-inhibitor and alpha 1-antitrypsin, and (6) the presence of circulating immune complexes in 22% of extrinsic, in 8% of intrinsic and 13% of ASA-sensitive asthmatics. Circulating immune complexes can be found in all three asthma groups and may correlate with complement deviation.

Adult↗
PubMed2002

Constitutive activation and endocytosis of the complement factor 5a receptor: evidence for multiple activated conformations of a G protein-coupled receptor.

Serpentine receptors relay hormonal or sensory stimuli to heterotrimeric guanine nucleotide-binding proteins (G proteins). In most G protein-coupled receptors (GPCRs), binding of the agonist ligand elicits both stimulation of the G protein and endocytosis of the receptor. We have begun to address whether these responses reflect the same sets of conformational changes in the receptor using constitutively active mutants of the human complement factor 5a receptor (C5aR). Two different mutant receptors both constitutively activate G protein-mediated responses, but one (F251A) is endocytosed only in response to ligand stimulation, while the other (NQ) is constitutively internalized in the absence of ligand. Both the constitutive and ligand-dependent endocytosis are accompanied by recruitment of beta-arrestin to the receptor. An inactivating mutation (N296A) complements the NQ mutation, producing a receptor that is activated only upon exposure to agonist; this revertant receptor (NQ/N296A) is nevertheless constitutively endocytosed. Thus one mutant (F251A) requires agonist for triggering endocytosis but not for activation of the downstream G protein signal, while another (NQ/N296A) behaves in the opposite fashion. Dissociation of two responses normally dependent on agonist binding indicates that the corresponding functions of an activated GPCR reflect different sets of changes in the receptor's conformation.

Animals↗
PubMed2003

Identification of novel alternative splice variants of APOBEC-1 complementation factor with different capacities to support apolipoprotein B mRNA editing.

Two novel mRNA transcripts have been identified that result from species- and tissue-specific, alternative polyadenylation and splicing of the pre-mRNA encoding the apolipoprotein B (apoB) editing catalytic subunit 1 (APOBEC-1) complementation factor (ACF) family of related proteins. The alternatively processed mRNAs encode 43- and 45-kDa proteins that are components of the previously identified p44 cluster of apoB RNA binding, editosomal proteins. Recombinant ACF45 displaced ACF64 and ACF43 in mooring sequence RNA binding but did not demonstrate strong binding to APOBEC-1. In contrast, ACF43 bound strongly to APOBEC-1 but demonstrated weak binding to mooring sequence RNA. Consequently ACF45/43 complemented APOBEC-1 in apoB mRNA editing with less efficiency than full-length ACF64. These data, together with the finding that all ACF variants were co-expressed in rat liver nuclei (the site of apoB mRNA editing), suggested that ACF variants might compete with one another for APOBEC-1 and apoB mRNA binding and thereby contribute to the regulation of apoB mRNA editing. In support for this hypothesis, the ratio of nuclear ACF65/64 to ACF45/43 decreased when hepatic editing was inhibited by fasting and increased when editing was re-stimulated by refeeding. These findings suggested a new model for the regulation of apoB mRNA editing in which the catalytic potential of editosomes is modulated at the level of their assembly by alterations in the relative abundance of multiple related RNA-binding auxiliary proteins and the expression level of APOBEC-1.

APOBEC-1 Deaminase↗
PubMed1987

Human complement factor I: analysis of cDNA-derived primary structure and assignment of its gene to chromosome 4.

Factor I is a serine proteinase of complement which together with one of several specific cofactors cleaves activation products of the third and fourth components of complement (C3b and C4b) and modulates the activity of C3 convertase. A heterodimer glycoprotein (Mr = 88,000), factor I is synthesized as a single-chain precursor, prepro-I, which undergoes intracellular proteolytic processing. The human hepatoma line HepG2, however, secretes predominantly the single-chain precursor pro-I. In order to determine the molecular basis for this apparent processing defect, factor I cDNA clones were isolated from a HepG2 mRNA-derived library. Sequencing of the largest insert, HI1971, revealed that it contains 14 base pairs of 5' untranslated region, the complete coding sequence for the 583-residue prepro-I (NH2-signal peptide-heavy chain-linking peptide-light chain-COOH), two polyadenylation signals within the 200-base pair 3' untranslated region, and a portion of poly(A) tail. Analysis of the derived protein structure 1) reveals a mosaic multidomain structure of the heavy chain; 2) demonstrates structural similarity between intracellular conversion of pro-I and activation of other serine proteinase zymogens; and 3) indicates that the light chain of factor I resembles most closely the active subunit of tissue plasminogen activator among all serine proteinases and factor D among complement proteinases. Furthermore, this protein sequence was compared to the sequences of factor I cDNA clones isolated from normal human liver libraries and found to be identical. By exclusion, this defines as cellular the basis for the inefficient processing of pro-I by the HepG2 line. Chromosomal localization by the somatic cell hybrid method maps the factor I gene to chromosome 4.

Amino Acid Sequence↗
PubMed1982

Distribution of complement factors Bf, C2 and C6 in the Western Pacific.

Complement components Bf, C2 and C6 have been typed in various Micronesian, Polynesian, Melanesian and Indian populations of the Western Pacific. BfS and BfF gene frequencies are heterogeneous throughout the region but the number of alleles in the Bf system is restricted. C2 is also restricted with the C22 gene frequency from 0-1.3% in all groups except Fijian Indians where it is 4.8%. The C6A and C6B frequencies of Polynesians, Melanesians and Fijian Indians are within the narrow range of frequencies reported for these alleles from other parts of the world. In the Micronesians of Nauru, a third polymorphic allele (C6Nauru) occurs together with a number of rare alleles (C6R). The Nauruan C6 gene frequencies are C6A 44.6%, C6B 45.2%, C6Nauru 6.7% and C6R 3.5% C6Nauri is present in low frequencies in most other Western Pacific populations and C6R variants occur in Polynesians.

Alleles↗
PubMed1998

Human complement factor H deficiency associated with hemolytic uremic syndrome.

This study reports on six cases of deficiency in the human complement regulatory protein Factor H (FH) in the context of an acute renal disease. Five of the cases were observed in children presenting with idiopathic hemolytic uremic syndrome (HUS). Two of the children exhibited a homozygous deficiency characterized by the absence of the 150-kD form of Factor H and the presence, upon immunoblotting, of the 42-kD Factor H-like protein 1 (FHL-1) and other FH-related protein (FHR) bands. Southern blot and PCR analysis of DNA of one patient with homozygous deficiency ruled out the presence of a large deletion of the FH gene as the underlying defect for the deficiency. The other four children presented with heterozygous deficiency and exhibited a normal immunoblotting pattern of proteins of the FH family. Factor H deficiency is the only complement deficiency associated with HUS. These observations suggest a role for FH and/or FH receptors in the pathogenesis of idiopathic HUS.

Acute Disease↗
PubMed2004

Gene structure and expression of the mouse APOBEC-1 complementation factor: multiple transcriptional initiation sites and a spliced variant with a premature stop translation codon.

Editing of apolipoprotein (apo) B mRNA is mediated by an enzyme-complex that consists of the catalytic cytidine deaminase APOBEC-1 and the mRNA binding protein APOBEC-1 complementation factor or APOBEC-1 stimulating protein (ACF/ASP). Here we describe the detailed characterization of the structure, expression and splicing pattern of the mouse ACF/ASP gene. ACF/ASP mRNA is mainly expressed in mouse liver, small intestine and kidney. The deduced protein sequences of ACF/ASP from mouse and man share an identity of 93%. The mouse ACF/ASP gene consists of 12 exons and gives rise predominantly to full-length transcripts. To a minor extent (<10%) ACF/ASP mRNA with unspliced exon 8 is generated in liver, kidney and small intestine that encodes a truncated protein with a predicted molecular weight of 43 kDa. The promoter of the mouse ACF/ASP gene lacks a canonical TATA-box, but contains a cluster of Sp1 binding sites and uses multiple transcriptional initiation sites. Transfection studies demonstrated a preference of this promoter for cell lines derived from the gastrointestinal tract and proved the location of the promoter core region. The high sequence identity between man and mouse-much higher as observed for APOBEC-1-indicates a strong evolutionary constraint on the structure-function relationship of ACF/ASP, most probably due to a central role in editing and processing of apo B mRNA.

Alternative Splicing↗
PubMed2001

Complement factors C3a and C5a are increased in bronchoalveolar lavage fluid after segmental allergen provocation in subjects with asthma.

Allergic asthma is thought to be the result of an inappropriate specific immune response against common environmental antigens. However, studies of animal asthma models have also linked the innate immune system, in particular complement factors C3a and C5, to murine airway hyperresponsiveness. Because the possible role of these anaphylatoxins in patients with asthma is not understood, we tested the hypothesis that C3a and C5a will increase in the bronchoalveolar lavage (BAL) fluid of patients with asthma after segmental allergen provocation. In a group of 15 subjects with mild asthma we found a significant upregulation of C3a and C5a 24 h after allergen challenge compared with baseline values (p < 0.01). In a control group of healthy volunteers the concentrations remained basically unchanged. Furthermore, we found a strong correlation between both anaphylatoxins and the number of eosinophils (p < 0.01) and, to a lesser degree, with the number of neutrophils (p < 0.05) in BAL fluid. These data suggest a contribution of anaphylatoxins C3a and C5a to the pathogenesis in asthma. However, the pathogenic role of these substances in relation to asthma remains to be elucidated, for example, by using anaphylatoxin receptor blockers as a possible new therapeutic principle.

Adult↗
PubMed2006

Random mutagenesis of the complement factor 5a (C5a) receptor N terminus provides a structural constraint for C5a docking.

The N terminus of G protein-coupled receptors has been implicated in binding to peptide hormones. We have used random saturation mutagenesis to identify essential residues in the N terminus of the human complement factor 5a receptor (C5aR). In a library of N-terminal mutant C5aR molecules screened for activation by C5a, residues 24-30 of the C5aR showed a marked propensity to mutate to cysteine, most likely indicating that sulfhydryl groups at these positions are appropriately situated to form disulfide interactions with the unpaired Cys(27) of human C5a. This presumptive spatial constraint allowed the ligand to be computationally docked to the receptor to form a model of the C5a/C5aR interaction. When the N-terminal mutant C5aR library was rescreened with C5a C27R, a ligand incapable of disulfide interactions, no individual position in the N terminus was essential for receptor signaling. However, the region 19-29 was relatively highly conserved in the functional mutants, further demonstrating that this region of the C5aR makes a productive physiologic interaction with the C5a ligand.

Amino Acid Sequence↗
PubMed2007

The C-terminus of complement factor H is essential for host cell protection.

Complement is a powerful self-amplifying system of innate immune defense with the capacity to eliminate microbes directly. Factor H is a central regulator in plasma which protects host tissue from complement mediated damage. Here we characterize the relevance of surface attached factor H, and study the regulatory activity of factor H on endothelial cells. Although these cells expressed membrane bound regulators, cell bound factor H contributed substantially to complement regulatory activity at the cell surface. Blockade of the C-terminus of factor H with monoclonal antibodies inhibited cell binding of this soluble regulator and resulted in enhanced complement activation on the cells. In the absence of factor H, increased deposition and slower inactivation of C3b resulted in higher amount of membrane attack complexes on the cell surface. When the membrane regulators CD55 and CD59 were removed by enzymatic treatment, complement mediated cell lysis was enhanced in the absence of factor H. Importantly, inhibition of the C-terminus did not compromise the regulatory function of factor H in fluid phase. Altogether these data point to a highly relevant, yet so far underestimated role of factor H for complement control at cellular surfaces, and reveal a decisive role of the factor H C-terminus in host cell recognition and protection.

Antibodies, Monoclonal↗
PubMed1990

Immunoglobulin G, complement factor C3 and lymphocytes in proliferative intraocular disorders.

This study examines a possible immunological contribution to the development of proliferative intraocular disorders (PID) with traction retinal detachment. We analysed 24 periretinal membranes and 35 vitreous aspirates from patients with idiopathic proliferative vitreoretinopathy (PVR), traumatic PVR, and proliferative diabetic retinopathy (PDR). Lymphocytes and complement factor C3 deposits could not be detected in any of the membrane specimens. IgG was present in all but one of the PVR membranes but in less than half of the PDR specimens and there to a lesser extent. The IgG immunoreactivity was not collocalized with macrophages but instead located to the extracellular matrix. The intravitreal levels of IgG (ELISA) and protein were elevated in PID but the range of these biochemical changes was so wide that there were no significant differences of the IgG levels between the single types of PID. Using electrophoresis and Western blotting, C3 was detected in normal and pathologic vitreous but smaller C3 fragments indicative of C3 breakdown were only found in PID.

Blotting, Western↗
PubMed2000

Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma.

The prevalence and severity of allergic asthma continue to rise, lending urgency to the search for environmental triggers and genetic substrates. Using microarray analysis of pulmonary gene expression and single nucleotide polymorphism-based genotyping, combined with quantitative trait locus analysis, we identified the gene encoding complement factor 5 (C5) as a susceptibility locus for allergen-induced airway hyperresponsiveness in a murine model of asthma. A deletion in the coding sequence of C5 leads to C5-deficiency and susceptibility. Interleukin 12 (IL-12) is able to prevent or reverse experimental allergic asthma. Blockade of the C5a receptor rendered human monocytes unable to produce IL-12, mimicking blunted IL-12 production by macrophages from C5-deficient mice and providing a mechanism for the regulation of susceptibility to asthma by C5. The role of complement in modulating susceptibility to asthma highlights the importance of immunoregulatory events at the interface of innate and adaptive immunity in disease pathogenesis.

Animals↗
PubMed2000

Identification of GRY-RBP as an apolipoprotein B RNA-binding protein that interacts with both apobec-1 and apobec-1 complementation factor to modulate C to U editing.

C to U editing of apolipoprotein B (apoB) mRNA involves the interaction of a multicomponent editing enzyme complex with a requisite RNA sequence embedded within an AU-rich context. This enzyme complex includes apobec-1, an RNA-specific cytidine deaminase, and apobec-1 complementation factor (ACF), a novel 65-kDa RNA-binding protein, that together represent the minimal core of the editing enzyme complex. The precise composition of the holo-enzyme, however, remains unknown. We have previously isolated an enriched fraction of S100 extracts, prepared from chicken intestinal cells, that displays apoB RNA binding and which, following supplementation with apobec-1, permits efficient C to U editing. Peptide sequencing of this most active fraction reveals the presence of ACF as well as GRY-RBP, an RNA-binding protein with approximately 50% homology to ACF. GRY-RBP was independently isolated from a two-hybrid screen of chicken intestinal cDNA. GRY-RBP binds to ACF, to apobec-1, and also binds apoB RNA. Experiments using recombinant proteins demonstrate that GRY-RBP binds to ACF and inhibits both the binding of ACF to apoB RNA and C to U RNA editing. This competitive inhibition is rescued by addition of ACF, suggesting that GRY-RBP binds to and sequesters ACF. As further evidence of the role of GRY-RBP, rat hepatoma cells treated with an antisense oligonucleotide to GRY-RBP demonstrated an increase in C to U editing of endogenous apoB RNA. ACF and GRY-RBP colocalize in the nucleus of transfected cells and, in cotransfection experiments with apobec-1, each appears to colocalize in a predominantly nuclear distribution. Taken together, the results indicate that GRY-RBP is a member of the ACF gene family that may function to modulate C to U RNA editing through binding either to ACF or to apobec-1 or, alternatively, to the target RNA itself.

APOBEC-1 Deaminase↗