[Functions and structure of complement inactivators in membrane proteins. 3). Membrane cofactor protein].
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Animals↗
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Deposition of C4-binding protein and beta 1H globulin in kidneys of patients with IgA nephropathy.
A study on the deposition of complement control proteins in renal tissues from patients with IgA nephropathy is described. Renal biopsy specimens were obtained from patients with IgA nephropathy and other glomerular diseases. These biopsy samples were stained with antisera to human C4-binding protein and beta 1H globulin by indirect immunofluorescent staining. It was shown that the complement system is activated in IgA nephropathy via the both alternative and classical pathways.
Carrier Proteins↗
Inhibition of the hemolytic activity of the first component of complement C1 by an Escherichia coli C1q binding protein.
Molecular mimicry is a well established mechanism via which bacteria protect themselves from complement-mediated killing. We have previously demonstrated that a number of human cells express receptors for C1q (C1qR) and that the soluble form of this receptor inhibits activation of the classical pathway of complement. We now investigated whether Escherichia coli possesses a C1qR-like protein that protects these bacteria from complement-mediated injury. By FACS analysis it was shown that approximately 60% of the bacteria bound C1q directly in the absence of Abs. With ELISA we confirmed that the bacterial cell envelope was able to bind C1q in a dose-dependent fashion. We isolated a cell envelope associated C1q binding protein (C1qBP) by C1q affinity chromatography, then by anion exchange chromatography and gel filtration chromatography. On SDS-PAGE, the m.w. of C1qBP appeared to be 57 kDa and 51 kDa under reducing and nonreducing conditions, respectively. It was demonstrated that C1qBP specifically binds C1q and inhibits the hemolytic activity of C1q in both a dose- and time-dependent fashion. The binding of C1qBP to C1q is inhibited by C1q itself and also by the collagen-like stalks and the globular heads of C1q. In this respect, bacterial C1qBP is different from human C1qR because the binding of C1q to C1qR is only inhibited by the collagen-like stalks of C1q and not by the globular heads of C1q. C1qBP, when bound to C1q, prevents the assembly with C1r and C1s to form a functional C1 complex. The occurrence of C1qBP is not limited to certain E. coli strains, but is also found on Staphylococcus aureus, Citrobacter freundii, and Pseudomonas aeruginosa. Also, the binding of 125(I)-labeled C1q to these bacteria is specific because the binding of C1q to these bacteria is inhibitable with isolated soluble C1qBP. These findings provide evidence for the existence of a C1qR-like protein on bacteria that might protect them from complement-mediated damage.
Animals↗
[Functions and structure of complement inactivators in membrane proteins. 2). Decay-accelerating factor].
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Amino Acid Sequence↗
Factor I deficiency and C3 nephritic factor: immunochemical findings and association with Neisseria meningitidis infection in two patients.
The complement system was examined in two patients with systemic Neisseria meningitidis infections, both of whom had reduced or nondetectable CH50 as analysed by both pathways. C3 measured by conventional technique revealed 19% anti-C3c-reactive protein in the plasma of patient 1 and 3% in patient 2. Patient 1 had circulating C3b but no detectable C3c, C3d, or C4d, whereas patient 2 had normal levels of C3c and C4d and strongly elevated levels of C3d. Factor B analysis revealed no demonstrable native factor B and small amounts of Bb in patient 1 and normal concentration of native factor B plus trace amounts of Bb in patient 2. The depletion of C3 in both patients was due to uncontrolled activation caused by complete factor I deficiency (patient 1) and circulating C3 nephritic factor (patient 2). Both parents of patient 1 had factor I concentrations below (mean-2 SD) that seen in normal healthy individuals (n = 20). Circulating immune complexes (IC) were demonstrated in patient 1 only, whereas serum from both patients had strongly reduced capacity to solubilize preformed IC.
Adolescent↗
Complement resistance of Borrelia burgdorferi correlates with the expression of BbCRASP-1, a novel linear plasmid-encoded surface protein that interacts with human factor H and FHL-1 and is unrelated to Erp proteins.
The etiologic agent of Lyme disease, Borrelia burgdorferi, is capable of circumventing the immune defense of a variety of potential vertebrate hosts. Previous work has shown that interaction of host-derived complement regulators, factor H and factor H-like protein 1 (FHL-1), with up to five complement regulator-acquiring surface proteins (CRASPs) expressed by resistant B. burgdorferi sensu lato isolates conferred complement resistance. In addition expression of CRASP-1 is directly correlated with complement resistance of Borrelia species. This work describes the functional characterization of BbCRASP-1 as the dominant factor H and FHL-1-binding protein of B. burgdorferi. The corresponding gene, zs7.a68, is located on the linear plasmid lp54 and is different from factor H-binding Erp proteins that are encoded by genes localized on circular plasmids (cp32). Deletion mutants of BbCRASP-1 were generated, and a high affinity binding site for factor H and FHL-1 was mapped to the C terminus of BbCRASP-1. Similarly, the predominant binding site of factor H and FHL-1 was localized to the short consensus repeat 7. Factor H and FHL-1 maintain their cofactor activity for factor I-mediated C3b inactivation when bound to BbCRASP-1, and factor H is up to 6-fold more efficient in mediating C3b conversion than FHL-1. In conclusion, BbCRASP-1 (i). binds the host complement regulators factor H and FHL-1 with high affinity, (ii). is the key molecule of the complement resistance of spirochetes, and (iii). is distinct from the Erp protein family. Thus, BbCRASP-1 most likely contributes to persistence of B. burgdorferi and to pathogenesis of Lyme disease.
Amino Acid Sequence↗
[Functions and structure of complement inactivators in membrane proteins. 1). C3b/C4b receptor].
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Animals↗
Increased plasma concentrations of complement modulating proteins (C1 inhibitor, C4-binding protein, factor H and factor I) in psoriasis.
By using single radial immunodiffusion we measured the plasma levels of four complement modulating proteins, i.e., C1 inhibitor, C4-binding protein, factor H and factor I in 19 psoriatic patients in comparison with those of healthy controls. Except for C1 inhibitor which was only marginally elevated, they were found to be significantly increased in psoriatic patients. When psoriatic patients were classified into subgroups based on the clinical severity, the levels of factor H and those of factor I showed a close positive correlation with the activity and extent of the skin lesions, whereas such clear relationship could not be found with C1 inactivator or with C4-binding protein. These results offer additional support for the hypothesis that the complement system is involved in psoriasis.
Adult↗
Polymorphism and deficiency of human factor H-related proteins p39 and p37.
We described previously cDNA clones representing a novel factor H-related 1.4 kilobase mRNA. This mRNA species codes for a doublet of serum proteins of M(r) 39,000 and 37,000 (p39/p37). The respective recombinant proteins of the three clones H-69, pFH1.4a, and pFH1.4b differ in the expression of the epitope recognized by the monoclonal antibody (mAb) 3D11. This probably reflects the difference of three amino acid residues of the deduced protein sequence. Here we report evidence for corresponding alterations in the native proteins p39/p37 in human sera. Employing mAb 3D11 and a polyclonal factor H-specific antiserum we detected three different patterns in western blot analyses of human sera which we provisionally termed FH1.4p+m+, FH1.4p+m-, and FH1.4p-m-. In the first pattern, p39/p37 were recognized by both antibodies, while in the second pattern the two proteins reacted only with the polyclonal antiserum. Both antibodies failed to detect p39/p37 in the third pattern. These phenotypes are found in the healthy population with frequencies of 0.556, 0.40, and 0.044, respectively. The frequencies of the alleles FH1.4*p+m+, FH1.4*p+m-, and FH1.4*p-m- were estimated to be 0.33, 0.46, and 0.21, respectively, assuming the gene distribution to be in Hardy-Weinberg equilibrium. Studies of 98 members from 27 families revealed an autosomal Mendelian inheritance. Southern blot data support our assumption of a polymorphism of the factor H-related proteins p39 and p37.
Blood Proteins↗
Functional consequences of the genetic polymorphism of the third component of complement.
The third component of complement, the central protein of the complement cascade, occurs in two principal allotypes, C3S and C3F. An excess frequency of the F allotype has been implicated in a number of disease states, including some forms of glomerulonephritis. These associations have been explained by functional differences between C3S and C3F. We examined several complement functions, using purified preparations of C3S or C3F. The C3S allotype was 1.3 times more efficient than C3F in a hemolytic assay employing sensitized sheep erythrocytes; this difference was shown to arise from a slightly more efficient deposition of C3F on the cell surface. These differences are trivial and of much less magnitude than the functional differences between C4A and C4B. There were no differences between allotypes in their ability to be converted to inactive C3b (C3bi) by complement factors H and I or by CR1 and factor I. No significant differences were seen between the allotypes and their ability to support solubilization of preformed immune complexes.
Animals↗
Changes in the acute phase complement component and IL-6 levels in patients with chronic hepatitis C receiving interferon alpha-2b.
In order to study the effect of interferon alpha on the levels of acute phase complement proteins in vivo, serum concentrations of C9 and C1-inhibitor (C1-INH) were measured in patients with chronic hepatitis C before and 3 months after the beginning of interferon alpha2b therapy. Serum levels of the activation product of terminal complement pathway, C5b-9, HCV RNA and IL-6 were also determined. IFN alpha treatment significantly (P<0.0001) increased the serum concentrations of both complement proteins. C5b-9 levels were found to significantly decrease during the same period of time. When the patients were divided into responders or non-responders (more or less than 50% decrease in plasma HCV RNA concentrations) C9 and C1-INH levels were elevated only in the responder patients. There was no correlation between the changes of IL-6 levels or the amounts of IFN alpha administrated on one hand, and the changes in the complement protein levels on the other. These findings suggest that the marked increase in the serum concentrations of the acute phase complement proteins is a secondary phenomenon due to the IFN alpha-caused diminution of the viral load and the resulting immune complex-induced complement activation.
Acute-Phase Proteins↗
High normal serum levels of C3 and C1 inhibitor, two acute-phase proteins belonging to the complement system, occur more frequently in patients with Crohn's disease than ulcerative colitis.
Few data are available on measurements of serum concentrations of complement proteins in inflammatory bowel disease (IBD). Therefore we measured serum levels of C3, C4, and C1-esterase inhibitor (C1-INH) as well as C-reactive protein (CRP) in 167 patients with Crohn's disease (CD) and 111 patients with ulcerative colitis (UC). Median serum concentrations of C3 and C1-INH were significantly higher in CD than in UC. According to multiple logistic regression analysis adjusted to age, sex, activity of disease, and presence of extraintestinal manifestations, IBD patients with high-normal (> or = 128%, > or = 75th percentile ) C1-INH concentrations had significantly (0.0275) higher odds ratio to have a diagnosis of CD than UC. Patients with high-normal C3 (> or = 1.40 g/liter) and high (> or =20 mg/liter) CRP concentrations had an even higher odds ratio of a CD diagnosis (P = 0.0132). Our findings indicate that measurement of C3, C1-INH, and CRP can be used as an additional marker to pANCA/ASCA for distinguishing patients with CD and UC.
Adult↗
Enzymic assay of C3b receptor on intact cells and solubilized cells.
The C3b receptor of human erythrocytes is known to act as a cofactor for the cleavage of the complement protein C3b by the serine proteinase C3b/C4b Ina. The same cofactor activity is shown to be present on human tonsil B-lymphocytes. The cofactor activity of the C3b receptor can be assayed, on intact cells or in solubilized extracts of cells, by determining the rate of C3b cleavage in the presence of fixed concentrations of C3b and of C3b/C4b Ina. This assay method was used to compare the characteristics and relative quantities of C3b receptors on erythrocytes and lymphocytes. The cofactor activities associated with these two cell types resemble each other, but are distinct from the serum cofactor proteins, C4bp and Factor H, in antigenicity and in pH- and ionic-strength-dependence, and are distinct from Factor H in substrate specificity. Assay of cofactor activity in intact cells indicates that there are about 80-fold more receptors per cell on the lymphocyte surface than on erythrocytes. Assays with cells made permeable by detergent show that, whereas essentially all of the receptors on erythrocytes are on the cell surface, B-lymphocytes contain a large internal receptor pool, which makes up more than 80% of the total cofactor activity of the cell.
B-Lymphocytes↗
Release of endogenous anti-inflammatory complement regulators FHL-1 and factor H protects synovial fibroblasts during rheumatoid arthritis.
Rheumatoid arthritis is a chronic inflammatory disease of unknown aetiology predominantly affecting cells and tissues of synovial joints. Here we show that the two important complement regulators FHL-1 and factor H play a protective anti-inflammatory role in rheumatoid arthritis. Expression analyses at the mRNA- and protein level show in vitro expression and secretion of both regulators by synovial fibroblasts derived from patients with rheumatoid arthritis. Similarly the two regulators are synthesized in vivo in diseased synovial tissue, and in particular synovial lining cells express high levels of FHL-1. The anti-inflammatory role of these regulators in rheumatoid arthritis is highlighted by their induction with IFN-gamma and dexamethasone, whilst the pro-inflammatory cytokine TNF-alpha had no effect. Transient transfection experiments with various FHL-1/factor H promoter-luciferase reporter constructs into cells of distinct origin show independent cell and tissue specific promoter regulated transcription of these two regulators. The inducible expression, specifically of FHL-1 has physiological consequences. By binding directly to surfaces the released proteins protect cells from inflammatory damage and complement-mediated cell lysis. This study shows a novel protective and anti-inflammatory role of the two important complement regulators FHL-1 and factor H in rheumatoid arthritis and suggests a disease controlling role of the two proteins.
Arthritis, Rheumatoid↗
SERPIN regulation of factor XIa. The novel observation that protease nexin 1 in the presence of heparin is a more potent inhibitor of factor XIa than C1 inhibitor.
In the present studies we have made the novel observation that protease nexin 1 (PN1), a member of the serine protease inhibitor (SERPIN) superfamily, is a potent inhibitor of the blood coagulation Factor XIa (FXIa). The inhibitory complexes formed between PN1 and FXIa are stable when subjected to reducing agents, SDS, and boiling, a characteristic of the acyl linkage formed between SERPINs and their cognate proteases. Using a sensitive fluorescence-quenched peptide substrate, the K(assoc) of PN1 for FXIa was determined to be 7.9 x 10(4) m(-)(1) s(-)(1) in the absence of heparin. In the presence of heparin, this rate was accelerated to 1.7 x 10(6), M(-)(1) s(-)(1), making PN1 a far better inhibitor of FXIa than C1 inhibitor, which is the only other SERPIN known to significantly inhibit FXIa. FXIa-PN1 complexes are shown to be internalized and degraded by human fibroblasts, most likely via the low density lipoprotein receptor-related protein (LRP), since degradation was strongly inhibited by the LRP agonist, receptor-associated protein. Since FXIa proteolytically modifies the amyloid precursor protein, this observation may suggest an accessory role for PN1 in the pathobiogenesis of Alzheimer's disease.
Amyloid beta-Protein Precursor↗
Role for specific complement phenotypes and deficiencies in the clinical expression of IgA nephropathy.
IgA nephropathy, the most commonly occurring type of chronic glomerulonephritis in individuals of European and Asian descent, exhibits marked heterogeneity of clinical signs and ultimate prognosis. Based upon their studies of regional clustering of the ancestors of related patients in eastern Kentucky, the authors have postulated the existence of an inherited disease susceptibility for IgA nephropathy. They examined serum concentrations of individual complement proteins and phenotypes for C3, C4A, C4B, and factor B (Bf) for related and unrelated patients with IgA nephropathy from Kentucky and for patients from the Mid-South region of Tennessee, Mississippi, and Alabama. In these populations, they have described partial complement deficiencies or specific phenotypes which may be associated with the disease. Their findings include the following: (1) partial deficiencies for C2, beta 1H (H), properdin (P), or C4 binding protein (C4BP) in four patients with end-stage renal disease, (2) an association between the C3*F allele with IgA nephropathy in the combined group of unrelated patients from Kentucky and the Mid-South, (3) the occurrence of C4B deficiency in two siblings with IgA nephropathy, and (4) an association between C4A deficiency and poor outcome in patients with IgA nephropathy diagnosed as adults. In addition, the related patients differ from the unrelated patients from Kentucky with respect to frequencies of Bf*F and the BfF (FF + FS + F1F + F1S) phenotype, suggestive of immunogenetic difference between these groups. Important functional differences exist between C4A and C4B isotypes and functional differences are also possible based upon C3 or Bf phenotype.(ABSTRACT TRUNCATED AT 250 WORDS)
Carrier Proteins↗
Acquisition of regulators of complement activation by Streptococcus pyogenes serotype M1.
Opsonization of bacteria by complement proteins is an important component of the immune response. The pathogenic bacterium Streptococcus pyogenes has evolved multiple mechanisms for the evasion of complement-mediated opsonization. One mechanism involves the binding of human regulators of complement activation such as factor H (FH) and FH-like protein 1 (FHL-1). Acquisition of these regulatory proteins can limit deposition of the opsonin C3b on bacteria, thus decreasing the pathogen's susceptibility to phagocytosis. Binding of complement regulatory proteins by S. pyogenes has previously been attributed to the streptococcal M and M-like proteins. Here, we report that the S. pyogenes cell surface protein Fba can mediate binding of FH and FHL-1. We constructed mutant derivatives of S. pyogenes that lack Fba, M1 protein, or both proteins and assayed the strains for FH binding, susceptibility to phagocytosis, and C3 deposition. Fba expression was found to be sufficient for binding of purified FH as well as for binding of FH and FHL-1 from human plasma. Plasma adsorption experiments also revealed that M1(+) Fba(+) streptococci preferentially bind FHL-1, whereas M1(-) Fba(+) streptococci have similar affinities for FH and FHL-1. Fba was found to contribute to the survival of streptococci incubated with human blood and to inhibit C3 deposition on bacterial cells. Streptococci harvested from log-phase cultures readily bound FH, but binding was greatly reduced for bacteria obtained from stationary-phase cultures. Bacteria cultured in the presence of the protease inhibitor E64 maintained FH binding activity in stationary phase, suggesting that Fba is removed from the cell surface via proteolysis. Western analyses confirmed that E64 stabilizes cell surface expression of Fba. These data indicate that Fba is an antiopsonic, antiphagocytic protein that may be regulated by cell surface proteolysis.
Adhesins, Bacterial↗
Borrelia burgdorferi regulates expression of complement regulator-acquiring surface protein 1 during the mammal-tick infection cycle.
During the natural mammal-tick infection cycle, the Lyme disease spirochete Borrelia burgdorferi comes into contact with components of the alternative complement pathway. B. burgdorferi, like many other human pathogens, has evolved the immune evasion strategy of binding two host-derived fluid-phase regulators of complement, factor H and factor H-like protein 1 (FHL-1). The borrelial complement regulator-acquiring surface protein 1 (CRASP-1) is a surface-exposed lipoprotein that binds both factor H and FHL-1. Analysis of CRASP-1 expression during the mammal-tick infectious cycle indicated that B. burgdorferi expresses this protein during mammalian infection, supporting the hypothesized role for CRASP-1 in immune evasion. However, CRASP-1 synthesis was repressed in bacteria during colonization of vector ticks. Analysis of cultured bacteria indicated that CRASP-1 is differentially expressed in response to changes in pH. Comparisons of CRASP-1 expression patterns with those of other infection-associated B. burgdorferi proteins, including the OspC, OspA, and Erp proteins, indicated that each protein is regulated through a unique mechanism.
Animals↗